University of Würzburg Medical Faculty Research Report 2010

University of Würzburg University of Würzburg Universitätsklinikum Würzburg Medical Faculty

Medical Faculty

Josef-Schneider-Str. 2 · 97080 Würzburg 2010 Report – Research University of Würzburg Medical Faculty http://www.uni-wuerzburg.de/ueber/fakultaeten/ Research Report 2010 medizin/startseite/ University of Würzburg Medical Faculty

Research Report 2010 Content

1 General Part 1.1 Preface ...... 4 1.2. Medical Education ...... 10 1.3 Students’ Representatives ...... 13 1.4 The History of the Würzburg Medical Faculty ...... 14

2. Research Institutes 2.1 Institute of Anatomy and Cell Biology, Chair of Anatomy I ...... 16 2.2 Institute of Anatomy and Cell Biology, Chair of Anatomy II ...... 18 2.3 Institute of Anatomy and Cell Biology, Chair of Anatomy III ...... 20 2.4 Institute of Physiology, Chair of Vegetative Physiology ...... 22 2.5 Institute of Physiology, Chair of Neurophysiology ...... 24 2.6 Biocenter Würzburg, Chair of Physiological Chemistry I ...... 26 2.7 Biocenter Würzburg, Chair of Physiological Chemistry II ...... 28 2.8 Biocenter Würzburg, Chair of Developmental Biochemistry ...... 30 2.9 Institute for the History of Medicine ...... 32 2.10 Institute of Psychotherapy and Medical Psychology ...... 34 2.11 Institute for Hygiene and Microbiology ...... 36 2.12 Institute of Virology and Immunobiology, Chair of Virology ...... 38 2.13 Institute of Virology and Immunobiology, Chair of Immunology ...... 40 2.14 Institute for Molecular Infection Biology ...... 42 2.15 Institute of Pharmacology and Toxicology, Chair of Toxicology ...... 44 2.16 Institute of Pharmacology and Toxicology, Chair of Pharmacology ...... 46 2.17 Institute of Forensic Medicine ...... 48 2.18 Institute of Pathology ...... 50 2.19 Institute for Medical Radiation and Cell Research (MSZ) ...... 52 2.20 Institute of Human Genetics ...... 54 2.20.1 Division of Medical Genetics ...... 56

3 University Hospital 3.1 Introduction ...... 58 3.2 Department of Anaesthesia and Critical Care ...... 60 3.3 Department of General, Visceral, Vascular and Pediatric Surgery (Surgery I) ...... 62 3.4 Department of Trauma-, Hand-, Plastic- and Reconstructive Surgery ...... 64 3.5 Institute of Transfusion Medicine and Haemotherapy ...... 66 3.6 Department of Thoracic and Cardiovascular Surgery ...... 68 3.7 Department of Urology and Paediatric Urology ...... 70 3.8 Department of Orthopaedics ...... 72 3.9 Department of Obstetrics and Gynaecology ...... 74 3.10 Department of Pediatrics ...... 76 3.11 Department of Internal Medicine I ...... 78 3.12 Department of Internal Medicine II ...... 81 3.12.1 Division of Molecular Internal Medicine ...... 84 3.13 Institute of Clinical Biochemistry and Pathobiochemistry - Central Laboratory (IKBZ) ...... 86 3.14 Department of Dermatology, Venereology and Allergology ...... 88 3.15 Institute of Radiology ...... 90 3.15.1 Division of Neuroradiology ...... 92 3.16 Department of Nuclear Medicine ...... 94 3.17 Department of Radiation Oncology ...... 96 3.18 Department of Oto-Rhino-Laryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery ...... 98 3.19 Department of Ophthalmology ...... 100 3.20 Department of Neurosurgery ...... 102 3.21 Department of Neurology ...... 104 3.22 Institute for Clinical Neurobiology ...... 106 3.23 Department of Psychiatry, Psychosomatics and Psychotherapy with Division of Forensic Psychiatry ...... 108 3.24 Department for Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy ...... 110 3.25 Chair of Experimental Biomedicine - Vascular Medicine ...... 112 3.26 Chair of Tissue Engineering and Regenerative Medicine ...... 114

4 Dental Hospital ...... 116 4.1 Introduction ...... 117 4.2 Department of Orthodontics ...... 118 4.3 Department of Functional Materials in Medicine and Dentistry ...... 120 4.4 Department of Oral and Maxillofacial Surgery ...... 122 4.5 Department of Prosthodontics ...... 124 4.6 Department of Conservative Dentistry and Periodontology ...... 126 4.6.1 Division of Periodontology ...... 128

2 5 Additional Scientific Units

5.1 Collaborative Research Centers ...... 131 5.1.1 Collaborative Research Center 479, Variability of Pathogens and Host Reactions in Infectious Diseases ...... 131 5.1.2 Collaborative Research Center 487, Regulatory Membrane Proteins: From Molecular Recognition to Drug Targets ...... 132 5.1.3 Collaborative Research Center 567, Mechanisms of Interspecific Interactions of Organisms ...... 134 5.1.4 Collaborative Research Center 581, Molecular Models for Diseases of the Nervous System ...... 136 5.1.5 Collaborative Research Center 630, Recognition, Preparation and Functional Analysis of Agents against Infectious Diseases ...... 138 5.1.6 Collaborative Research Center 688, Mechanisms and Imaging of Cell-Cell Interactions in the Cardiovascular System ...... 140 5.1.7 Transregio-Collaborative Research Center 17, Ras-Dependent Pathways in Human Cancer ...... 142 5.1.8 Transregio-Collaborative Research Center 34, Pathophysiology of Staphylococci in the Post-genomic Era ...... 144 5.1.9 Transregio-Collaborative Research Center 52, Transcriptional Programming of Individual T-Cell Subsets ...... 146 5.1.10 Transregio-Collaborative Research Center 58, Fear, Anxiety, Anxiety Disorders ...... 148

5.2 Research Centers ...... 150 5.2.1 Rudolf Virchow Center / DFG Research Center for Experimental Biomedicine ...... 150 5.2.2 Interdisziplinary Center for Clinical Research (IZKF) ...... 153 5.2.3 Research Center for Infectious Diseases ...... 156 5.2.4 Center for Experimental and Molecular Medicine (ZEMM) ...... 158 5.2.5 Interdisciplinary Center for Addiction Research (ICAW) ...... 160 5.2.6 Interdisciplinary Center for Familial Breast and Ovarian Cancer ...... 162 5.2.7 Transplant Center (TPZ) ...... 164 5.2.8 Comprehensive Cancer Center Mainfranken ...... 166 5.2.9 Comprehensive Hearing Center Würzburg ...... 168 5.2.10 Center for Intestinal Medicine ...... 170 5.2.11 Center for Rheumatic Diseases ...... 171 5.2.12 Center for Stem Cell Therapy ...... 172 5.2.13 Cleft Lip and Palate Center ...... 174 5.2.14 Level I Perinatal Center ...... 176 5.2.15 Cardiovascular Center ...... 178

5.3 Research Training Groups ...... 180 5.3.1 Research Training Group 520, Immunomodulation ...... 180 5.3.2 Research Training Group 1048, Molecular Basis of Organ Development in Vertebrates ...... 181 5.3.3 International Research Training Group 1141, Signal Transduction: Where Cancer and Infection Converge ...... 182 5.3.4 Research Training Group 1156, From Synaptic Plasticity to Behavioural Modulation in Genetic Model Organisms ...... 183 5.3.5 Research Training Group 1253, Emotions ...... 185 5.3.6 International Research Training Group 1522, HIV/AIDS and Associated Infectious Diseases in Southern Africa ...... 186

5.4 Research Units ...... 187 5.4.1 Clinical Research Unit 103, „Osteogenic Stem Cell Differentiation and Therapy of Bone Loss“ and Orthopedic Center for Musculoskeletal Research ...... 187 5.4.2 Clinical Research Unit 124, The Tumor Microenvironment: Target Structure and Modulator of Immune Responses ...... 189 5.4.3 Clinical Research Unit 125, Attention-Deficit/Hyperactivity Disorder - Translational Research Focus on Molecular Pathogenesis and Treatment Across the Life Cycle ...... 191 5.4.4 Clinical Research Unit 216: Characterization of the Oncogenic Signaling-Network in Multiple Myeloma: Development of Targeted Therapies ...... 193

5.5 Research Alliances ...... 195 5.5.1 Rehabilitation Research Network of Bavaria ...... 195 5.5.2 BMBF-Competence Network: Genome Research on Pathogenic Bacteria - PathoGenoMik-Plus ...... 197 5.5.3 Network of Excellence EuroPathoGenomics ...... 198 5.5.4 Research program of the BMBF: Effects and Mechanisms of Psychotherapy in the Treatment of Attention Deficit-Hyperactivity-Disorder (ADHD) in Children and Adults ...... 200 5.5.5 Bavarian Immunotherapy Network (BayImmuNet): Generation of Clinical Grade Antigen-Specific T-cells with an Early Effector Phenotype for Adoptive T-cell Immunotherapy ...... 202 5.5.6 German Research Foundation: SPP 1356, Pluripotency and Cellular Reprogramming ...... 203 5.5.7 BMBF Project, SARA: Systems Biology of PGI2 and ADP P2Y12 Receptor Signaling ...... 204 5.5.8 BMBF Joint Project, CB-HERMES: Expansion of Cord Blood Stem Cells ...... 206

5.6 MD/PhD-Program ...... 208

5.7 University of Würzburg Graduate Schools – Graduate School of Life Sciences ...... 209

6. The Medical Faculty: Basic Data ...... 212

3 1 General Part 1.1 Preface

After having published the Research Re- The ZIM building has been directly annexed of Würzburg holds the 4th rank in the sec- port 2008 a number of important develop- to the ZOM building which has been occu- tor of life sciences in the ranking of the Ger- ments have taken place in quick succes- pied in 2005. 22,600 square meters of ef- man universities with the highest DFG sup- sion between 2008 and 2009 at the Fac- fective area have been constructed with a port volumes in 2005 and 2007. Among ulty of Medicine of the Julius-Maximilians- 157 million € budget. The surface is being the Bavarian universities only Munich (LMU) Universität Würzburg. It has therefore be- shared by the Departments of Internal Medi- is topping Würzburg: Taking into account the come necessary to again present a report cine I and II, the Department of Nuclear relativised numbers regarding third third- documenting the personnel and structural Medicine, the Institute of Clinical Biochem- party funding per professorship, however, progress and to highlight the thereof result- istry and Pathobiochemistry with the cen- Würzburg holds indeed the leading position ing perspectives in a timely manner. tral laboratory, the Institute for Transfusion in Bavaria with 505,000 €, and, within the A generation break is taking place at the Medicine and Haemotherapy and the Insti- national competence, it shares rank 6 with Faculty of Medicine evidenced by the huge tute of Radiology. the universities of Hannover, Ulm, Cologne, number of new appointments on the theo- A few weeks before inaugurating the Cen- Freiburg and Heidelberg. Würzburg holds retical and clinical chairs. During the past ter for Internal Medicine (ZIM) the Faculty one of the top places among the compe- years the chairs at the theoretical and clini- of Medicine celebrated the delivery of the tent research universities in medicine also cal institutes have been restocked as fol- new DFG-Research Center for Experimental according to the present CHE-ranking. lows: Physiology – core theme neuroyphys- Biomedicine (Rudolf-Virchow Center) build- Starting with this year the clinical research iology (Professor Dr. Manfred Heckmann), ing and the building of the Research Center will receive numerous important impulses, Physiological Chemistry II (Professor Dr. for Infectious Diseases (with the Institute and it will complement the defined profile Martin Eilers), Molecular Infection Biology for Molecular Infection Biology and four Ju- of the University of Würzburg and the Fac- (Professor Dr. Jörg Vogel), Forensic Medi- nior Research Groups). A modern research ulty of Medicine in the biomedical basic re- cine (Professor Dr. Christoph Meißner), Pa- building of 10,000 m2 effective area has search in the clinical epidemiologic area. thology (Professor Dr. Andreas Rosenwald) emerged replacing the ancient surgical clin- With the Federal Ministry of Education and and Human Genetics (Professor Dr. Thom- ic. Both research centers are united under Research’s successful concept appraisal for as Haaf). In the clinical section Professor this roof and thus decisively chracterize the an integral research and a treatment Cen- Dr. Christoph-Thomas Germer has taken the biomedical research profile the University of ter (Comprehensive Heart Failure Center) in chair for Surgery, Professor Dr. Ralf-Ingo Er- Würzburg. The total cost for the mentioned 2009 and the announced start of this affir- nestus for Neurosurgery and Professor Dr. construction project has amounted to 78 mative measures, the Faculty of Medicine Maximilian Rudert the chair for Orthopae- million €. has successfully won a very competitive se- dics. New chairs have been established for With these two construction projects the lection process and has acquired subsidies Anatomy III (Professor Dr. Jens Waschke), Faculty of Medicine’s declared scientific fo- in the amount of 50 million € for the coming Developmental Biochemistry (Professor Dr. cuses have received significantly improved 10 years. By focussing on heart failures the Manfred Gessler), Experimental Biomedi- conditions for research for meeting the in- Faculty of Medicine addresses the most fre- cine with focus on Vascular Medicine (Pro- ternational competition challenges. The quent cause for referrals to hospitals, which fessor Dr. Bernhard Nieswandt) and Tissue Bavarian state government has decided to is showing a higher mortality rate than most Engineering and Regenerative Medicine stabilize the Rudolf-Virchow Center after the of the cancer occurrences. The heart fail- (Professor Dr. Heike Walles). With the men- DFG support expiry. The basis for the above ure syndrome is having an increasing rele- tioned appointments the Faculty of Medi- mentioned far-sighted decision has been vance for the health policy due to the ageing cine has perfectly succeeded to reinforce laid by the DFG’s external assessment of population. Innovative concepts in research and extend the scientific and clinical core the Rudolf-Virchow Center which has attest- and treatment are meeting this challenge. themes. In addition, six W2-professor posi- ed international importance and scientific For this purpose, new and permanent coop- tions have been filled in the clinical and the quality on a supreme international level. erative structures are being established for preclinical/clinical-theoretical area. The supreme scientific performance of the the interdisciplinary research and teaching In the year 2000 the Bavarian Parliament researching staff at the Rudolf-Virchow Cen- in heart failure. For this purpose appoint- has accepted the building and structural ter is not only being documented by numer- ments for several new chairs have been concept for the Faculty of Medicine which, ous publications in the most important pro- made and a specific study course “Clinical for example, implies new buildings for the fessional journals but also by the fact that Epidemiology and Biometry” has been con- surgical fields and for Internal Medicine, and during the past years a number of Rudolf- ceived for the training of students and clini- which aims at joining institutes on the Cam- Virchow Center junior scientists have been cal researchers. pus in the Grombühl city district in the pro- appointed for professorships and chairs in The Bavarian State has concluded an ex- cess of re-use of the ancient medical and Germany and abroad. The DFG has again pansion program in 2008 which will create surgical clinics. The start-up and solemn in- very positively assessed the Rudolf-Virchow 38,000 new study places in preparation of auguration of the ZIM (Zentrum für Innere Center in 2009 and conceded a last four- the double Abitur (school leaving examina- Medizin / Center for Internal Medicine) has year funding period. In 2013 the Federal tion) age group. Although the study plac- taken place on the 11th December 2009 State of Bavaria will take over the financial es in human and dental medicine are ex- in the presence of Prime Minister of Ba- responsibility for this central scientific insti- empted from this extension program, the varia Horst Seehofer. This central project of tution of the University of Würzburg. Faculty of Medicine will make a contribu- the Faculty of Medicine’s construction and A glance at the most recent ranking values tion for the young generation and offer new structural concept has made possible an makes evident that the huge investment study courses across faculties. Together economically optimized medical care which sums resulting from the building projects with the Faculty for Chemistry and Phar- has become more attractive for patients. It and the permanency process of the Ru- macy the new study course “Biochemistry also offers improved conditions for teach- dolf-Virchow Center are to be considered B.Sc.” has been introduced in the winter ing and will give new impulses to research. as perfectly invested capital: The University semester 2009/2010. The Bachelor study

4 Fig. 1: CHE-Ranking from 9th December 2009 / Medicine. course “Technology of Functional Materi- vice of externs. I thank the expert witness- als”, introduced by the Faculties for Physics es from our research centers and research and Chemistry/Pharmacy in 2006, will be units. With their critical and constructive topped up to 60 study places; a respective advice they have essentially contributed to master study course has been introduced the positive development of our faculty. I in the 2009/2010 winter semester. The of- also thank the donors of external funds who fer of these study courses, which are being give essential support to our faculty. Final- complemented by meanwhile established ly, I thank all my colleagues of the Faculty further study courses “Biomedicine” and of Medicine, who are notably contributing “Experimental Medicine” makes evident to the reputation and further development that the Faculty of Medicine feels obliged of the faculty with their engagement and to junior scientists training in the biomedi- creativity. cal basic disciplines. The medical graduates from Würzburg regularly return top results; Würzburg, February 2010 this shows that a huge importance is being Professor Dr. Matthias Frosch attributed to the core tasks: teaching and Dean training of junior specialists in human and dental medicine. The fact that Würzburg has attained the best results in Germany with the best 2nd state examination past autumn gives prove of the high quality of the medical training at the Faculty of Medicine and the big commitment of the teachers, who are continually improving their teaching with innovative teaching concepts. On the following pages, the clinical departments and institutes are presenting themselves with their profiles and results. The results and the positive developments to which I have been alluding in this preface would not have been possible without manifold support. Finally, I am very grateful for the huge support from the Bavarian state government and the Bavarian Parliament which the Fac- ulty of Medicine has received during the implementation of the construction concept and which it is still receiving. I want to spe- cially thank H. Dierl from the Bavarian Min- istry for Sciences, Research and the Arts as well the ancient member of the Bavar- ian Parliament, Mr. M. Ach, who have rendered outstanding services to the Faculty of Medicine. I am grateful for the valuable ad-

5 Inauguration of the new Building for the Rudolf Virchow Center and the Research Center for Infectious Diseases on October, 8, 2009

Fig. 1: Handing over of keys for the new Research Center. From left to right: D. Maußner, building authority Würzburg, F. W. Rothenpieler, head of the office, Bavarian Ministry of Science , Fig. 2: The new lecture hall for the Rudolf Virchow Center and the the President of the University A. Forchel, M. Lohse from the Ru- Research Center for Infectious Diseases at the commemorative dolf Virchow Center and M. Frosch (Research Center for Infec- event for the inauguration during the address by M. Lohse. tious Diseases).

Fig. 3: The foyer with the historical front of the old lecture hall. Fig. 4: The historical staircase.

Fig. 5: The historical south front of the former Departments of Fig. 6: The new laboratory building with the main entrance. Surgery.

6 Inauguration of the Center for Internal Medicine (ZIM) on December, 12, 2009

Fig. 1: Aerial view of the ZOM/ZIM complex. Fig. 2: The Dean M. Frosch (right) and the Managing Medical Di- rector C. Reiners (2nd from right) guide District President P. Bein- hofer (left) and Prime Minister of Bavaria H. Seehofer (2nd from left) through the main thoroughfare of the ZOM/ZIM.

Fig. 3: During the commemorative event for the inauguration of the ZIM. First row from left: Managing Medical Director C. Reiners, Fig. 4: View form the terrace of the ZIM towards one of the bed- President of Parliament B. Stamm, Prime Minister of Bavaria H. houses. Seehofer and President of the University A. Forchel.

Fig. 5: Interior view of the main thoroughfare of the ZIM. Fig. 6: View of the bed-houses and the illuminated main thoroughfare.

Fig. 7: One of the inner courtyards between the bed-houses. Fig. 8: A look inside the central laboratory.

7 Honors awarded by the Medical Faculty

Fig. 1: Awarding of the honorary doctorate to Professor Dr. Harald zur Hausen during the graduation ceremony on May, 31, 2008 in the Neubaukirche through the Dean Professor Dr. M. Frosch (right). Pro- fessor H. zur Hausen was faculty member at the Institute of Virology and Immuno- biology of the University of Würzburg from 1969 to 1972 prior to accepting a chair in Erlangen. The Medical Faculty honored his outstanding scientific achievements in the field of virology and especially his contributions leading to the identification of the human papilloma virus as the causative agent of cervix-carcinoma. With Professor Dr. H. zur Hausen the Medical Faculty not only honored an internationally regarded scientist, but also appreciated his long- lasting connections to the Medical Faculty of the University of Würzburg.

Fig. 2: For his long standing achievements in the Medical Faculty of the University of Würzburg, the Rinecker-Medal in gold was awarded to Professor Dr. Volker ter Meulen (right) on May, 23, 2009 during the graduation ceremony of the faculty in the Neubaukirche. The medal and the certificate were handed over by the Dean Professor Dr. M. Frosch (left). In his lauda- tion, Vice-dean Professor Dr. M. Lohse appreciated, besides the scientific achievements of the virologist who was born in Osnabrück in 1933, especially his contributions to the development of a scientific strategy of the Medical Faculty.

8 Fig. 3: The Siebold-Medal honors people, who rendered outstanding services to the Medical Faculty and the Univer- sity Hospital. On May, 8, 2009 Manfred Ach, Member of Parliament, off duty (2nd from left) and Professor Dr. Walter Eyk- mann, Member of Parliament, off duty (3rd from left) were honored by the Dean Pro- fessor Dr. M. Frosch (left) and the Man- aging Medical Director Professor C. Rein- ers (right) with the newly created Siebold- Medal.

9 1.2. Medical Education

The Faculty of Medicine continuously im- ect “Teaching in Medicine in Bavaria” fi- proves medical education. Comprehensive nanced by the Bavarian State Government. teaching evaluations, also for the practi- Seven project applications of the Faculty of cal year, are being performed since many Medicine have been approved by the vhb years. They reveal areas for improvements; (virtual Bavarian university) in 2009. positively evaluated teaching models may also be transferred to other areas. The Al- Promotion of junior scientists bert-Koelliker teaching price amounting to The Faculty of Medicine not only teaches 10,000 Euro is being awarded twice a year the transfer of medical skills, but also claims for extraordinary teaching achievements. Fig. 1: Student training with a simulation that the medical education shall convey the The Dean for Student Affairs’ Office is close- patient. scientific basics of medicine and introduce ly and successfully cooperating with the stu- the student into the current biomedical re- dents’ representatives, so that constructive search. In order to ensure the students’ in- improvement suggestions may be quickly in medical education. Although the treat- tensive education in the biomedical basic set into action. ment of virtual patients cannot substitute research, the additional study course “Ex- the real patient contact it constitutes a per- perimental Medicine” has been introduced Würzburg’s medical students regularly fect means for the preparation since nota- in the 2005/2006 winter semester. achieve first places at the state examina- bly the theoretical basis of the patient treat- tions which are identical all over Germany ment can be trained in a case-oriented way. The additional study course “Experimental (ranking among 35 faculties of medicine). Numerous studies are proving that dealing Medicine” is performed with a research ori- The Würzburg students have reached the with didactically prepared cases consider- entation and shall convey current scientific first place in the 2nd state examination in ably increases the learning success. At the issues in the area of life sciences as well autumn 2009. The Faculty of Medicine’s same time the cases’ complexity may be as the experimental procedures and me- main aim in medical education is to offer adapted to the students’ progress. thodical principles at the intercept points of to students an excellent theoretical training medicine, biology, chemistry and physics. and a comprehensive training in practical Didactically prepared cases are success- The interdisciplinary education is being re- medical skills as well as in a qualified sci- fully being employed and evaluated since flected by the participation of further facul- entific education. a few years at Würzburg’s Faculty of Medi- ties – biology, chemistry, physics – besides cine, notably in rheumatology1 and haema- medicine. The student’s intensive support Teaching clinic tology2. Due to the successful results the is guaranteed by limiting the number of stu- Since 2009 the previous Skills Lab is being university is aiming at a systematic applica- dents to 5 per semester. expanded to a teaching clinic which will oc- tion by means of the university-wide Blend- cupy 1,500 m2 with a fully functioning oped Learning Project which is being financed With the 2009/2010 winter semester the erating theatre. After a comprehensive ren- by study fees since 2007. Case-training master study course Experimental Medicine ovation, the teaching clinic, as integral part cases have been developed for the follow- has been developed out of the additional of clinical training of medical students, will ing subjects: Internal Medicine (cardiovas- study course. The ‘state exam medicine’ concentrate the practical courses in a con- cular diseases, pneumology, haemato-on- qualifies for application. Course achieve- ceptive and spatial way and at the same cology, endocrinology, nephrology, gastro- ments of the additional course can be cred- time integrate preclinical and clinical sub- enterology), infectiology, clinical immunol- ited, so that the graduation can be obtained jects. A division into operative section, ward ogy/rheumatology, geriatrics, surgery, der- with the master thesis already after one se- section, skills training rooms with phan- matology, neurology, medical terminology, mester. By this means, an additional final toms for e.g. blood sampling, auscultation clinical chemistry, ophthalmology, psychia- degree can be obtained besides a qualifi- ultrsound, lumbal puncture, and seminar try and psychosomatics, neurosurgery, gyn- cation. Also students from other universities rooms reflects the training concept. The aecology, nuclear medicine, urology. with a final degree are allowed to follow the earlier compulsory courses for the 5th se- master study course in Würzburg. mester are complemented by compulsory The university-wide e-learning platform courses with higher clinical demands for the WueCampus is a further improvement made In addition to the MDPhD program, financed 7th and 10th semesters. Students will also possible by tuition fees. In Wue-Campus e- by the IZKF, the Faculty of Medicine grants have to pass an OSCE (objective structured learning materials all are being centrally ad- 30 scholarships for experimental doctor- clinical examination) for these courses. A ministered and are made accessible to stu- ates and thus improves the quality of the unit with standardized patients to simulate dents by a single-sign-on. Two semesters medical doctor for students, who spent an clinical settings is financed by tuition fees ago, electronically supported examinations additional semester to write an outstanding and is integrated as inherent part into the have been introduced in some areas. The doctoral thesis. teaching clinic’s concept. Study rooms and aim of this project is to perform electronic lounges will be at the students’ disposal. examinations in the near future. Mentoring The use of the new seminar rooms shall A mentoring program for female students, be open to many clinics and institutes. The Since April 2008 the Faculty of Medicine financed by tuition fees, has been intro- medical administration of the teaching clin- Würzburg has been appointed to be the e- duced in the 2008/2009 winter semester. ic has been transformed from a honorary to learning competence center within the proj- Even though the majority of medical stu- a part-time occupation. 1 Reimer S, Hörnlein A, Tony, HP, Krämer D, Oberück S, Betz C, Puppe F, Kneitz C (2006). Assessment of a case- based training system (d3web.Train) in rheumatology. Rheumatology International 26 (10), 942-948, E-Learning, Wue-Campus 2 Krämer D, Reimer S, Hörnlein A, Betz C, Puppe F, Kneitz C (2005). Evaluation of a novel case-based Training Pro- Patient case training plays a central role gram (d3web.Train) in Hematology. Annals of Haematology 84 (12), 823-829.

10 ies are organized according to the currently valid Medical Licensure Act for dentistry students, and all required practical and theoretical courses are offered. The dental clinic is located in the city centre. The dental clinic’s location guarantees a high patient accessibility and an immediate proximity to the local population. This becomes evident by the high patient influx: more than 26,600 out-patients and more than 1,300 in-patients have been treated in 2008.

All departments are equipped according to the newest technical standard (exception: conservative dentistry). State-of- the-art equipment necessary for a modern dentist training is available. In diverse departments, interactive training concepts and problem-based learning integrated in the clinical training are now offered. With Fig. 2: A medical student from Würzburg (r.) in the operating room of the Bugando Hos- the new Medical Licensure Act for dentist- pital Mwanza, Tanzania, during his last year elective third. ry students the teaching concept will pass through further modifications. Students have access to an extensive library with nu- dents and graduates are women, only 10 % ter facilities to pass part of their studies merous computer work stations with inter- of them, or even less, finally occupy lead- abroad. net connection for their private studies. The ing positions (senior physicians, chief physi- tuition fees allotted to the dental clinic are cian, professors). Studies reveal that differ- Dental Medicine mainly used for the financing of tutors and ent career goals and career tracks of men At present, 600 dental students are en- a part-time teaching coordinator as well as and women become evident already few rolled at the University of Würzburg, 300 of for the financing of partly extremely expen- years (1-3) after graduation. Therefore it is them in the preclinical, 300 in the clinical sive instruments and expendable items for our aim to give our female students the pos- part of their education. The clinical stud- the student courses. A part of the financial sibility to reflect their situation, to become aware of their career goals and to pursue Tab. 1: ERASMUS partners of the Faculty of Medicine Würzburg these goals already during their studies. The Land Stadt Universität students are accompanied during their lec- Belgium Antwerp Universiteit Antwerpen tures, workshops and seminars by female and male mentors who give them profes- Finland Turku Turun Yliopisto, Turku sional career advice and support. France Caen Université de Caen Grenoble Université Joseph Fourier The current mentoring program design for Limoges Université de Limoges female students is now being adapted and also opened for male students. In addition, Strasbourg Université Louis Pasteur Strasbourg foreign students are supported in a men- Greece Salonika Aristoteleio Panepistimio Thessalonikis toring program which has been especially Italy Ferrara Università degli Studi di Ferrara adapted to their needs and to overcome Rome Università Campus Bio-Medico di Roma their language barriers. Rome Università degli Studi di Roma “La Sapienza” Internationalization Poland Wroclaw Uniwersytet Wrocławski A part-time employee, financed by study Cracow Uniwersitet Jagiellonski w Krakowie fees, supports the international student ex- Portugal Coimbra Universidade do Porto change. Apart from the faculty partnership agreements with the University of Roch- Porto Universidade do Porto ester/USA and the University of Nagasaki Schweden Umeå Umeå Universitet new cooperation agreements have been Slowenia Maribor Univerza v Mariboru signed in the meantime with the Weill Bu- gando University College of Health Sciences Spain Barcelona Universitat Internacional de Catalunya in Mwanza, Tanzania, and the University of Granada Universidad de Granada Sao Paulo, Brazil. Salamanca Universidad de Salamanca Turkey Bursa Uludag˘ Üniversitesi, Bursa A number of new ERASMUS partnerships have been contracted with European uni- Izmir Ege Üniveritesi versities, which offers more students bet- Hungary Budapest Semmelweis Egyetern, Budapest

11 burden, which dental students have to bear today, is thus taken off.

In winter term 2007/2008, for the first time, a Dean for Student Affairs and a Committee for Student Affairs have been appointed for the dental school. The new Medical Licen- sure Act (ZAppO) for dentistry, which has been announced for a long time, will be is- sued soon and will require a significant effort for restructuring the studies of dental medicine.

Prof. Dr. med. J. Deckert, Dean of Student Affairs Human Medicine Prof. Dr. med. Dr. med. dent. A. Kübler, Dean of Student Affairs Dental Medicine Dr. E. Lüneberg, Dean of Student Affairs’ Office

12 1.3 Students’ Representatives

The student council is a group of students medical equipment (e.g. stethoscopes) as Josef-Schneider-Str. 2 who advocate on the interests of the medi- well as the bvmd which among other things 97080 Würzburg cal students at the University of Würzburg cares about international exchange pro- Medical Faculty. It is our objective to en- grams for medical students, find a room in Tel.: 0931/201-53859 hance the conditions for studying and our premises for their consultation hours. Fax: 0931/201-53858 teaching by our student engagement in cooperation with the academics at our facul- The group of MSV is an interactive preven- E-mail: [email protected] ty. To solve conflicts, develop new concepts tion project of medical students for pupils. www.fi-med.de and ideas, we beat bridges between aca- The MSV informs about save and tolerant demics and studying. dealing with sexuality and contraception. The teddy bear clinic, which shall easily lead We mainly work on two major aspects: On children up to the situation with the doctor one hand we represent the medical stu- and in the clinic, enlarges the supply around dents in a various number of committees: the student engagement. in the faculty council, in the committee of study affairs, in the student council and in Our students’ council meeting takes place the appointment board of the faculty. weekly. This serves the exchange of in- Since tuition fees had been implemented, formation and offers room for discussion we are engaged in the fee commission and about current requests and for the planning we are working for a wise and efficient use of new projects. of the money. The second working field complies of differ- Among other things, results of our engage- ent tasks around consultation and support ment are the AG teaching co-ordinators of the students, e.g. organisation of infor- which represent a close cooperation with mative meetings, office work and improve the teaching coordinators financed from social life by organizing parties and various tuition fees to initiate innovative teaching other meetings. strategies and the PromoMed convention which supports students when finding a At the beginning of the studies we welcome medical dissertation. the freshers in the context of the first semester days. We give them the opportunity We organize film- and cinema evenings, live here to get to know better their new fellow assignments of the soccer European cham- students, the city of Würzburg and the uni- pionships and World Cups and numerous versity. At the beginning of the clinical part parties, to the better social networking of of their medical studies, we take the new the medical students. clinical semester on a guided tour of the hospital and introduce them to the differ- Within the next semesters, furthermore we ent clinical complexes and institutes. For want to commit ourselves to the improve- the two events we publish an information ment in the teaching; this is yet concretely booklet which informs the students about comprehensible at the idea and conception the faculty, lectures, courses, examina- of the teaching clinic with library, practical- tions, books, events and many broader top- clinical examination courses, recreation, ics. In addition, we offer information on our study, and conference rooms, whose open- redesigned home page. During the lecture ing lies ahead soon. We look forward to a time our office serves as a contact point furthermore active and constructive coop- for questions and problems of the students. eration within the faculty. Here, we offer further study and informative material around the study of medicine. The students’ representatives of the medical faculty The Segmed, a nationwide association of medical students, which offers favourable

13 1.4 The History of the Würzburg Medical Faculty

The Medical Faculty of Würzburg ranks claim, succeeded in establishing a flourish- It was due primarily to the incessant activi- among the four oldest medical faculties in ing culture of medical dissertations and dis- ties of one man, Carl Caspar Siebold, that Germany. It was preceded only by Heidel- putations and promoted a number of medi- this rather desolate situation changed with- berg, Cologne and Erfurt, and thus has to- cal students to doctors. At the same time, in a couple of decades and the Würzburg day a history of more than 600 years be- conditions for clinical, practical training had Medical Faculty became one the foremost hind it. Together with theology and law, markedly improved, thanks to the newly institutions of its kind in Germany. Siebold, medicine had its place assigned among the founded Julius-Spital. In contrast to many since 1769 professor of anatomy, surgery three higher faculties in 1402 already, at other contemporary hospitals which cared and obstetrics, began a systematic drive the original foundation of Würzburg Univer- almost exclusively for the aged and invalid, to improve medical education, introduc- sity. It is not clear, however, to what degree the Julius-Spital was, from its very begin- ing new modern teaching methods. Since formal medical teaching was inaugurated at ning, explicitly designated also as a hospi- 1766, medical students had been offered the time. Certainly, any regular teaching ac- tal “in aegrorum curationem”, i.e. for the regular clinical instruction again, in the Ju- tivities must have come to an end within a medical treatment of the curable sick. With lius-Spital. Towards the end of the 18th few decades, due to the rapid decline of the its many patients, the Julius-Spital thus of- century, large- scale reconstruction work University as a whole. Long before 1402 al- fered a welcome opportunity to medical stu- created space for about 200 curable pa- ready, Würzburg was held in high esteem dents to observe manifold diseases and to tients and thus markedly improved the con- as a center of medical learning, however. witness the effects of different curative ap- ditions for bedside teaching. Siebold was Already in the late 13th century the abbot proaches. Such bedside teaching was very also a driving force behind the rebuilding of of the monastery of Aldersbach in Lower Ba- popular among contemporary medical stu- the Theatrum anatomicum and behind the varia undertook a journey of more than 300 dents and was a major reason, why a num- establishment, in 1805, of a modern oper- kilometers to consult the learned physicians ber of medical students crossed the Alps ation theatre in the Julius-Spital. Siebold’s in Würzburg about his failing health. About and frequented one the Northern Italian sons were to follow their father’s footsteps the same time, probably around 1280, one universities, where they were commonly al- and like him contributed to the moderniza- of the most influential vernacular medical lowed to accompany the professors on the tion of the hospital care and medical in- handbooks of the Middle Ages was written, visits to the large municipal hospitals. struction. Johann Barthel von Siebold who the “Arzneibuch” of Ortolf von Baierland who After van Roomen’s retirement and death worked primarily as an anatomist and sur- called himself explicitly a “physician from and due to the recurring outbreaks of plague geon lectured on pathological anatomy for Würzburg”. Compiled “from all the Latin and the Thirty Years’ War the Würzburg Med- the first time. Adam Elias von Siebold con- medical books I have ever read”, Ortolf’s ical University lost much of its international tinued his father’s efforts to improve obstet- “Arzneibuch” offered of summa of medieval renown, however. Only very few medical stu- rical training for medical students and mid- medical learning. From the mid-14th cen- dents continued to find their way to Würz- wives. In 1805, he opened the first obstetri- tury, a topographical illustration of the brain burg and even fewer were promoted to doc- cal hospital in Würzburg in a building which by the Würzburg canon Berthold von Blu- tors of medicine. From the late 17th century, formerly housed epileptics. mentrost has come down to us, which at- the government tried to counteract this trend The rapid ascent of the Medical Faculty un- tributed the major rational faculties – imagi- and initiated important reforms. The num- der Siebold and his sons was ultimately cru- nation, cogitation and memory – to the vari- ber of medical chairs was raised to five in cial for the survival of the University as a ous cerebral ventricles. This made perfect 1709; originally there were only two or three. whole. When Würzburg came under Bavar- sense within the ruling Galenic paradigm, Following the example of leading protestant ian rule in 1803, it was the university in which associated the rational faculites with universities such as Leiden and Halle a bo- Bamberg rather than the one in Würzburg very subtle and mobile animal spirits in the tanical garden was set up; botanical gardens which was closed. In the process, the Würz- ventricles rather than with the cerebral sub- were then considered important teaching burg Medical Faculty even saw its fame fur- stance itself. tools which helped medical students get father promoted by leading professors from In the 16th century, various learned physi- miliar with the various plants used as medici- the former Bamberg institution. One of Ger- cians of renown were active in Würzburg, nal drugs. An anatomical theater was built in many’s foremost anatomists, physiologists Burckhard von Horneck, for instance, and the garden pavilion of the Julius-Spital and and embryologists, Ignaz Döllinger, joined Johannes Posthius. Only with the second the famous Parisian surgeon Louis Sievert its ranks. Like Döllinger, Wilhelm von Hoven, foundation of the University in 1582, how- was brought in to improve anatomical teach- a former school mate of Friedrich Schiller, ever, formal academic medical teaching ing. The professor of anatomy was instruct- came from Bamberg to Würzburg. Later he was put into place again. Again, medicine ed to dissect a corpse at least every four became a major medical figure in Nurem- ranked among the University’s three high- weeks in the winter time, in the presence berg, and was, by all appearances, the driv- er faculties from the start, though it took of the other professors. Academic disputa- ing force behind the first double-blind trial in several years until the Medical Faculty truly tions and dissertations were encouraged. history, which was organized in Nuremberg came to life. In 1587, the faculty’s statutes Yet these efforts bore little fruit, at first. The 1835 in an attempt to disprove the effica- were approved. By 1593, finally, the profes- Faculty lacked professors whose fame could cy of homeopathic drugs. The strongest at- sors had been appointed and began teach- attract medical students from further away, traction on German medical students was ing. Würzburg had come to offer exception- and the teaching methods remained rather exerted, for a couple of years, by the phi- ally good conditions for a sound medical ed- old-fashioned. In 1739, the professors still losopher Wilhelm Schelling who sought to ucation. Adriaan van Roomen, also known had to be explicitly forbidden to dictate their put medicine on new, philosophical foun- as Adrianus Romanus, had been appointed lectures word by word. In 1758, Karl Philipp dations. At the height of his fame in Würz- to the first and most prestigious professor- von Greiffenklau began his request for a sur- burg, 270 medical students immatriculated ship, the chair for medical theory. Within vey of the Faculty’s state bluntly by asking: in one year. Soon, growing disillusionment a couple of years, van Roomen, who was “Wherein lies the cause of the immense de- set in, however, and his audience shrank also a mathematician of international ac- cline of the Medical Faculty?” rapidly.

14 Over the following decades, Würzburg in- who was appointed professor of psychia- The trend towards interdisciplinary research creasingly turned into a center of empiri- try in Würzburg in 1939, played a leading and medical care gained further momen- cal-observational and, finally, laboratory- role in the so-called „Aktion T4”, the orga- tum over the last years, with the creation based, experimental approaches. Clinical nized mass murder of 10.000s of psychi- of a “Zentrum Operative Medizin” (ZOM), a instruction was further improved thanks to atric patients and handicapped men, wom- “Zentrum Experimentelle Molekulare Med- a massive expansion of policlinical care. en and children between 1939 und 1941. izin” (ZEMM) and a “Zentrum Innere Med- Thousands of out-patients provided medi- Based on the „Gesetz zur Verhütung erb- izin” (ZIM). cal students with unique possibilities to visit kranken Nachwuchses“ (1933) steriliza- and observe the patients in their homes and tions and abortions were performed in the Professor Dr. med. Dr. phil. to take responsibility for their care, guid- Maternity Hospital under Carl Gauß. George Michael Stolberg ed by a more experienced physician. Jo- Schaltenbrand, professor of neurology and Institute for the History of Medicine hann Lukas Schönlein, the foremost rep- later widely acknowledged as one of the resentative of the so-called “natural histo- leading researchers on multiple sclerosis in ry school” in medicine, introduced scores the world, vaccinated inmates of the psychi- of students to his approach. He called for atric hospital in Werneck with the cerebral a detailed and unprejudiced observation of fluid of monkeys who, he believed, suffered signs and symptoms as the basis of a new, from that diseases, in order to examine the empirically founded nosology. Thanks to his contagious nature of the disease. Most of method Schönlein described various dis- the other hospitals and institutes were also eases for the first time and some like the in some way or other implicated in National Schoenlein-Henoch purpura (Vasculitis al- Socialist medicine and almost all professors lergica) carry his name to this day. Nikolaus lost their chairs after 1945. Anton Friedreich gave an account of facial The massive air raid in the spring of 1945 nerve paralysis. Johann Georg Pickel and damaged or destroyed large parts of the uni- Johann Joseph von Scherer helped lay the versity and the hospitals. Already a couple groundwork for a modern science of phar- of days after the raid, the first operations maceutics and medical chemistry respec- were performed again, however, and out- tively. Around the middle of the 19th cen- patient care as well as work on the wards tury, Franz von Rinecker was the Faculty’s was resumed. Only ten years after the end dominant figure. He made important contri- of the war, the Faculty counted three of the butions to pediatrics, psychiatry and derma- big names in contemporary Western medi- tology alike and thanks to his efforts Würz- cine among its members, the surgeon Wer- burg can boast one the first pediatric hos- ner Wachsmuth, the internist Ernst Woll- pitals at any university in the world. Under heim and the otorhinolaryngologist Horst Rinecker’s leadership, Rudolf Virchow and Wullstein. Wullstein not only acquired inter- Albert Kölliker were appointed professors, national fame with his new method of tym- who helped turn anatomy and pathology panoplasty and his operation microscope. into modern laboratory sciences and, in the As the driving force behind the foundation case of Virchow’s cellular pathology, provid- of a “head clinic” he also set the path for a ed contemporary medicine as a whole with development towards the establishment of a new theoretical basis. Outstanding contri- interdisciplinary centers which increasingly butions also came from researchers outside came to shape the Faculty and which acted of the Medical Faculty, from the biologists as crucial catalysts for cutting edge biomed- Julius Sachs and Theodor Boveri, for exam- ical research. In 1992, a new center for bio- ple, and from the physicist Wilhelm Conrad medical research was opened on the Hub- Röntgen who discovered the x-rays. land, which today brings together members By 1900, the Julius-Spital – in 1800 still to of ten different institutions, from the facul- a large degree a last resort for poor, single ties of medicine, chemistry and pharmacy patients and invalids – and the various uni- as well as biology., In 2002, the “Virchow versity hospitals had become the most im- Zentrum” was established as a national re- portant providers of medical care in Würz- search center for experimental biomedi- burg. In the 1920s, the close and fruitful, cine, endowed with a number of research though sometimes conflict-ridden ties be- professorships and research groups head- tween the Juliusspital and the Medical Fac- ed by junior researchers, which plays a ma- ulty were somewhat loosened when the new jor role in the “Graduate School of Life Sci- Luitpold-Hospital was built in Grombühl. ences”. Würzburg also has come to house The National Socialist period left deep a center for research on infectious diseas- marks on the Würzburg Medical Facul- es and a center for interdisciplinary clini- ty. The Institut für Vererbungswissenschaft cal research. In addition, since 1971, a fair und Rasseforschung (Institute of Genet- number of so-called “Sonderforschungs- ics and Racial Research) conducted large bereiche” (special research areas) have scale genetic surveys of the population in been active, financed by large grants from the area around Würzburg. Werner Heyse, the Deutsche Forschungsgemeinschaft.

15 2. Research Institutes 2.1 Institute of Anatomy and Cell Biology, Chair of Anatomy I

Mission Professor Dr. med. Hermann Koepsell and Structure (Head) The research at Chair I is dedicated to the Koellikerstr. 6 structure, function, distribution and regula- 97070 Würzburg tion of membrane proteins, in particular to Tel.: 0931/31-82700 transporters of sugars and drugs. Further- Fax: 0931/31-82087 more, the function of an intracellular regulatory protein for plasma membrane trans- E-mail: [email protected] porters is investigated. This regulatory pro- www.uni-wuerzburg.de/anatomie tein represents a novel target for the modu-

CONTACT DETAILS CONTACT lation of transport processes. The methods used in this research include molecular biology, cell biological and biochemical investigations, transport measurements, electrical measurements on Xenopus laevis oo- cytes, and breeding and characterisation of Fig. 1: Model of the interaction of corti- transgenic mice. costerone with the outward-facing substrate binding pocket of the organic cation Members of chair I are: the department transporter rOCT1. For the indicated ami- head, four assistant professors, three tech- no acids an interaction with corticosterone nicians and MD-students. One Post-Doc has been shown experimentally. and four PhD-students funded by the Col- laborative Research Centre (SFB 487) are also included. identified seven amino acids in OCT1 that are critical for the binding of substrates and inhibitors. Computer modeling of the OCT1 tertiary structure in analogy to the elucidated Major Research structure of a bacterial transporter (lactose Interests permease) revealed a large binding pocket in which the critical seven amino acids are The main focus is the elucidation of the mo- directed to the aqueous phase (Fig.1). Us- lecular mechanisms of function and regu- ing fluorescent labeling of single amino ac- lation of physiologically important transport ids of OCT1 we could demonstrate motion proteins in the plasma membrane. One of the 11th transmembrane domain during project deals with polyspecific cation trans- transport of organic cations. We have suc- porters of the SLC22-family, which are in- cessful expressed members of the SLC22- volved in the absorption of drugs in small in- family in insect cells and in a cell free ex- testine as well as in excretion of drugs and pression system. Furthermore, we purified drug metabolites in kidney and liver. The first and reconstituted active transporters in pro- member of this family (OCT1, SLC22A1) of teoliposomes. In collaboration with another polyspecific drug transporters was cloned in research group attempts will be undertaken 1994 in this department. Another project to crystallize expressed and purified trans- deals with the sodium-dependent D-glu- porters and to determine tertiary structures cose transporter SGLT1. SGLT1 absorbs di- by X-ray diffraction. etary D-glucose in the small intestine and reabsorbs D-glucose from the primary urine in the proximal tubule of the kidney. A key Function and regulation of the sodium element in this project is the investigation of D-glucose cotransporter SGLT1 the regulator protein RS1 (RSC1A1), which was cloned in 1992 in this group. RS1 regu- We generated SGLT1-specific antibodies, lates the trafficking of SGLT1 to the plasma which are used to investigate the function membrane and modulates SGLT1 transcrip- and localization of SGLT1 in intestine, kid- tion in the nucleus. ney, liver, lung, and different glands. Fur- thermore, we generated mice with a SGLT1 (SLC5A1 gene) knock out, which survive on Substrate recognition and transport a D-glucose and D-galactose free diet. A mechanism of the polyspecific trans- couple of years ago we cloned the intracel- porters of the SLC22-family lular regulator protein RS1, which is encoded by the intronless gene RSC1A1. RS1 is The SLC22-family of transporters includes localized at the trans-golgi network, where transporters for organic cations and organic it inhibits the budding of SGLT1-containing anions. Using site directed mutagenesis we vesicles. During mitosis or in less differen-

16 tiated cells, RS1 is localized in the nucleus, where it inhibits SGLT1-transcription. In mice with a RS1 (RSC1A1 gene) knock out, absorption of D-glucose in the small intestine was increased. We identified two RS1 domains, which are responsible for the post-transcriptional inhibition of SGLT1. Tri- peptides derived from these domains inhibited SGLT1 function at nanomolar intracellular concentrations. The inhibiting tripeptides are taken up by enterocytes via a peptide transporter and are, therefore, potential drugs for the treatment of adipositas.

Teaching

Education of medical and dental medical students in microscopical and macroscopi- cal anatomy and in cell biology. Education of PhD and MD students. Classes in transporters and channels.

Vernaleken A, Veyhl M, Gorboulev V, Kot- tra G, Palm D, Burckhardt B-C, Burckhardt G, Pipkorn R, Beier N, van Amsterdam C, Koepsell H (2007) Tripeptides of RS1 (RSC1A1) inhibit a monosaccharide-dependent exocytotic pathway of Na+-D-glucose cotransporter SGLT1 with high affinity. J. Biol. Chem. 282, 28501-28513.

Gorbunov D, Gorboulev V, Shatskaya N, Mueller T, Bamberg E, Friedrich T, Koep- sell H (2008) High-affinity cation binding to organic cation transporter 1 induces movement of helix 11 and blocks transport after mutations in a modeled interaction domain between two helices. Mol. Pharmacol. 73, 50-61.

Keller T, Schwarz D, Bernhard F, Dötsch V, Hunte C, Gorboulev V, Koepsell H (2008) Cell free expression and functional recon- SELECTED PUBLICATIONS stitution of eukaryotic drug transporters. Biochemistry 47, 4552-4564.

Volk C, Gorboulev V, Kotzsch A, Müller TD, Koepsell H (2009) Five amino acids in the innermost cavity of the substrate binding cleft of organic cation transporter 1 interact with extracellular and intracellular corticosterone. Mol. Pharmacol. 76, 1-15.

Filatova A., Leyerer M, Gorboulev V, Chin- talapati C, Reinders Y, Müller TD, Sriniva- san A, Hübner S, Koepsell H (2009) Novel shuttling domain in a regulator (RSC1A1) of transporter SGLT1 steers cell cycle- dependent nuclear location. Traffic 10, 17 1599-1618. 2.2 Institute of Anatomy and Cell Biology, Chair of Anatomy II

Professor Dr. med. Detlev Drenckhahn Mission how GCs and estrogen regulate BBB per- (Head) and Structure meability. Effects of GCs and estrogen are known to be mediated by their cognate ste- Koellikerstr. 6 Research in the department is focused on roid hormone receptors, the GC and estro- 97070 Würzburg two main areas of interest. The research gen receptor, so that a special emphasis is Tel.: 0931/31-82702, group on cell biology (head scientist: Prof. laid on their function acting as ligand-de- Fax: 0931/31-82712 Dr. D. Drenckhahn) analyses structural, mo- pendent transcriptional regulators. E-mail: [email protected] lecular and functional properties of the cy- www.uni-wuerzburg.de toskeleton and the regulation of endothelial /ueber/fakultaeten/medizin/institute/institut_ and epithelial barrier. Pemphigus pathogenesis fuer_anatomie_und_zellbiologie/startseite/ The research group on neurobiology (head (D. Drenckhahn, J. Waschke, A Hübner)

CONTACT DETAILS CONTACT scientist: Prof. Dr. P. Kugler, Prof. Dr. E. Professor Dr. med. Peter Kugler Asan) studies the transport and metabolism The life-threatening blistering skin dis- Tel.: 0931/31-82704 of neurotransmitter glutamate and investi- ease pemphigus is primarily caused by an- gates the organization and ultrastructure of tibodies against cell adhesion molecules various CNS regions (e.g. amygdala). (desmo¬cadherins). We investigate wheth- Research in the department is carried out er these autoantibodies directly interfere by 11 postdoctoral scientists, 18 Ph.D.-stu- with binding of these adhesion molecules dents, and 12 technical assistants. or whether cell signalling pathways are re- Two existing experimental systems to mea- sponsible for skin blistering. sure forces between molecules and cells (atomic-force-microscopy, laser-tweezers) were further improved and a new technique Proteins of the nucleus to measure vascular permeability in rats (S. Hübner) in vivo (single-microvessel perfusion technique) was established. The nucleus represents the “control center” of eukaryotic cells with many proteins playing an important role in maintaining its structural and functional integrity. We Main research focus focus on such proteins (i.e. lamins and kanadaptin) and perform investigations in Endothel barrier regulation in vivo and the context of fundamental and pathophysi- in vitro ological aspects (i.e. lamino-pathies) (D. Drenckhahn, J. Waschke, N. Schlegel, A. Hübner) Glutamate transporters in the brain The endothelium lines the inner surface of (P. Kugler) the vascular wall. We investigate how inflammatory mediators induce the formation Glutamate is used as an excitatory of gaps between endothelial cells which neuro¬transmitter by numerous neuronal allow the leakage of plasma into the sur- systems in the brain. Synaptically released rounding tissue and thereby may lead to se- glutamate has to be eliminated rapidly from vere edema. We focus on the regulation of the extracellular space via glutamate trans- cell adhesion molecules (cadherins, clau- porters (EAAT1-5), since otherwise it would dins, integrins) and of the cytoskeleton. overexcite and damage neighboring neurons. We try to obtain insights into the subcellular localization and translocation of glu- Molecular mechanisms of steroid-in- tamate transporters in glutamatergic neu- duced regulation of permeability in the rons. haematoencephalic barrier (C. Förster) Emotions The integrity of the blood brain barrier (BBB) (E. Asan) is compromised in many disorders of the human CNS leading amongst others to in- The corpus amygdaloideum (amygdala) is creased vascular permeability and reduced of decisive importance for emotional pro- expression of tight junction and adherens cesses. Malfunctions in interconnections of junction proteins. Therapeutical strategies this brain area may contribute to neuropsy- include treatment with the vasoprotective chiatric, especially affective disorders. We steroid hormones, glucocorticoids (GC) and analyze the structure of amygdaloid network estrogen which improve permeability prop- and investigate which factors could be re- erties of the BBB. Research projects con- sponsible for normal function and patholog- centrate on elucidating the molecular basis ic changes.

18 Förster C, Burek M, Romero IA, Weksler B, Couraud PO, Drenckhahn D (2008) Dif- ferential effects of hydrocortisone and TNF alpha on tight junction proteins in an in vitro model of the human blood-brain barrier. J. Physiol. 586:1937-1949.

Lang EM, Schlegel N, Reiners K, Fig. 1: Cytoskeleton and adhesion molecules (cadherins) control the barrier between Hofmann GO, Sendtner M, Asan E (2008) blood and tissue (endothelial layer). How inflammatory stimuli modify the barrier is one Single-dose application of CNTF and BDNF aspect investigated by the group. improves remyelination of regenerating nerve fibers after C7 ventral root avulsion and replantation. J. Neurotrauma 25: 384-400 Ultrastructure of tissues and cells of the nervous system Teaching activity Busch A, Kiel T, Heupel WM, Wehnert M, (E. Asan) Hübner S. (2009) Nuclear import is reduced in cells expressing nuclear envel- Courses in microscopic and macroscopic opathy-causing lamin A mutants. Exp. Cell Morphological investigations, especially on anatomy, neuroanatomy and cell biology Res. 315: 2373-2385.

an electron microscopy level, deliver impor- are held for medical, biomedical and den- SELECTED PUBLICATIONS tant contributions to the analysis both of tistry students (a total of 430 students per Heupel WM, Efthymiadis A, Schlegel A, Baumer Y, Baumgartner W, Drenckhahn D, changes in the nervous system which may year). The department hosts a yearly meet- Waschke J (2009) Endothelial barrier sta- be the cause of neuropsychiatric disorders, ing of the Anatomical Society (last week of bilization by a cyclic tandem peptide tar- and of regeneration processes. By carrying September). geting VE-cadherin transinteraction in vitro out such investigations, we support stud- and in vivo. J. Cell Sci. 122:1616-1625. ies in numerous clinical and basic science Heupel WM, Zillikens D, Drenckhahn D, projects dedicated to elucidate molecular Waschke J (2009) Pemphigus vulgaris mechanisms of nervous system disorders. IgG directly inhibit desmoglein 3-mediated transinteraction. J. Immunol.181:1825- 19 1834. 2.3 Institute of Anatomy and Cell Biology, Chair of Anatomy III

Professor Dr. med. Jens Waschke Mission Adhesion mediated by desmosomal (Head) and Structure cadherins (V. Spindler, D. Drenckhahn, J. Waschke) Koellikerstr. 6 At department III (PI: Prof. Dr. med. J. 97070 Würzburg Waschke), which was newly established in Stratified epithelia such as the epidermis of Tel.: 0931/31-82706 2008, research is focussed on three ma- the skin rely on specialized adhesion con- Fax: 0931/31-81065 jor research interests. Research is carried tacts (desmosomes) to provide efficient E-mail: [email protected] out by scientists Dr. med. N. Schlegel who barrier properties against the environment. www.uni-wuerzburg.de since 4/2009 joins the Department for Sur- Desmosomal adhesion proteins belong to /ueber/fakultaeten/medizin/institute/ gery (Director: Prof. Dr. med. Ch. Germer) the cadherin superfamily. In this project, insti¬tut_fuer_anatomie_und_zellbiologie/ and now is an external member of our group which is funded in SFB 487 (Project lead- CONTACT DETAILS CONTACT startseite/ as well as by Dr. med. V. Spindler. Further er: Prof. Dr. med. J. Waschke and Prof. Dr. experiments are performed by 7 MD and med. D. Drenckhahn), we use biophysical Ph.D. students as well as 4 technicians. approaches to characterize the molecular binding properties of different cadherin family members and study ways to modulate their interaction.

Major Research Interests Teaching Endothelial barrier regulation by Rho GTPases in vivo and in vitro Courses in microscopic and macroscopic (N. Schlegel, V. Spindler, D. Drenckhahn, anatomy, neuroanatomy and cell biology J. Waschke) are held for medical and dentistry students (a total of 450 students per year). Addition- The project is funded in SFB 688 (Project ally, interdisciplinary lectures are given to- leader: Prof. Dr. med. J. Waschke and Prof. gether with Prof. Dr. med. Ch. Germer (De- Dr. med. D. Drenckhahn) and characterizes partment for Surgery). the mechanisms by which cAMP and the GTPase Rac1 stabilize endothelial barrier functions. This signaling pathway apparently is compromised in inflammation and sepsis leading to fluid extravasation from blood vessels into surrounding tissues.

Pemphigus pathogenesis (V. Spindler, D. Drenckhahn, J. Waschke)

We are interested how skin blister formation is induced by autoantibodies in the severe autoimmune blistering skin disease pemphigus. Pemphigus serves as a good model because it is well established that autoantibodies against adhesion molecules of specialized cell contacts (desmosomes), i.e. desmogleins, are pathogenic. Besides new therapeutical approaches these studies are sought to gain basic insights into the regulation of desmosomal adhesion.

20 Fig. 1: cAMP and the GTPase Rac1 are crucial for maintenance of endothelial barrier functions. We investigate how inflammatory mediators interfere with this signaling pathway.

Schlegel N, Waschke J (2009) VASP is involved in cAMP-mediated Rac 1 activation in microvascular endothelial cells. AJP Cell Physiology, 296(3): C453-462

Heupel WM, Efthymiadis A, Müller T, Schlegel N, Baumer Y, Baumgartner W, Drenckhahn D, Waschke J (2009) Endo- thelial barrier stabilization via a cyclic peptide targeting VE-cadherin transinteraction. J. Cell Sci., 122:1616-1625

Schlegel N, Baumer Y, Drenckhahn D, Waschke J (2009) LPS-induced endothelial barrier breakdown is cAMP-dependent in vivo and in vitro. Crit. Care Med., 37(5): 1735-43

Heupel WM, Engerer P, Schmidt E, Waschke J (2009) Pemphigus vulgaris IgG

SELECTED PUBLICATIONS cause loss of desmoglein-mediated adhesion and keratinocyte dissociation independent of epidermal growth factor receptor. Am. J. Pathol., 174(2): 475-485

Spindler V, Heupel WM, Efthymiadis A, Schmidt E, Eming R, Rankl C, Hinterdor- fer P, Müller TD, Drenckhahn D, Waschke J (2009) Desmocollin 3-mediated binding is crucial for keratinocyte cohesion and impaired in pemphigus. J. Biol. Chem., 21 284(44):30556-30564 2.4 Institute of Physiology, Chair of Vegetative Physiology

Mission Atrial natriuretic peptide (ANP) regulates ar- Professor Dr. med. Michaela Kuhn and Structure terial blood pressure and intravascular vol- (Head) ume as well as metabolism. To dissect the The Institute of Physiology comprises Chairs cell-specific actions of ANP in vivo, we gen- Röntgenring 9 for Vegetative Physiology and for Neuro- erated genetic mouse models with cell-re- 97070 Würzburg physiology (Prof. Heckmann). The building stricted GC-A-deletion in vascular endothe- Tel.: 0931/31-82721 accomodates the research laboratories and lial or smooth muscle cells, cardiac myo- Fax: 0931/31-82741 offices, a lecture hall seating 200 students, cytes and pancreatic ß-cells. Our observa- E-mail: [email protected] course laboratories, seminar rooms, and a tions demonstrate that concerted renal and www.physiologie.uni-wuerzburg.de/ library. Facilities for animal husbandry, for endothelial actions of ANP maintain intra- physiologieI/ work with radioactive isotopes and a re- vascular volume homeostasis. ANP, via en-

CONTACT DETAILS CONTACT pair shop are also available. The research dothelial GC-A and cGMP-dependent acti- Professor Dr. rer. nat. Andreas Friebe at Vegetative Physiology is focused on Car- vation of a specific Protein Kinase (cGKI), Tel.: 0931/31-88730 diovascular Physiology and three research modulates transendothelial, caveolae-me- groups are led by the University Professors diated transport of albumin (Fig. 1). This Professor Dr. rer. nat. Kai Schuh Dr. Michaela Kuhn (Head since 2005), Dr. shifts the balance of hydrostatic and col- Tel.: 0931/31-82740 Andreas Friebe and Dr. Kai Schuh. loid osmotic forces across capillary walls in favor of moving protein-free fluid from the plasma into interstitial pools of the skin and Major Research skeletal muscle and thereby adjusts intra- Interest vascular fluid volume.

Our research focuses on elucidating the reg- Pathophysiological conditions such as hy- ulation and physiological functions of gua- poxia induce the cardiac and extracardi- nylyl cyclase (GC) receptors and their sec- ac formation of B-type natriuretic peptide ond messenger cGMP. This receptor fam- (BNP), a second specific ligand for GC-A. ily comprises transmembrane receptors for Local BNP, via GC-A/cGMP signaling, stim- cardiac and intestinal natriuretic peptides ulates pathways involved in microvascular (e.g. GC-A for ANP and BNP; GC-C for gua- endothelial proliferation (such as the p38 nylin) and the intracellular nitric oxide (NO)- MAPK) and migration (i.e. VASP) and there- sensitive GC. We investigate whether these by acts as a stress-responsive regulator of different GC-receptors mediate the forma- angiogenesis. tion of cGMP in separate intracellular com- partments to regulate different third mes- In patients with cardiac hypertrophy and in- sengers and cell functions. A second re- sufficiency, ANP plasma levels are marked- search focus is the role of SPRED (Sprouty- ly enhanced, but the cardiovascular effects related protein with an EVH1 domain) in cell are diminished, indicating GC-A dysfunc- proliferation and differentiation. Our proj- tion. In collaboration with Prof. Albert Sick- ects are funded by grants from the DFG, in mann (Leibnitz-Institut für Analytische Wis- particular the SFB 487 and 688, and the senschaften) we applied mass spectrom- IZKF Würzburg. etry to characterize the phosphorylation of GC-A and its changes during ANP-provoked desensitization. Together with site-directed Regulation and functions of Guanylyl mutagenesis the results indicate that ANP- Cyclase-A (GC-A), the receptor for the provoked phosphorylation at Ser487 in- cardiac hormones ANP and BNP duces the dephosphorylation of neighbor- (M. Kuhn, K. Völker, B. Gaßner, M. Hart- ing residues. In addition, we observed that mann, M. Klaiber, W. Chen, M. Hünerberg, alternative splicing of the GC-A gene results J. Schröter, A. Gazinski, B. Dankworth, C. in the formation of a silent GC-A-mutant, Siegl) which forms inactivating dimers with the

Fig. 1: The figure shows (A) that ANP stim- ulates the extravasation of FITC-albumin in the microcirculation, as observed by intra- vital microscopy; and (B) a model for the participating endothelial signaling pathways.

Teaching

The chairs of Vegetative Physiology and Neurophysiology offer a broad spectrum of lectures, integrative seminars and practical courses for students of Medicine, Dentistry, Pharmacy, Biology and Biomedicine. A major focus is the intensive teaching of Vegeta- tive Physiology and Pathophysiology to students of Medicine (3th - 4th term).

Fig. 2: Immunohistochemical analysis of NO-GC deletion in vascular smooth muscle. Tissue sections from femoral vessels from WT and smooth muscle-specific knock out mice (SM-NO-GC-KO) were stained with specific antibodies against NO-GC (red) and α- smooth muscle actin (SMA; green). wildtype receptor. We are currently investi- specific functions of the NO/GC/cGMP sig- gating whether these processes contribute naling system. to inhibition of the NP/GC-A system in patients with chronic heart failure. Physiological functions of SPRED and ATIP1 The significance of NO/cGMP signaling (K. Schuh, M. Ullrich, D. Fetting, T. Fischer, in the cardiovascular and gastrointes- M. Abeßer, P. Benz) tinal system (A. Friebe, D. Groneberg, R. Jäger, M. Küm- Gene trapping is an elegant tool to com- mel) bine ablation of a specific gene with parallel analyses of promoter activity of this Kuhn M, Völker K, Schwarz K, Carbajo-Lo- The nitric oxide (NO)-sensitive intracellular trapped gene in mice. Trapping of the ubiq- zoya J, Flögel U, Jacoby C, Stypmann J, van Eickels M, Gambaryan S et al. (2009) guanylyl cyclase (NO-GC) is also involved uitous MAPK signalling pathway inhibitor The natriuretic peptide/guanylyl cyclase- in many physiological processes. We have SPRED2 resulted in a complex phenotype, A system functions as a stress-responsive generated mice with global deletion of with dwarfism, renal failure and severe al- regulator of angiogenesis in mice. J Clin NO-GC. These mice show increased blood terations in the production of hormones of Invest. 119, 2019-30. pressure, gastrointestinal dysmotility, early the hypothalamic-pituitary-adrenal axis. Our Hartmann M, Skryabin BV, Müller T, Gazin- postnatal lethality and shortened bleeding observations in this new mouse model em- ski A, Schröter J, Gassner B, Nikolaev VO, time. To identify the specific cell types me- phasize that SPRED2 is critically involved in Bünemann M, Kuhn M (2008) Alternative diating the effects of NO on blood pressure the regulation of cell proliferation and differ- splicing of the guanylyl cyclase-A receptor and gastrointestinal peristalsis, we gener- entiation in various organs. modulates atrial natriuretic peptide signaling. J Biol Chem. 283, 28313-20. ated mice in which NO-GC is specifically deleted in smooth muscle cells (Fig. 2) We applied the same strategy to delete the Schmidt H, Stonkute A, Jüttner R, Koesling or interstitial cells of Cajal. A third project murine gene encoding the Angiotensin re- D, Friebe A, Rathjen FG (2009) C-type na- characterizes the role of NO-GC in endo- ceptor interacting protein 1 (ATIP1). ATIP1 triuretic peptide (CNP) is a bifurcation factor for sensory neurons. Proc Natl Acad thelial cells. Although a fundamental role interacts with the AT2-receptor for Angio- Sci U S A. 106, 16847-52. of NO in angiogenesis has been described, tensin II, but the functional implications SELECTED PUBLICATIONS the function of NO-GC in endothelium re- remain unclear. Interestingly, ATIP-1-defi- Groneberg D, König P, Wirth A, Offer- mains unclear. To clarify the role of NO- cient mice exhibit blood pressure-indepen- manns S, Koesling D, Friebe A (2010) GC in angiogenesis we plan to generate dent cardiac hypertrophy. We are current- Smooth muscle-specific deletion of NO- sensitive guanylyl cyclase is sufficient to mice with endothelium-restricted deletion ly investigating the molecular mechanisms induce hypertension in mice. Circulation, of this receptor. By comparing the pheno- accounting for these different phenotypes 121, 401-9. type of these different genetic mouse lines and overall the (patho)physiological roles of we hope to gain new insights into the cell- SPRED and ATIP1. Ullrich M, Schuh K (2009) Gene trap – knockout on the fast lane. Methods Mol Biol. 561, 145-59. 23 2.5 Institute of Physiology, Chair of Neurophysiology

Professor Dr. med. Manfred Heckmann Mission BMP-ligand Gbb ameliorates these defects, (Head) and Structure indicating that the phenotype in MAN1 mutants reflect changes in BMP signaling at Röntgenring 9 Our research focusses on synaptic trans- the neuromuscular junction. 97070 Würzburg mission, synaptogenesis and neuronal ex- Tel.: 0931 31/82730 citability from the molecular to the cellular and systems levels. We use the mouse Functional characterization of K chan- Fax: 0931 31/ 82741 2P E-mail: [email protected] and the fruitfly Drosophila melanogaster as nels from mouse and fly www.uni-wuerzburg.de/en/ueber/faculties_ prime model organisms and combine elec- (F. Döring) departments_and_schools/medizin/institute/ trophysiological methods, molecular biological and genetic tools, with high-end mi- Two-pore domain K+ (K ) channels give rise physiologisches_institut/neurophysiologie/ 2P CONTACT DETAILS CONTACT home/ croscopy. to time- and voltage- independent background currents that substantially control cellular excitability and K+ homeostasis.

Major Research The activity of K2P channels is modulated Interests by various physical and chemical stimuli as well as by G-protein coupled receptors. Mo- Latrophilins - the molecular bridge be- lecular mechanisms underlying such regu- tween neuronal organization and synap- lation and processes of membrane target- tic function ing were analyzed in detail for pH-sensi-

(T. Langenhan) tive K2P channels (TASK, TRESK). Knockout mice deficient in these channels were used Latrophilins are ancient surface receptors, to discover their physiological role in differ- which are found on neuronal and epider- ent organs. As we previously analyzed the mal cell types from earliest developmental elementary properties of K2P channel or- stages onwards. Latrophilins are involved in thologs from Drosophila, the genetic advan- coordinating the distribution of polarity in- tages of this model organism are currently formation within an epithelium, a process used to reveal the physiological function of described as planar cell polarity. Planar cell Drosophila TASK channels by imaging tech- polarity is required to shape the proper ar- niques and behavioral studies. chitecture of epithelial structures such as the lamination of the mammalian cortex. At the same time, latrophilins appear to Antidepressants interact with potassi- control key events during synaptic vesicle um background currents exocytosis through unknown mechanisms, (E. Wischmeyer) and can thereby partake in synaptic trans-

mission. We investigate, which properties Several members of the K2P channel fam- of latrophilin receptor molecules allow for ily are expressed in brain as well as in the these widely differing tasks using the fruit- heart and are directly influenced by antide- fly and the nematode C. elegans as model pressants like fluoxetine (‚Prozac’). Closure systems. of these channels leads to an augmented excitability in neurones and cardiac cells, hence to wanted antidepressive effects as Drosophila MAN1 regulates BMP signal- well as unwanted cardiac arrhythmias. Un- ing at the neuromuscular junction raveling the mechanism of the interaction

(N. Wagner) between antidepressants and K2P-channels might elucidate our understanding of the Bone morphogenic proteins (BMPs) regu- correlation betweeen neuronal and cardiac late a variety of cellular processes, including effects. cell differentiation, developmental processes and tissue homeostasis. BMP signaling responses are refined by distinct secreted Serotonergic regulation of fear behav- and intracellular antagonists in different cel- iour by potassium channels lular and temporal contexts. We could show (M. Weber) that the inner nuclear protein MAN1 is a tissue-specific antagonist of BMP signaling in The modulation of neuronal excitability by Drosophila. MAN1 mutants show reduced TASK-3 channels is mediated by serotonin

locomotor activity and electrophysiology re- receptor (e.g. 5-HT2C) coupling. We could cordings uncovered a new presynaptic role show that this mechanism is active in me- of MAN1 at the neuromuscular junction. We dial amygdala neurones and thereby reduc- found that synaptic transmission is severely es innate fear behaviour. Serotonin modu- impaired and short-term synaptic plasticity lates in a similar way brainstem neurones is altered in MAN1 mutants. Reduction of a that mediate the startle response (PnC gi-

24 Fig. 1: Caudal pontine reticular formation (PnC) brain stem neurones express TASK-3 (in situ hybridisation) as well as 5-HT2C receptors (immunohistochemistry) and receive serotonergic input from Raphe (RMg/Pg) neurones. Inactivation of TASK-3 potassium channels by α-met.-Serotonin enhances excitability of these neurones. ant neurones, see figure). This finding may veyed in integrated seminar series, which explain the enhanced startle response in are held in collaboration with clinicians, anxious and depressive patients. which co-lecture on physiological topics.

Physiology and plasticity of the active zone in vivo (R. J. Kittel, DFG Emmy-Noether research group leader)

Synapses are specialised intercellular contact sites, which serve as the communication link between neurons and their partner Langenhan T, Prömel S, Mestek L, Es- cells. At chemical synapses, calcium-ion in- maeili B, Waller-Evans H, Hennig C, Ko- flux triggers the fusion of transmitter-laden hara Y, Avery L, Vakonakis I, Schnabel R, vesicles with the presynaptic membrane at Russ AP (2009). Latrophilin signaling links a specific sub-cellular region termed the ac- anterior-posterior tissue polarity and ori- tive zone. Transmitter substances released ented cell divisions in the C. elegans embryo. Dev Cell.17:494-504. by this process then diffuse across the synaptic cleft and are sensed by postsynaptic Meuth SG, Herrmann AM, Simon OJ, Sif- receptors to convey signal transduction. A frin V, Melzer N, Bittner S, Meuth P, Langer hallmark of synaptic transmission is its plas- HF, Hallermann S, Boldakowa N, Herz J, Munsch T, Landgraf P, Aktas O, Heckmann ticity, which enables synapses to regulate M, Lessmann V, Budde T, Kieseier BC, complex brain processes by filtering, modi- Zipp F, Wiendl H (2009). Cytotoxic CD8+ fying, or integrating information. The details T cell-neuron interactions: perforin-depen- of active zone physiology and how its modu- dent electrical silencing precedes but is lation contributes to synaptic plasticity are, not causally linked to neuronal cell death. J. Neurosci. 29:15397-409. however, barely understood. By combining genetics with high resolution opto- and Schmid A, Hallermann S, Kittel RJ, Khor-

electrophysiological methods in Drosophila SELECTED PUBLICATIONS ramshahi O, Frölich AM, Quentin C, Rasse melanogaster, this project tests the hypoth- TM, Mertel S, Heckmann M, Sigrist SJ. (2008). Activity-dependent site-specific esis that active zone physiology is modified changes of glutamate receptor composi- during activity-induced plasticity in vivo. tion in vivo. Nat Neurosci. 11:659-66.

Wagner N, Weyhersmueller A, Blauth A, Schuhmann T, Heckmann M, Krohne G, Samakovlis C (2009). The Drosophila Teaching LEM-domain protein MAN1 antagonizes BMP signaling at the neuromuscular junc- We teach physiology and pathophysiology to tion and the wing crossveins. Dev Biol. undergraduates enrolled in medicine, den- doi:10.1016/j.ydbio.2009.11.036 tistry, biomedicine, pharmacy, psychology Weber M, Schmitt A, Wischmeyer E, and neurobiology (lectures, practical and Döring F (2008). Excitability of pontine comprehensive courses, seminars). The startle processing neurones is regulated by clinical aspect of human physiology is con- the two-pore domain K+ channel TASK-3 coupled to 5-HT2C receptors. Eur J Neuro- sci 28: 931-940. 25 2.6 Biocenter Würzburg, Chair of Physiological Chemistry I

Mission that a high signalling output of the mela- Professor Dr. rer. nat. Dr. h.c. Manfred Schartl and Structure noma inducing growth factor receptor Xmrk (Head) leads to senescence of melanocytes and a Complying to the perspectives of research nevus cell-like appearance. This contributes Biozentrum at the Biocenter, extending from functional to the clinical important, but still unsolved Am Hubland molecular biology to questions, which con- question whether nevi are benign, precan- 97074 Würzburg cern the development of the total organs cerous state of the malignant melanoma. Tel.: 0931/31-84148 and its interactions with the environment. The intracellular signaling network is criti- Fax: 0931/31-84150 All research groups at this unit use molecu- cally involved in bringing about the neoplas- E-mail: [email protected] lar methods to understand problems in Bi- tic phenotype of tumor cells. The changes http://pch1.biozentrum.uni-wuerzburg.de ology and Medicine on all levels of the bio- that occur on this level during tumor forma-

CONTACT DETAILS CONTACT logical organization. The multi-faceted ap- tion from the first transformed cell to final Professor Dr. rer. nat. Stefan Gaubatz proach is well reflected in the fact that the malignant stage are therefore the key for a Tel.: 0931/31-84138 scientists of the department are biologists, better understanding of cancerous disease. chemists and physicians and that the head Consequently, components of the signaling of the institute is a member of the Medical network are intensively scrutinized for diag- Faculty as well as of the Biological Faculty. nostic markers and therapeutic targets. The research focus is the molecular under- In the Xiphophorus melanoma model sys- standing of developmental processes and tem, on the molecular level, the primary the pathobiochemistry of cancer. signal transduction events induced by the receptor tyrosine kinase Xmrk are reason- ably well understood. Importantly, similar Major Research events occur during the generation of hu- Interests man melanoma, such as the activation of the MAP kinase pathway by BRAFV600E Molecular analysis of melanoma forma- and NRASQ61K or the activation of the PI3 tion kinase pathway by NRASQ61K or by PTEN (M. Schartl) deletion. The “division of labor“ between the MAP kinase and the PI3 kinase path- Due to the enormous complexity and vari- way in human melanoma is one subject of ety of human cancerous diseases, animal our studies. models are especially suited to analyse basic mechanisms of tumour development and progression on the genetic and molecular level. Small laboratory model fish species, the Me- daka and Xiphophorus are used to study melanoma formation in- vivo in a comparative approach with mouse and human melanoma cell lines. This led to a better understanding of the intracellular processes, which are responsible for the transformation of normal, healthy pigment cells to tumour cells. Through proteome and microarray analyses interest- ing, novel melanoma molecules were identified. The usefulness of these as tumour mark- Fig. 1: Structure model of the extracellular domain of the mela- ers or therapeutic tar- noma-inducing EGF receptor variant Xmrk. Red box highlights an gets is currently evalu- intermolecular cystein bridge generating covalent dimers, which ated. Of special impor- are constitutively active receptors . Permanent signaling of this tance was the finding receptor leads to pigment cell transformation.

26 protein complex in human cells that is related to similar complexes in invertebrates. We found that this complex, called human DREAM or LINC, regulates the expression of mitotic genes and is essential for entry into mitosis. Inactivation of the LIN9 subunit of DREAM in the mouse results in early embryonic lethality at the peri-implantation stage. In contrast, the incomplete depletion of LIN9 promotes tumorigenic transformation. We are currently investigating the possibility that the inhibition of LIN9 promotes tumorigenesis by weakening the mitotic spindle checkpoint and increasing genomic instability. We are also interested the function of B-MYB, another subunit of DREAM. B-MYB is an oncogenic transcription factor that is highly expressed in different human cancers. We found that B-MYB is required for recovery from the DNA-damage induced G2 checkpoint in p53-negative cells. High levels of B-MYB are also consistently associated with mutated p53 and with a poor prognosis in human cancers. These observations suggest B-MYB overexpression contributes to tumor progression in a p53-negative background and that B-MYB could be a future target for therapy.

Fig. 2: Inactivation of the mammalian DREAM complex in conditional LIN9 knockout MEFs results in formation of chaotic multipolar mitotic spindles. Red: gamma-tubulin; green: alpha-tubulin; blue: DNA.

Many additional melanoma-relevant path- genesis and high throughput drug screens. ways are simultaneously activated by the We have generated a transgenic line, which oncogenic Xmrk receptor, which offers the produces spontaneously pigment cell tu- possibility to use this oncogene to search mors due to overexpression of xmrk under for new molecular players relevant for mela- control of the mitf promoter. Candidate tu- Leikam C, Hufnagel A, Schartl M, Meier- johann S. (2008) Oncogene activation in noma in general. By high-throughput meth- mor modifier genes are functionally ana- melanocytes links reactive oxygen to multi- ods revealed a large number of genes and lyzed in double transgenics. To identify nov- nucleated phenotype and senescence On- proteins that are regulated in response to el modifiers, a whole genome mutagenesis cogene, 27, 7070-82. Xmrk activation were identified. These in- screen on the mitf::Xmrk transgenic back- clude several transcription factors, but also ground is performed. Genes that enhance Lokaj K., Meierjohann S., Schuetz C., Teutschbein J., Schartl M., Sickmann A. antioxidant proteins such as peroxiredoxins. or ameliorate the malignant process will (2009) Quantitative differential proteome We have observed that peroxiredoxins are be identified by their phenotypic effect af- analysis in an animal model for human also upregulated by the endogenous onco- ter outcrossing, mapped and isolated by re- melanoma. J Proteome Res, 8, 1818- genes of many human melanoma cell lines. verse genetic approaches. 1827. An efficient antioxidant capacity is particu- Mannefeld M., Klassen E., Gaubatz S larly important to counteract melanoma on- (2009) B-MYB is required for recovery cogenes. Those can generate high amounts The role of the pRB/E2F pathway in gene from the DNA-damage induced G2 check- of reactive oxygen species. We have shown expression and cell cycle progression point in p53-mutant cells. Cancer Re- that this leads to high levels of DNA dam- (S. Gaubatz) search 69: 4073-4080. age and the generation of multinucleated Pala, I. Coelho, M.M., Schartl M. (2008) senescent melanocytes. The characteriza- Our research focuses on E2F transcription SELECTED PUBLICATIONS Dosage Compensation by Gene-CopySi- tion of the senescence process and its ef- factors, the retinoblastoma protein and re- lencing in a Triploid Hybrid Fish. Curr Biol, fect on the melanocytes are subject of our lated pocket proteins. These proteins play 18, 1344-1348. ongoing studies. key roles in the regulation of cellular prolifer- Schartl M., Wilde B., Laisney J., Taniguchi The role of tumor modifiers is studied in the ation, differentiation and apoptosis and they Yoshihito, Takeda Shunichi, Meierjohann fish medaka, which offer the possibility of have been implicated in tumorigenesis. We S. (2010) A mutated EGFR is sufficient to genetic alterations, whole genome muta- have recently identified a novel E2F/ pocket induce malignant melanoma with genetic background-dependent histopathologies. J Investigative Dermatology 130, 249–258. 27 2.7 Biocenter Würzburg, Chair of Physiological Chemistry II

Mission Metabolic pathways in peroxisomes: al- Professor Dr. phil. Martin Eilers and Structure pha-methylacyl-CoA-racemase (Head) (E. Conzelmann)

Biozentrum The department of Physiological Chemistry • Elucidation of structure and mechanism Am Hubland II (PCII) is part of the „Biozentrum“ found- of the enzyme 97074 Würzburg ed in 1990, where 10 institutions from the • Significance of the enzyme in the me- Tel.: 0931/318-4111 faculties of Biology, Chemistry and Medi- tabolism of cholesterol and of branched- Fax: 0931/318-4113 cine cooperate in teaching and research. chain fatty acids, i.e. by analysis of a E-mail: martin.eilers@biozentrum. PCII teaches biochemistry for preclinical mouse knock-out model uni-wuerzburg.de students in Medicine and Dentistry and for • Simultaneous targeting of the same www.pch2.biozentrum.uni-wuerzburg.de CONTACT DETAILS CONTACT the Bachelor students in Biomedical sci- enzyme to different cellular compart- ences. Seven research groups work at PCII, ments Professor Dr. rer. nat. Ernst Conzelmann two of which are headed by junior inves- • Role as marker for tumours of the pros- Tel.: 0931 318-4120 tigators (Dr. Nikita Popov and Dr. Daniel tate and of other organs Murphy). The aim of PCII is to contribute to Professor Dr. rer. nat. Peter Gallant therapy and diagnosis of human cancer by Tel.: 0931 318-4112 the establishment of biological model sys- Role of murine caspase-12 tems and the setup of chemical/biochemi- (J. Hoppe) Professor Dr. rer. nat. Jürgen Hoppe cal methodology. Tel.: 0931 318-4130 Caspase-12 was originally described as initiator caspase, which is activated in a [Ca2+] Major Research i dependent manner after ER-Stress. Our Interests results do not support this model. In contrast caspase-12 was found to be cleaved Function and Regulation of the Human after asp-94 by caspase-3 independently Myc Proto-oncogene of ER-stress. By using cleavages site-spe- (M. Eilers) cific antibodies we could exclude a further processing of caspase-12 in the intersub- The c-myc proto-oncogene participates unit regions. Our model locates caspase-12 in the genesis of the majority of all hu- downstream of caspase-3, questioning its man tumors. The gene encodes a nuclear proposed role as initiator caspase. protein (Myc) that is a central regulator of cell growth and cell proliferation. Myc ex- erts this control at least in part by binding Structure, mechanism and cellular func- to specific DNA sequences and affecting tions of growth and differentiation fac- the transcription of multiple genes involved tors in protein synthesis, metabolism and cell (W. Sebald) proliferation. Many central questions about the basic function of Myc and the regula- We are focussing on Interleukins involved tion of its multiple activities remain unan- in generation and maintenance of allergic swered. Our research tries to unravel how diseases and asthma, as well as on BMP´s/ Myc functions and to devise strategies to use this knowledge for the treatment of human disease. The junior group of Niki- ta Popov studies ubiquitination of Myc and its functional consequences; the group of Dan Murphy develops novel mouse models to study the role of Myc in tumor progression.

Control of Cell Growth in Drosophila Fig. 1: Depletion of the Aurora-A kinase (P. Gallant) leads to loss of the N-Myc protein in MYCN-amplified neuroblastoma cells. The The fruit fly Drosophila melanogaster offers panels shows immunoblots documenting a unique model system that allows the ge- the amount of N-Myc in IMR32 cells after netic analysis of pathways controlling cellu- treatment with nocodazole in combination lar growth, and of their effects on organis- with a PI3-kinase inhibitor either in control mal growth and on cell proliferation. We use cells or in cells that were depleted of Auro- several strategies to identify novel growth ra-A. The figure documents that Aurora-A regulators that act either in a cell autono- is required to stabilize N-Myc in these cells mous or a systemic manner. (from Otto et al., Cancer Cell 2009).

28 Fig. 2: Drosophila Myc overexpression in the eye induces growth (as revealed by increased ommatidial size) and apoptosis (as revealed by disturbed eye morphology, i.e. roughness) in a largely Max-dependent and -independent manner, respectively. The Meyer, M., Gliesing, D., Slany, R., Stabla, panels show scanning electron micrographs of adult eyes overexpressing the indicat- K., Roth, P., Eilers, M., and Neubauer, A. ed transgenes (top), and the average ommatidial sizes for the corresponding genotypes (2009) Oncogenic RAS enables DNA dam- (lower); note that „p35“ blocks apoptosis and „max-IR“ indicates knockdown of Max. age- and p53-dependent differentiation of This figure illustrates one facet of Myc’s activities that do not require association with acute myeloid leukemia cells in response Max (from Steiger et al., Nature Genetics 2008). to cytarabine. PLoS One, 4(11): e7768. Gallant, P., and Steiger, D. (2009) Myc‘s secret life without Max. Cell Cycle 8, 3848-3853. TGF-betas, which regulate the development mental Biochemistry teaches Biochemis- Herold, S., Herkert, B, and Eilers, M. and regeneration of tissues and organs. try and Molecular Biology to the more than (2009) Facilitating replication under Our ongoing projects concern the molecu- 400 annual students of Medicine and Den- stress: an oncogenic function of MYC? Nat lar recognition and primary activation steps tistry. We also teach Biochemistry to the Rev Cancer 9, 441-4. in BMP/GDF-receptor complexes as well as 24 annual students of Biomedicine (B.Sc./ the analysis of interleukin-4 antagonists. M.Sc.). Schwinkendorf, D., and Gallant, P. (2009) The conserved Myc box 2 and Myc box 3 regions are important, but not essential, for Myc function in vivo. Gene 436, 90-

SELECTED PUBLICATIONS 100. Teaching Otto, T., Horn, S., Brockmann, M., Eilers, U., Schüttrumpf, L., Popov, N., Kenney, The chair of Physiological Chemistry II in A., Schulte, J., Beijersbergen, R., Chris- conjunction with the Chair of Physiological tiansen, H., Berwanger, B., and Eilers, M. Chemistry I and with the Chair of Develop- (2009) Stabilization of N-Myc is a critical function of Aurora-A in human neuroblastoma. Cancer Cell 15: 67-78. 29 2.8 Biocenter Würzburg, Chair of Developmental Biochemistry

Mission The target genes of Hey factors in these Professor Dr. med. Manfred Gessler and Structure processes are still largely unknown. Current (Head) efforts are directed towards their identifica- The Chair of Developmental Biochemistry tion through gene expression analyses and Biozentrum was newly established in 2008. Its scien- sequencing of binding sites in the genome Am Hubland tific interests range from elucidation of the of genetically engineered cardiomyocytes. 97074 Würzburg molecular control of development and dif- These are generated from embryonic stem Tel.: 0931/31-84159 ferentiation processes to uncovering of dis- cells that are differentiated in vitro. Fax: 0931/31-87038 ease mechanisms that are caused by de- E-mail: [email protected] regulation of these pathways. The current Hey genes are also important for embryo- www.ebch.biozentrum.uni-wuerzburg.de focus is on the development of the kidneys nal angiogenetic remodeling and for arteri-

CONTACT DETAILS CONTACT and the cardiovascular system as well as alization of blood vessels. They repress exon childhood kidney cancers, i.e. nephro- pression of the venous regulator Coup-TFII blastomas. These projects are funded by (NR2F2) in the context of the hypoxia re- the DFG (individual grants, GK and SFB), sponse. A lack of Hey1 and Hey2 results in the BMBF and the Wilhelm-Sander-Foun- a lethal angiogenesis defect. Again, in vitro dation. The chair participates in the train- differentiation systems are employed to re- ing of students of Medicine and Dentistry, capitulate these processes and to identify or Biology, Chemistry and Biomedicine. Since to modulate corresponding target genes. fall 2009 the teaching spectrum has been expanded to include the newly established Besides these cardiovascular functions we study program in Biochemistry. could identify first hints for a role of Hey2 in the development of the organ of Corti and for Hey1 in the activation macrophages Major Research and the control of their cytokine production. Interests While Hey2 functions in the inner ear appear to be independent of Notch signaling, Analysis of Hey gene functions the latter is essential in macrophages. This In their function as central transducers of underscores that Hey genes can be activat- Delta/Notch signals, Hey genes control the ed by different stimuli and they likely regu- embryonic development of the cardiovascu- late a multitude of physiological functions, lar and other organ systems. In the develop- as has been expected from their complex ing heart Hey1, Hey2 and HeyL are critical expression patterns in numerous organs. for epithelial-mesenchymal transformation (EMT). This is a prerequisite for the forma- With the fjx1 ligand that is part of the planar tion of precursor cells that are in turn need- cell polarity signaling (PCP), another signal- ed to form the cardiac septum and valves. ing pathway critical of embryonic develop- This could be demonstrated convincing- ment was analyzed. Fjx1 could be shown ly through high resolution magnetic reso- to regulate dendrite growth and extension nance microscopy and in vitro time-lapse in the CNS, but also PCP processes in oth- monitoring of knockout mouse embryos. It er organs. As an example, fjx1 appears to could be shown that Hey2 as well as Hey1/ be causally involved in the formation of kid- HeyL exert similar functions and they exhib- ney cysts. it partial redundancy. Hey1 and Hey2 also appear to participate in the positioning of the atrio-ventricular canal as an organizing Nephroblastomas / Wilms tumors center. Wilms tumors are early childhood kidney cancers that originate from a failure of em-

Fig. 1: The Delta/Notch signaling pathway activates transcription of the Hey genes.

30 Fig. 2: Wilms tumors are often comprised of different cell types and these can initially be seen in cell culture as well.

bryonic precursor cells to fully differentiate. lish and validate a larger set of primary tu- Within the framework of the German Wilms mor cell cultures will help to create an in tumor study we have established a tumor vitro system for preclinical assessment of bank that by now includes more than 800 tumor response to new therapeutics such tumors and corresponding control tissues. as retinoic acid derivatives. These are routinely screened for chromosomal alterations and mutations in known tumor genes like WT1 or CTNNB1 and they Doetzlhofer, A., Basch, M.L., Ohyama, T., Gessler, M., Groves, A.K., and Segil, N. are used to identify novel markers and tar- Teaching (2009). Hey2 regulation by FGF provides a get structures for improved diagnosis and Notch-independent mechanism for main- treatment. The Chairs of Physiological Chemistry I and taining pillar cell fate in the organ of Corti. II and the Chair of Developmental Biochem- Dev Cell 16, 58-69. Gene expression analyses led to the identi- istry offer a broad spectrum of lectures, Hu, X., Chung, A.Y., Wu, I., Foldi, J., Chen, fication of promising and novel tumor mark- seminars and practical courses. A focus is J., Ji, J.D., Tateya, T., Kang, Y.J., Han, J., ers. All known or proposed candidate genes on the theoretical and practical training of Gessler, M., Kageyama, R. and Ivashkiv, were systematically reevaluated in a large more than 400 students of Medicine and L.B. (2008). Integrated regulation of Toll- cohort of more than 200 Wilms tumors. A Dentistry in their curricular subjects Bio- like receptor responses by Notch and interferon-gamma pathways. Immunity 29, number of genes could be identified, whose chemistry and Molecular Biology. In addi- 691-703. expression correlates with the prognosis of tion, 24 students of Biomedicine (B.Sc./ tumors. Moreover, the nature and relevance M.Sc.) are taught in Biochemistry, Molecu- Saburi, S., Hester, I., Fischer, E., Ponto- of changes in WTX were systematically an- lar Biology and Developmental Biology. For glio, M., Eremina, V., Gessler, M., Quag- alyzed in a large tumor collection. Howev- Biology students advanced modules with a gin, S.E., Harrison, R., Mount, R., and McNeill, H. (2008). Loss of Fat4 disrupts er, these data showed that WTX alterations focus on biochemistry and developmental PCP signaling and oriented cell division poorly correlate with clinical data and they biology are offered. Further course units will SELECTED PUBLICATIONS and leads to cystic kidney disease. Nat appear to occur rather late in the course of be offered for the new B.Sc./M.Sc. study Genet 40, 1010-1015. tumor development. program in Biochemistry, which was initi- Wegert, J., Wittmann, S., Leuschner, I., Microarray analysis revealed that tumors ated by the Chairs of Biochemistry (Fac- Geissinger, E., Graf, N., and Gessler, M. which poorly respond to chemotherapy ulty of Chemistry and Pharmacy) and De- (2009). WTX inactivation is a frequent, but treatment are characterized by a decreased velopmental Biochemistry, starting with the late event in Wilms tumors without appar- activity of the retinoic acid signaling path- winter term 2009/10. Additional training ent clinical impact. Genes Chromosomes way. This finding could be substantiated in courses for PhD students are offered with- Cancer 48, 1102-1111. experiments with primary tumor cell cul- in the framework of the research training Wittmann, S., Wunder, C., Zirn, B., Furt- tures. First therapeutic trials of individual group 1048 (Graduiertenkolleg Organogen- wangler, R., Wegert, J., Graf, N., and cases have already been initiated based on ese) and the Graduate School of Life Sci- Gessler, M. (2008). New prognostic mark- these results. Our current efforts to estab- ences (GSLS). ers revealed by evaluation of genes correlated with clinical parameters in Wilms tumors. Genes Chromosomes Cancer 47, 31 386-395. 2.9 Institute for the History of Medicine

Professor Dr. med. Dr. phil. Michael Stolberg Mission Out-Patient Medical Care 1600-1850 (Head) and Structure (M. Stolberg, K. Nolte, S. Schlegelmilch, F. Wiesendanner) Oberer Neubergweg 10a 97074 Würzburg The origins of the Institute for the History In two projects which are part of a German- Tel.: 0931/318-3093 of Medicine date back to the 19th century Swiss-Austrian research network funded E-mail: [email protected] when medical history became an established by the Deutsche Forschungsgemeinschaft www.medizingeschichte.uni-wuerzburg.de part of the medical curriculum in Würzburg. (DFG) and coordinated by M. Stolberg a In the 1920s the University boasted of one physician*s medical practice around 1650 of the first institutes for medical history in and domestic out-patient care provided by Germany under Georg Sticker. The Institute the policlinics in Würzburg and Göttingen

CONTACT DETAILS CONTACT was closed under National-Socialist rule but around 1800 are studied. Work focuses, in revived after 1945. The Institute is housed particular, on the organization of ordinary in a former ONT-clinic generously donated medical practice, the class, age and gen- for the purpose by the late Würzburg pro- der of the patients and the way in which the fessor Horst Wullstein and his wife Sabina. medical theories of the time informed ordi- It occupies additional rooms in the former nary diagnostic and therapeutic practice at Zoology building in the city center. The Insti- the bed-side. tute’s library comprises about 60.000 volumes and ranks among the largest of its kind in the German speaking area. History of Palliative Medicine (M. Stolberg, H. Langrieger, K. Max)

Major Research The long pre-history of modern palliative Interests medicine is virtually unknown. In this DFG- funded project we pursue for the period Research at the Institute focuses on pre- from the 16th to the 20th centuries how modern medicine (ca. 1400-1850). More physicians and nurses dealt with incurable recently, the history of medical ethics and and dying patients and analyze the chang- palliative care from the Middle Ages until to- ing role of hospitals, poor-houses and simi- day has emerged as a second area of spe- lar institutions in the care of such patients. cial interest. A number of research projects are currently undertaken at the Institute or are just about to be concluded. Medical Ethics in Ordinary Medical Practice (M. Stolberg, K. Nolte) Early modern physicians’ correspondence (M. Stolberg, S. Gröne, S. Herde, U. While a fair amount of research has been Schlegelmilch, T. Walter) done on the historical development of the theological and philosophical debates Under the auspices of the Bayerische Akad- about euthanasia and other major ethical emie der Wissenschaften, a work group issues, we know very little, so far, about the for the study of early modern physicians’ way ordinary physicians, nurses, relatives correspondences was established in early and patients dealt with these issues on a 2009. Over the next 15 years, the group day-to-day basis. Work on this project which will undertake a systematic survey of the was orignally funded by the Fritz Thyssen- thousands of letters written by and to 16th- Stiftung has changed established historical and 17th-century physicians in the German knowledge in crucial respects. It has shown, speaking area which have come down to for example, that various means to achieve us in libraries and archives all over Europe. active euthanasia were widely accepted These letters are valuable sources for the among the population across Europe and study of wide range of topics. They reflect, that individual physicians already around for example, professional networks and the 1800 publicly endorsed active euthanasia dissemination of new medical findings and on dying patients, a century earlier than theories but they also provide manifold in- had hitherto been assumed. Analysis of the sights into the mentalities, the professional changing attitudes towards truth-telling in lives and the domestic affairs of the ear- the case of fatal prognosis and towards in- ly modern upper classes in general. From formed consent to painful and risky opera- 2011, detailed summaries of the letters’ tions has shown the crucial importance of contents and, if possible, digital reproduc- changing roles and patterns of interaction tions of the original letters will be made ac- among patients, relatives, physicians, nurs- cessible to the international research comes and priests. munity via OPAC.

32 online-courses in medical terminology are currently being developed. The Institute is also responsible for the course in “History, Theory and Ethics” for medical students in their third year. Furthermore, a wide variety of elective courses and seminars is offered, ranging from Medical English and courses in bibliography and paleography to seminars dealing with specific topics of medico-historical interest. The Institute is also responsible for the teaching of medical history and medical theory at the University of Regens- burg and individual staff members and col- laborators support teaching activities at the Historical Faculty in Würzburg.

Fig. 1: Doctor’s visit (Egbert van Heem- skerk III, ca. 1725).

Cultural History of Uroscopy, 1500- 1850 (M. Stolberg)

Based on printed and manuscript medical writing, court records and letters and auto- biographies written by physicians and patients as well as on visual evidence in early modern painting this project traces the changing fate of uroscopy as the major means of diagnosis from the 16th to the 19th centuries.

Monastic Medicine (J. G. Mayer, R. Windhaber)

This interdisciplinary research group was formed at the Institute several years ago bringing together medical historians and specialists of pharmacology. The group Nolte, K. (2007) Vom Umgang mit unhei- lbar Kranken und Sterbenden in „Krank- works on the history of Western monastic en-Besuchs-Anstalten“ zu Beginn des 19. healing and more generally on the histo- Jahrhunderts. In: Würzburger medizinhisto- ry of medicinal plants in the medieval and rische Mitteilungen 26: 28-52. early modern period. One of its major aims is to preserve this historical knowledge and Nolte, K. (2006) Wege zu einer „Patien- tengeschichte des Sterbens“ 19. Jahr- make it accessible to modern medical prac- hundert. In: BIOS 19/2006, Heft 1, 36- titioners. 51.

Stolberg, M. (2007) Active euthanasia in early modern society. Learned debates and popular practices. In: Social history of medicine 20: 205-221. Teaching Stolberg, M. (2007) „Cura palliativa“. The Institute offers 16 compulsory courses Begriff und Diskussion der palliativen Krankheitsbehandlung in der vormodernen in Medical Terminology and Professional Ori- Medizin (ca. 1500-1850). In: Medizinhis- entation every term, for students of medi- SELECTED PUBLICATIONS torisches Journal 42: 7-29. cine and of dentistry, as well as two medico- historical seminars. In addition, with fund- Stolberg, M (2009) Aktive Sterbehilfe und Eugenik vor 1850. In: Ignacio Czeguhn et ing from the “Virtuelle Hochschule Bayern”, al. (eds): Eugenik und Euthanasie 1850- 1945. Frühformen, Ursachen, Entwicklun- 33 gen, Folgen. Baden-Baden, 9-26. 2.10 Institute of Psychotherapy and Medical Psychology

Professor Dr. med. Dr. phil. Hermann Faller Mission ongoing multi-center study: What is the (acting Head) and Structure prevalence of psychological distress and psychological disorders among cancer pa- Klinikstr. 3 The Institute of Psychotherapy and Medi- tients? What are cancer patients’ needs for 97070 Würzburg cal Psychology was founded in 1958 as the psychosocial support? In this study, pa- Tel.: 0931/31-82713 first of its kind in Germany. Its focus areas tients with various cancer types and in vari- Fax: 0931/31-86080 include research, education, and patient ous treatment stages (acute care, rehabili- E-mail: [email protected] care. The research topics comprise both tation) and settings (in-patient and out-pa- www.psychotherapie.uni-wuerzburg.de psychosocial factors of somatic diseases tient care) are included. and processes involved in coping with illness and rehabilitation. In the area of med-

CONTACT DETAILS CONTACT ical education, the institute is responsible Psychonephrology for the subjects Medical Psychology and So- (S. Neuderth) ciology in the pre-clinical study section and Psychotherapy and Psychosomatic Medi- In cooperation with the Department of In- cine as well as Rehabilitation in the clinical ternal Medicine I (Nephrology), both donors section. For the area of patient care, a psy- and recipients who had been psychological- chotherapeutic out-patient department and ly evaluated before a kidney transplantation consultation-liaison services for the Univer- are followed up with. The various aspects sity Hospital are provided. of the transplantation process, such as decision making, risk-perception and informa- Currently, 4.5 researchers are financed tion status as well as health-related quality through the institute’s budget and anoth- of life, psychological distress, sense of self- er 16 through third-party payers. Several worth, and benefit finding, are evaluated. close clinical and research co-operations with the University Hospital exist. The institute is a member of the Comprehensive Obesity Treatment Cancer Center, the Breast Center and the (M. Schowalter) Center of Cardiovascular Disorders of the University Hospital. Its section of Rehabili- In cooperation with the Obesity Center of tation Sciences coordinates the Rehabilita- the University Hospital of Würzburg, a com- tion Research Network of Bavaria (RFB; see prehensive evaluation of pre- and post-op- Ch. 5.6 Research Networks). erative psychological factors in patients with morbid obesity undergoing bariatric surgery is performed. Furthermore, behavioral cri- Major Research teria of decision making before surgery and Interests a post-surgical after-care program are developed. We evaluate both the success of Psychocardiology this after-care program and the short and (H. Faller) long-term psychosocial outcomes of the surgical treatment. In our research, which is performed in cooperation with the Department of Internal Medicine I (Prof. Angermann, Prof. Ertl), we examine the factors that put patients with chronic heart failure at risk for depression and whether depression itself is a risk factor for heightened mortality (Fig. 1). More- over, we evaluate an intervention for op- timizing disease management, including telephone-based patient education, in regards to mortality, morbidity, re-hospitaliza- tion, and quality of life (INH Study). In another study, the efficacy of pharmacotherapy for depression in reference to mortality of chronic heart failure is examined (MOOD- HF Study).

Psychooncology (H. Faller) Fig. 1: Depression and survival rate of patients with chronic heart failure according The following questions are examined in an to degree of depression.

Teaching

As part of the subjects Medical Psychology and Medical Sociology, the following classes are provided: Lectures, Courses, and In- tegrated Seminars/Seminars with Clinical Aspects. An optional seminar on Research Methods and Evaluation (Evidence-Based Medicine) is also offered. Moreover, the In- stitute takes part in the Integrated Lecture and Integrated Practical Courses of Psychi- atry, Psychosomatics, and Psychotherapy. (Teachings within the cross-sectional subjects are presented under RFB, Ch. 5.6 Re- search Networks).

Fig. 2: Impact of depression on disease-specific quality of life in chronic heart failure patients (Kansas City Cardiomyopathy Questionnaire).

Patient Education Quality Management (H. Faller, H. Vogel, K. Meng, A. Reusch) (H. Vogel, S. Neuderth)

Several research projects aim to advance Quality management programs have been the concepts of education for patients with developed for a large number of institu- chronic diseases, to enhance patient ori- tions. These include quality management entation, to perform a survey on the pres- concepts for medical rehabilitation carried ent state of educational practice, to devel- out by the German Statutory Accident In- op a patient education database, and to surance and for prevention and rehabilita- evaluate the effectiveness of education- tion in mother-child-clinics. Another meth- al programs for various disorders. Specif- od of quality assurance is the development ic strategies are implemented to increase of therapy standards for the rehabilitation the sustainability of education effects and process. In the context of the guideline to transfer newly learned skills to everyday program of the German Statutory Pension life situations. Examples include behavioral Insurance, the institute is responsible for Faller H, Koch GF, Reusch A, Pauli P, All- planning and after-care using modern me- the field of rehabilitation for children and gayer H (2009) Effectiveness of education dia (see also RFB, Ch. 5.6 Research Net- youth. for gastric cancer patients: a controlled works). prospective trial comparing interactive vs. lecture-based programs. Patient Education and Counseling 76:91-98 Quality of Life Measurement Occupational Rehabilitation (H. Faller) Faller H, Störk S, Schuler M, Schowalter (S. Neuderth, H. Vogel) M, Steinbüchel T, Ertl G, Angermann CE (2009) Depression and disease severity A final research focus is on the development as predictors of health-related quality of To increase the rehabilitants’ chance of re- and psychometric evaluation of self-assess- life in patients with chronic heart failure - turning to work, early identification of pa- ment instruments for health-related quality a structural equation modelling approach. tients with occupational impediments and of life. In collaboration with the Department Journal of Cardiac Failure 15:296-292 corresponding occupational treatments are of Internal Medicine I, an innovative tool for Faller H, Steinbüchel T, Störk S, Schowal- necessary. Thus, several projects aim to the assessment of disease-specific quality ter M, Ertl G, Angermann CE (2009) Im- develop screening instruments for occu- of life in chronic heart failure patients has pact of depression on quality of life as- pational impediments, to create a survey been psychometrically validated (Kansas sessment in heart failure. International of the present state of work-related treat- City Cardiomyopathy Questionnaire; Fig. 2). Journal of Cardiology (epub a head of

SELECTED PUBLICATIONS print) ments in rehabilitation and to foster shared In a multi-center study, the Health Educa- decision making regarding treatment selection Impact Questionnaire (heiQ) is being Schowalter M, Benecke A, Lager C, Heim- tion (see also RFB, Ch. 5.6 Research Net- translated and psychometrically evaluated bucher J, Bueter M, Thalheimer A, Fein works). in collaboration with the Medical University M, Richard M, Faller H (2008) Changes in of Hannover. depression following gastric banding operation: a 5 to 7-year prospective study. Obesity Surgery 18:314–320 35 2.11 Institute for Hygiene and Microbiology

Mission monitoring of putative outbreaks of menin- Professor Dr. med. Matthias Frosch and Structure gococci diseases. The institute is part of the (Head) pan-European network of reference centres The main tasks of the Institute for Hygiene “European Monitoring Group on Menin- Josef-Schneider-Str. 2 and Microbiology are the laboratory diagno- gococci”. In cooperation with the Europe- 97080 Würzburg sis of infectious diseases caused by bacte- an Center for Disease Control (ECDC) the Tel.: 0931/201-46160 ria, fungi and parasites, the advice of cli- “Laboratory surveillance and external qual- Fax :0931/201-46445 nicians with respect to diagnosis, therapy ity assurance of invasive bacterial diseases E-mail: [email protected] and prevention of infectious diseases, the in EU“ (IBD-labnet) project is coordinated www.hygiene.uni-wuerzburg.de research on infectious diseases and their by the Institue for Hygiene and Microbiol- www.meningococcus.de causative agents, hospital hygiene as well ogy which focuses on the establishment

CONTACT DETAILS CONTACT www.haemophilus.uni-wuerzburg.de the education of students in medicine, den- of an Eurpean laboratory network for the www.echinococcus.de tistry and related subjects. surveillance of invasive infections caused In addition to the comprehensive range of by Neisseria meningitidis, Streptococcus Professor Dr. rer. nat. Klaus Brehm routinely used diagnostic tools the institute pneumoniae und Haemophilus influenzae. Tel.: 0931/201-46168 also provides special molecular and sero- Moreover, on behalf of the Robert-Koch In- logical test systems. Our commitment to stitute the institute also functions as consil- Professor Dr. med. Dr. rer. nat. Bhanu Sinha patient care also includes the development iary laboratory for Haemophilus influenzae Tel.: 0931/201-46949 of strategies for the prevention of hospital and echinococcosis, employing special di- infections and the monitoring of hospital hy- agnostic tests and providing advice on di- Professor Dr. med. Ulrich Vogel giene. Annually approximately 85.000 mi- agnosis, therapy, prevention and epidemi- Tel.: 0931/201-46802 crobiological analyses are performed. The ology. research activity of the institute mainly focuses on the elucidation of the molecular mechanisms in the pathogenesis of infec- Major Research tious diseases. Using tools from molecular Interests genetics, cell biology, immunology and genome research the pathogenicity of bacte- Infection biology of meningococcal dis- ria, fungi and parasites is investigated and ease novel strategies for the diagnosis, therapy (A. Schubert-Unkmeir, O. Kurzai, M. and prevention of infectious diseases are Frosch) developed. At the institute the Robert-Koch-Institute Meningococci, an important cause of sep- established the national reference centre ticemia and meningitis in infants and ado- for meningococci (NRZM). The activities of lescents, are in the focus of research on the NRZM include the molecular typing of infection biology. The molecular basis of meningococci, an advisory service in case transmission across specialized endothelial management and the counselling of public cells underlining the blood-brain barrier is a health departments in the epidemiological major point of interest in our research. The

Fig. 1: Aggregate of Echinococcus multilocularis totipotent stem cells forming a parasite liver vesicle in vitro.

36 group works on the analyses of bacterial dents of medicine, dentistry, biomedicine, factors as well as host cell receptors, which pharmacy and food chemistry. Scientists at determine the interaction, and the charac- the institutes participated in the organiza- terization of a transcriptional regulator in- tion of several scientific and medical meet- volved in bacterial cell interaction. ings.

Population biology and biofilm formation of meningococci (U. Vogel, H. Claus)

The population biology of N. meningitidis Fig. 2: Human brain microvascular endo- and its spread among human hosts is an- thelial cells incubated with MitoTracker alyzed by bacterial finetyping. To study the Red CMXRos to label the mitochondria. Af- molecular mechanisms effective during as- ter fixation and permeabilization, the cells ymptomatic colonization of the nasophar- were stained with Alexa Fluor 488 phalloi- ynx, a biofilm model is applied. Further- din to label the filamentous actin (F-actin) more, the group works on the impact of the and finally counterstained with DAPI to la- capsular polysaccharide and its biochemi- bel the nucleus. cal modifications, since this surface structure is believed not only to support invasive tergents is analyzed. disease, but also to have a pivotal role in host-to-host transmission. Immune-response against fungal pathogens Genome research on pathogenic bac- (O. Kurzai) teria (C. Schoen, M. Frosch) Fungal infections are an increasing threat for immunocompromised patients. By char- Genomics of meningococci is another main acterizing the molecular basis of interaction research focus of the institute. The com- between Candida albicans and Aspergillus Claus, H., Stummeyer, K., Batzilla, J., parison of the genomes from pathogen- fumigatus and the innate immune system Mühlenhoff, M., Vogel, U. (2009). Amino ic as well as from non-pathogenic strains we try to identify correlates of protective im- acid 310 determines the donor substrate provides insights into the genetic basis of munity and possible ways for adjuvant im- specificity of serogroup W-135 and Y cap- the observed differences in the pathogenic mune therapy. sule polymerases of Neisseria meningiti- phenotypes and the evolution of pathogenic dis. Mol. Microbiol., 71: 960-71. strains. Whole-genome sequences are also Gelmedin, V., Caballero-Gamiz, R., and required for the construction of DNA micro- Fox-tapeworm and alveolar echinococ- Brehm, K. (2008). Characterization and arrays which allow for a genome-wide anal- cosis inhibition of a p38-like mitogen-activated ysis of gene regulation and genome varia- (K. Brehm) protein kinase (MAPK) from Echinococ- cus multilocularis: antiparasitic activities of tion. p38 MAPK inhibitors. Biochem. Pharma- Alveolar echinococcosis is a life-threatening col., 76: 1068-1081. parasitosis in humans causing destruction Host cell interaction with Staphylococ- of liver tissue by the tapeworm larva. We Hussain M, Schäfer D, Juuti KM, Peters G, cus aureus have shown that cells of this parasite make Haslinger-Löffler B, Kuusela PI, Sinha B. (2009) Expression of Pls (plasmin sensi- (B. Sinha) use of hormone based communication sys- tive) in Staphylococcus aureus negative for tems which are closely related to cell-cell pls reduces adherence and cellular inva-

Staphylococcus aureus is one of the most communication systems of the host. The SELECTED PUBLICATIONS sion and acts by steric hindrance. J Infect common causes of bacterial infection in hu- possibility of cross-communication between Dis. 200: 107-117. mans. Despite this, a high proportion of the the parasite and the host, which could be Schielke, S., Huebner, Spatz, C., Nägele, healthy population is colonized without suf- one reason for the long persistence of tape- V., Ackermann, N., Frosch, M., Kurzai, O., fering from infection. To understand this in- worm infections and their modulation of and Schubert-Unkmeir, A. (2009). Expres- teraction we characterize the interplay be- human immune responses is in the focus sion of the meningococcal adhesion NadA tween S. aureus and host cells. We have of current research. In genome- and pro- is controlled by a transcriptional regulator of the MarR-familiy. Mol. Microbiol., shown that S. aureus is able to invade host teome-based approaches parasite specific 72:1054-1067, cells and persist intracellularly during infec- factors suited as targets for anti-infective tion. Invasion of host cells involves a phago- therapy are identified. Schoen, C., Blom, B., Claus, H., Sch- cytosis related process. The maturation of ramm-Glück, A., Brandt, P., Müller, T.,Goesmann, A., Joseph, B., Konietzny, S. aureus containing phagosomes and a S.,Kurzai, O., Schmitt, C., Friedrich, T., possible correlation between invasive po- Linke, B., Vogel, U., Frosch, M. (2008). tential and virulence are in the focus of cur- Teaching Whole genome comparison of disease and rent research. In addition, the response of carriage strains provides insights into viru- S. aureus to contact with biocides and de- Student’s courses are organised for stu- lence evolution in Neisseria meningitidis. Proc. Natl. Acad. Sci. U.S.A., 105: 3473- 34788. 37 2.12 Institute of Virology and Immunobiology, Chair of Virology

Professor Dr. med. Axel Rethwilm Mission of the infectious agent and the resulting (Head) and Structure prion-induced neurodegeneration are analyzed within various projects Versbacher Str. 7 Research within the Chair of Virology is fo- 97078 Würzburg cused on the analysis of the regulation of Tel.: 0931/201-49554 viral replication and gene expression, com- Pathogenesis of Pneumoviruses Fax: 0931/201-49553 plex investigations of the pathogenesis of (C. Krempl) E-mail: [email protected] viruses, research into the sensitivity to an- www.virologie.uni-wuerzburg.de/ tivirals and the development of viral vectors Respiratory Syncytial virus (RSV) is a major towards gene therapy. The Chair of Virology viral cause of serious lower respiratory tract Professor Dr. med. Michael Klein is also responsible for the provision of vi- disease in the pediatric world, in the elderly CONTACT DETAILS CONTACT Tel.: 0931/201-49164 rus diagnostics to the University Hospital. and in severely immunocompromised pa- We host approx. 65 scientists and work in tients. However, our understanding of the close cooperation with the Chair of Immu- pathogenicity mechanisms of RSV-infection nology at our Institute as well as the Centre is still fragmentory. We use infection of mice for Infectious Diseases, a number of Ba- with molecular cloned and closely related sic Research Programmes (SFBs), Gradu- pneumonia virus of mice (PVM) that causes ate Schools and the Interdisciplinary Cen- symptoms similar to those induced by RSV- tre for Clinical Research. In addition, Axel infection of humans, as surrogate model. Rethwilm is speaker of the International Re- The goal is to contribute to a better under- search Training Group 1522 that was estab- standing of the mechanism of RSV-induced lished by the DFG as a joint research and disease and to develop rationally-designed educational project between Würzburg Uni- molecules. versity and Universities in Cape Town (South Africa). Model systems for virus uptake and mechanisms of virus spread Major Research (J. Schneider-Schaulies) Interests We investigate the mechanisms of virus Molecular mechanism of measles virus spread and the possibilities of blocking the (MV) induced immunosuppression spread in various model systems. In the fo- (S. Schneider-Schaulies) cus of interest are uptake and spread of measles virus, which is accompanied by A generalised suppression of cellular immu- a persisting CNS infection. We have de- nity is induced in the course of the acute veloped a mouse model with molecular- disease and almost exclusively accounts for ly cloned MV to test antiviral strategies in- the continuously high rates of measles as- cluding siRNA technology. Similar test sys- sociated morbidity and mortality. Most like- tems to identify inhibitors of virus uptake ly, the virus accesses secondary lymphat- and spread are being developed for Nipah- ic tissues by using dendritic cells (DCs) as and Dengueviruses. Trojan horses. Infection of which is mediated by surface expression of the MV entry receptor CD150 and DC-SIGN. It appears Molecular Biology of Foamy Viruses that MV impairs DC function to stimulate T- (J. Bodem, A. Rethwilm) cells via action of their glycoprotein using a complex signaling pathway. Retroviruses are divided into the orthoretro- viruses and the foamyviruses. Major differences in the replication strategies of both Neuroimmunology and Neurodegenera- subfamilies were responsible for this dis- tion of Prion Diseases tinction. We investigate these differences (M. Klein) on the transcriptional, post-transcriptional, and translational level Prion diseases are infectious neurodegenerative diseases, which affect both animals and humans. During disease progression, Development of Foamy Virus Vectors for PrPSc, an abnormal, detergent-insoluble Gene Therapy isoform of the host encoded cellular prion (C. Scheller, T. Wiktorowicz, A. Rethwilm) protein (PrPC) accumulates within infected tissues. The exact mechanisms of neuro- The benign character of natural foamy vi- invasion into the brain from the lymphoid rus infections and a variety of other favour- system, the role and function of PrPC, and able features has led to the development of the molecular aspects of axonal transport foamy virus-vectors for somatic gene ther-

38 apy. Such vectors for efficient transduction Development of new screening plat- of mesenchymal and haematopoietic stem forms to identify antiviral compounds cells are under development and are being (M. Kirschner, A. Rethwilm) applied in an animal model for rheumatoid arthritis. Inhibiting the interaction of the human cyti- din-deaminase Apobec3G (hA3G) with the HIV-1 specific viral infectivity factor (Vif) rep- CNS Gene Transfer resents a novel therapeutic approach where (E. Koutsilieri, C. Scheller, M. Klein, A. Reth- a cellular factor with potent antiviral activity wilm) (hA3G) plays a key role. In HIV-infected cells the interaction of Vif with hA3G leads to the M. Alzheimer and M. Parkinson are in the subsequent degradation of hA3G. We engi- center of our interest. AAV-vectors and neered a double transgenic cell line consti- siRNA technology (M. Alzheimer) as well tutively expressing an EYFP-hA3G fusion as as foamy virus-vectors (M. Parkinson) are well as Tet-Off controllable Vif protein as a being used to develop genetic strategies stable and convenient cellular testing plat- against these diseases. form for a high throughput screening of antiviral compound libraries.

Pathogenesis of HIV dementia (E. Koutsilieri, C. Scheller) Clinical Virology (B. Weißbrich, J. Schubert) HIV dementia is probably a result of an initial microglial activation in CNS, production 30-35 thousand clinical samples are proof inflammatory mediators with subsequent cessed in our Clinical Unit each year. Fur- direct cytocidal effect on non-infected neu- thermore, a variety of clinical virological rons. The pathogenesis of the disease is questions are being addressed. For in- studied in HIV patients from Germany and stance, in cooperation with the children’s Africa. Several factors that might be associ- hospital of the university clinic, recently ated with pathogenesis of HIV dementia are discovered respiratory viruses, such as the studied in greater detail, such as NMDA- 2005 discovered human bocavirus, are be- Receptor architecture, immune activation ing studied. and the subtype of the underlying HIV-infection.

Ermolayev, V., T. Cathomen, J. Merk, M. Pathogenesis of HIV-AIDS Teaching Friedrich, W. Hartig, G. S. Harms, M. A. (C. Scheller, E. Koutsilieri, A. Rethwilm) Klein, and E. Flechsig. 2009. Impaired ax- The Chair of Virology teaches students in onal transport in motor neurons correlates The pathogenesis of AIDS is driven by a Medicine, Biomedicine and Biology. with clinical prion disease. PLoS Pathog 5: chronic immune activation that eventual- e1000558. ly leads to the exhaustion of the regenera- Gärtner, K., T. Wiktorowicz, J. Park, A. tive capacities of the immune system. In Mergia, A. Rethwilm, and C. Scheller. this project the effects of low-dose immu- 2009. Accuracy estimation of foamy virus nosuppressives on disease progression are genome copying. Retrovirology 6:32. studied in a German HIV cohort and in pa- Gassert, E., E. Avota, H. Harms, G. tients who participate in a clinical study in Krohne, E. Gulbins, and S. Schneider- Tanzania. Schaulies. 2009. Induction of membrane ceramides: a novel strategy to interfere with T lymphocyte cytoskeletal reorgani- sation in viral immunosuppression. PLoS Lentiviral reportergen vectors for the Pathog 5:e1000623. detection and isolation of tumor stem

cells SELECTED PUBLICATIONS Singethan, K., N. Muller, S. Schubert, D. (M. Kirschner, A. Rethwilm) Luttge, D. N. Krementsov, S. R. Khurana, G. Krohne, S. Schneider-Schaulies, M. Thali, and J. Schneider-Schaulies. 2008. Using lentiviral-vectors and a histone-based CD9 clustering and formation of microvilli fusion protein, we developed a reporter to zippers between contacting cells regulates detect and isolate slow cycling, label retain- virus-induced cell fusion. Traffic 9:924-35. ing cells with stem cell properties. With this Nowotny, B., T. Schneider, G. Pradel, system we will be able to detect and iso- T.Schirmeister, A. Rethwilm, M. Kirsch- late label-retaining cells (LRC) with stem ner. 2010. Inducible APOBEC3G-Vif dou- cell properties (tumor stem cells) in vivo as ble stable cell line as a high-throughput well as in vitro. screening platform to identify antiviral compounds. Antimicrob Agents Chemother 54:78-87. 39 2.13 Institute of Virology and Immunobiology, Chair of Immunology

Professor Dr. rer. nat. Thomas Hünig Mission selectively destroy these cells with „killer“ (Head) and Structure CD8 T-cells in mice, in using MS-like lesions. We are using this system to explore Versbacherstr. 7 novel therapeutic approaches. 97078 Würzburg The individual research groups are interest- Tel.: 0931/201-49951 ed in basic and applied immunological top- Fax: 0931/201-49243 ics. These include the regulation of B cell The role of CD28 for the development E-mail: [email protected] apoptosis, suppressor mechanisms of regu- and persistence of Multiple Myeloma www.virologie.uni-wuerzburg.de/ latory T cells and myeloid-derived suppres- (I. Berberich and T. Hünig) sor cells, antigen recognition by NKT cells Professor Dr. rer. nat. Thomas Herrmann and tolerance induction by dendritic cells. CD28, which normally is expressed by T- CONTACT DETAILS CONTACT Tel.: 0931/201-49955 Many of the results from basic research lymphocytes, is also found in the final stage are then translated into preclinical therapy of B-cell differentiation, the plasma cell, Professor Dr. rer. nat. Manfred Lutz models for allergies, autoimmune diseases, and on the malignant myeloma cells de- Tel.: 0931/201-49957 transplant rejection and graft-versus-host- rived from this cell type. Since in humans, disease. Our research is supported by lo- this expression correlates with an unfavour- cal and international funding and support- able prognosis, we are studying the role of ed by various cooperations within Germany CD28 expression on myeloma cells in vitro and abroad. The institute also provides im- and in a mouse model. munodiagnostic analyses for autoantibodies from patients from the University Clinic (head PD Dr. T. Kerkau). T-cell activation by non-conventional T- cells (T. Herrmann) Major Research Interests Most T cells recognize with their antigen receptor complexes of MHC molecules and Function of the costimulatory receptor peptide-antigens. Moreover, „non-conven- CD28 tional antigens“ such as glycolipids and (T. Hünig) „phosphoantigens“ exist. The Herrmann group studies - preferentially in the rat – CD28 is a central regulator of T-cell re- the glycolipid-presenting molecule CD1d, sponses. Using conditionally CD28 delet- CD1d-restricted NKT cells and a „new“ MHC ing mice and blocking as well as stimulat- class II molecule (RT1Db2). Moreover, hu- ing CD28-specific monoclonal antibodies, man Vγ9Vδ2 T cells are investigated. These we study the contribution of this receptor cells recognize so called „phosphoantigens“ to the function of the immune system. and shall be used to fight tumors.

The response of human T-cells to the Tolerance induction by dendritic cells CD28 superagonist TGN1412 (M. Lutz) (T. Hünig) The generation of dendritic cells (DC) from Stimulatory CD28-specific monoclonal an- bone marrow progenitor cells and the ac- tibodies had proven therapeutically effec- tivation of their tolerogenic functions rep- tive in animal models against autoimmunity resent the major topics investigated with and inflammation. In contrast, the first-in- this cell type. Recent data showed that the man study of the human CD28 superago- expression of so-called co-inhibitory mole- nist TGN1412 led to a life-threatening re- cules by DC plays an important role for their lease of inflammatory cytokines. We are in- tolerogenicity. The expression of the co-investigating why animal and tissue culture hibitor B7-H1 on tolerogenic DC is required experiments did not predict this and work to control conventional T cells but also un- on the establishment of new preclinical test conventional type II NKT cells that recognize systems. glycolipid antigens on CD1d molecules.

CD8 T-cell-mediated autoimmunity in Immunosuppression by myeloid sup- mouse model of Multiple Sclerosis pressor cells (T. Hünig) (M. Lutz)

Through transgenic expression of a cytosolic Our latest investigations with myeloid-de- model antigen in oligodendrocytes, which rived suppressor cells (MDSC) in the murine form the myelin sheath of axons, we can system show that myeloid progenitor cells

40 Fig. 1: Suppression of immune responses by regulatory T cells in vivo. Different fluorescence-marked cell types were injected intrave- nously into mice and the development of cell clusters in the spleen was analysed. Antigen-loaded mature dendritic cells (blue) form clusters with CD4+ CD25- effector-T-cells (green) as a sign of their activationa and proliferation in the presence of CD4+ CD25+ resting regulatory T cells (red) (A). In contrast, activated regulatory T-cells inhibit clustering of dendritic ells with effector T-cells as a sign of their suppressor activity (B). Photographs Dr. Jens Hänig. can differentiate under steady state con- els of multiple sclerosis, we are particular- ditions to neutrophils, macrophages and ly interested in the development of novel dendritic cells or after activation by bacte- strategies for the treatment of Graft-versus- rial pathogenic factors (LPS) plus interfer- host-disease, a major complication after al- on-γ into suppressive MDSC. As a typical logeneic bone marrow transplantation. In marker for MDSC the Gr-1 antibody is used. case of GvHD, regulatory T cells have been Detailed analyses with it showed that the shown to modulate disease activity, but in antibody can mediate apoptosis of differ- most cases they are not powerful enough entiated neutrophils but also via phosphor- to prevent the disease. Therefore, novel ylation of STAT molecules the myelopoiesis monoclonal antibodies, which are able to into macrophages. activate regulatory T cells and/or to make pathogenic T cells more susceptible to sup- Beyersdorf, N., Ding, X., Hunig, T. and pression by regulatory T cells are now being Kerkau, T. Superagonistic CD28 stimu- B cell maturation assessed for their potential to keep GvHD lation of allogeneic T cells protects from (I. Berberich) in check. acute graft versus host disease. Blood 2009. B cells recognize microbes and foreign sub- Na, S.Y., Eujen, H., Gobel, K., Meuth, stances (antigens) invading an organism. S.G., Martens, K., Wiendl, H. and Hunig, After contact with antigens, B cells prolif- Teaching T. Antigen-specific blockade of lethal CD8 erate and differentiate to antibody-produc- T-cell mediated autoimmunity in a mouse ing „factories“. The proteins Blimp-1 and C/ Various theoretical and practical courses model of multiple sclerosis. J Immunol 182, 6569-75, 2009. EBPβ drive the maturation. So-called Bcl-2 are provided to students. These include ba- proteins allow the cells to survive this pro- sic immunology lectures for medical, bio- Herold, M.J., J. Zeitz, C. Pelzer, C. Kraus, cess. Currently, we analyse the function of medical and biology students, which are A. Peters, G. Wohlleben, and I. Berber- C/EBPβ and of the Bcl-2 protein A1/Bfl1 in complemented by a series of seminars for ich (2006) The Stability and Anti-apoptotic B cells in vivo and in vitro. advanced students together with practical Function of A1 Are Controlled by Its C Ter- minus. J. Biol. Chem. 281:13663-13671. courses of 8 weeks per year. Li, J., M.J. Herold, B. Kimmel, I. Müller, B.

Regulation of misguided immune reac- SELECTED PUBLICATIONS Rincon-Orozco, V. Kunzmann, T. Herrmann tions (2009) Reduced expression of the meval- onate pathway enzyme farnesyl pyrophos- (PD Dr. T. Kerkau, Dr. N. Beyersdorf) phate synthase unveils recognition of tumor cells by Vgamma9Vdelta2 T cells. The team is working on the significance J Immunol 182:8118-24. and therapeutic manipulation of regulatory T cells in the context of pathological im- Greifenberg, V., E. Ribechini E., S. Rößner, M.B. Lutz (2009) Myeloid-derived sup- mune reactions. In addition to animal mod- pressor cell activation by combined LPS and IFN-γ treatment impairs DC develop- 41 ment Eur. J. Immunol. 39: 2865–2876. 2.14 Institute for Molecular Infection Biology

Mission mensal relatives, additional DNA regions, Professor Dr. rer. nat. Jörg Vogel and Structure i.e. the so-called Pathogenicity- or Genom- (Head) ic Islands. The group characterizes process- The Institute for Molecular Infection Biology es involved in genetic diversity and genome Josef-Schneider-Str. 2 (IMIB) was founded in 1993 as an interdis- optimization of pathogenic and commensal 97080 Würzburg ciplinary institution at the Medical Faculty enterobacteria. The structure, function and Tel.: 0931-31-82575 of the University of Würzburg and is a part distribution of virulence-associated genes Fax: 0931-31-82578 of the „Research Center for Infectious Dis- as well as the regulation of gene expres- E-mail: [email protected] eases“. Traditionally, the chairman is also sion are studied. Furthermore, we aim at www.uni-wuerzburg.de/infektionsbiologie a member of the Faculty of Biology, thus the functional characterization of novel vir- IMIB constitutes a link between the Facul- ulence-associated genes of pathogenic en-

CONTACT DETAILS CONTACT Professor Dr. rer. nat. Dr. med. habil. ties of Medicine and Biology. The institute terobacteria. Heidrun Moll is closely associated with the young investi- Tel.: 0931-31-82627 gator groups of the Research Center for In- fectious Diseases. The research of the insti- Enterobacterial adhesins/ invasins and Professor Dr. rer. nat. Joachim Morschhäuser tute aims to elucidate fundamental aspects countermeasures Tel.: 0931-31-82152 of infection processes. We study molecular (T. Ölschläger) aspects of infections caused by a variety of bacteria, parasites and fungi, and the bio- Special attention is paid to the analysis of logical function of small non-coding RNAs invasion and adherence of pathogenic en- in pro- and eukaryotes. Additionally, the in- terobacteria. The research group aims at teractions between parasitic pathogens and the specific interference of adhesin-medi- the host immune system are investigated. ated host-pathogen interaction. Besides mechanisms of molecular pathogenicity, the use of probiotics in order to counteract Main Research bacterial infection is investigated using pro- Interests biotic E. coli strain Nissle 1917 as a model organism. The main interest of the working groups of the institute is the analysis of the mechanisms that allow pathogens to trigger in- Immunological and cell biological stud- fections. Furthermore, the host immune re- ies on the pathogenicity of Leishmania sponse to pathogens is studied. In addition parasites to bioinformatics, microbiological, molec- (H. Moll) ular and cell biological methods, genomic (genome analysis) and proteomic (protein Leishmania cause a spectrum of different expression analysis) approaches are ap- diseases, depending on the parasite spe- plied within the following projects: cies and the type of the host’s immune response. This model allows the analysis of the mechanisms involved in host resis- RNA biology tance or susceptibility to a microbial patho- (J. Vogel) gen. The development of new strategies for immunotherapy and vaccination based on Small, noncoding RNAs (sRNAs) as regu- the use of dendritic cells and the identifica- lators of gene expression in both prokary- tion and characterization of leishmanicidal otes and eukaryotes have attracted much compounds are the major research topics attention over the last few years. We use of this group. biochemical, genetic and biocomputational approaches to characterize bacterial sRNA functions, particularly with respect to host- Biology and Pathogenicity of Candida pathogen interactions of Salmonella and albicans Helicobacter species. Furthermore, we (J. Morschhäuser) study the biological role of small RNAs induced in eukaryotes in response to a bac- The group studies virulence mechanisms of terial infection. the pathogenic yeast Candida albicans and the molecular basis of antimycotic drug resistance in this fungus. For this purpose, Virulence mechanisms and genome di- the signals, signal transduction pathways versity of enterobacteria and transcription factors that control mor- (U. Dobrindt) phogenesis, virulence gene expression and antifungal drug resistance in C. albicans are Pathogenic enterobacteria possess, in con- analyzed. trast to many of their non-pathogenic com-

42 Fig. 1: Bioluminescent Staphylococcus aureus strain Xen29 in an abscess infection model (top) and quantification of bioluminescent signals and determination of colony forming units (CFU) (bottom center).

Virulence- and resistance mechanisms of pathogenic staphylococci (K. Ohlsen)

Staphylococci are among the most important nosocomical pathogens. The ability of these pathogens to form biofilms and to develop antibiotic resistance is intensively studied in this group. The gene expression of these pathogens is studied under conditions that mimic the host by the use of in vivo-infection models. These studies also include methods of functional and comparative genomics and proteomics. Pfeiffer, V., Papenfort, K., Lucchini, S., Hinton, J.C., Vogel, J. (2009) Coding se- Teaching quence targeting by MicC RNA reveals bacterial mRNA silencing downstream of activity translational initiation. Nature Structural and Molecular Biology. 16:840-846. A considerable part of the teaching activities contribute to the training of biology stu- Ramírez-Zavala, B., Reuß, O., Park, Y. N., dents in the Department of Microbiology. Ohlsen, K., Morschhäuser, J. (2008) En- vironmental induction of white-opaque These activities include lectures in general switching in Candida albicans. PLoS Pat- microbiology, on issues of pathogenicity and hog. 4:e1000089. immunology, as well as seminars on current topics of Infection Biology and courses and Remer KA, Bartrow M, Roeger B, Moll H, Sonnenborn U, Oelschlaeger TA. 2009. internships. Some of these events are also Split immune response after oral vaccina- part of the curriculum of the Biomedical tion of mice with recombinant Escherichia Education. The institute organizes lectures, coli Nissle 1917 expressing fimbrial adhe- courses, seminars and summer schools for sin K88. Int J Med Microbiol. 299:467- the members of the Graduate College „In- 478. SELECTED PUBLICATIONS fectiology“ in association with the Interna- Ponte-Sucre, A., Gulder, T., Wegehaupt, tional Graduate School “Life Sciences” at A., Albert, C., Rikanovi, C., Schaeflein, the University of Würzburg. L., Frank, A., Schultheis, M., Unger, M., Holzgrabe, U., Bringmann, G., Moll. H.. (2009) Structure-activity relationship and studies on the molecular mechanism of leishmanicidal N,C-coupled arylisoquino- linium salts. J Med Chem 52:626-636.

Putze J, Hennequin C, Nougayrède JP, Zhang W, Homburg S, Karch H, Bringer MA, Fayolle C, Carniel E, Rabsch W, Oel- schlaeger TA, Oswald E, Forestier C, Hack- er J, Dobrindt U. (2009) Genetic structure and distribution of the colibactin genomic island among members of the family En- terobacteriaceae. Infect Immun. 77:4696- 43 4703. 2.15 Institute of Pharmacology and Toxicology, Chair of Toxicology

Mission Chemical Carcinogenesis Professor Dr. rer. nat. Helga Stopper and Structure (acting Head) Our research focuses on elucidating the The departments of Pharmacology (chaired first-line interactions of mutagenic and car- Versbacher Str. 9 by Prof.Dr. Martin J. Lohse), and Toxicolo- cinogenic chemicals with biological targets, 97078 Würzburg gy constitute the Institute of Pharmacolo- with the aim of a mechanistically supported Tel.: 0931/201-48427 gy and Toxicology. The building accommo- risk characterization of chemically induced Fax: 0931/201-48446 dates the research laboratories and offices, cancer in humans. We investigate the ki- E-mail: [email protected] a lecture hall seating 300 students, course netics and metabolism of chemicals in vi- www.toxikologie.uni-wuerzburg.de laboratories, a seminar room, and a library tro, in cells, animals and humans, paying for pharmacology and toxicology. Facilities special attention to the metabolic activation

CONTACT DETAILS CONTACT Professor Dr. sc. techn. Werner Lutz for animal husbandry, work with high levels to chemically reactive intermediates, their (Head until 31. 3. 2009) of radioactive isotopes, a repair shop, and interaction with biological macromolecules computer facilities for medical students are such as DNA and protein, and their detox- Professor Dr. med. Gilbert Schönfelder also available. ification. We study genotoxicity by analyz- Tel.: 0931/201-48777 ing covalent DNA binding, induction of other The workforce of the department of Toxicol- types of DNA damage (see Figures) and the ogy comprises between 50 and 60 mem- course of events leading to mutations. Epi- bers. Six research groups are led by the Uni- genetic mechanisms include hormonal ef- versity Professors Dr. Helga Stopper, Dr. Gil- fects, changes in the cell cycle and distur- bert Schönfelder, the Associate Professors bance of cell differentiation. Dr. Erwin Eder and Dr. Wolfgang Dekant, the Research Associates PD Dr. Angela Mally and Dr. Nicole Schupp and the former head Biomarkers of toxicology Prof. Dr. Werner K. Lutz (until spring 2009). Three postdocs and on av- A second research focus are biomarkers in erage 18 Ph.D. students with degrees in both animals and humans. Biomarkers of chemistry, food chemistry, biology, phar- exposure are based mainly on the analy- macy, and medicine accomplish the experi- sis of metabolites in urine and on cytoge- mental work, supported by about an equal netic alterations, for example in peripher- number of technicians. al lymphocytes and buccal mucosa cells in humans. In animal models, early cytological alterations are also investigated in the Major Research search of early biomarkers of toxicity and Interests carcinogenicity in kidney and liver, including idiosyncratic reactions. Biomarkers of indi- Most of our research is funded by grants. vidual susceptibility are studied in connec- We rank on a top position among the Ba- tion with side effects of radiotherapy and varian Toxicological Departments in this re- differences in metabolism due to genetic spect. This is also reflected by the number polymorphisms or inhibition of enzymes in- of publications in refereed journals reaching volved in resorption, metabolism and excre- on average 20 per year. tion.

Fig. 1: “The Comet Assay”: DNA fragments induced by a genotoxic agent migrate in an electric field out of the cell nucleus (Head) into a Tail.

Teaching

Our staff covers all aspects of toxicology and shares the responsibility with the Pharma- cology Department for teaching general and systematic pharmacology for students of medicine and biomedicine, pharmacy, dentistry, and biology. For chemistry students, a special course meets the legal requirements according to the “Gefahrstoffverord- nung” to allow graduates to do business in chemical manufacture and sale. Prof. Stop- per is speaker of the class “Biomedicine” of the Graduate School of the University. Fig. 2: “The Micronucleus Test”: Chromo- The working group leaders contribute to the some damage is indicated by the presence postgraduate courses organized by the So- of a DNA-containing fragment in the cyto- ciety of Toxicology of the DGPT to register as plasm of the bi-nucleated cell in the mid- DGPT and EUROTOX-certified Toxicologist. dle of the three cells. The institute offers advanced education for the degree of Pharmacist for Toxicology and Ecology. Editing and reviewing for scientific journals, membership in national and inter- Risk Assessment national scientific committees and consulting of political and governmental bodies is Knowledge on the mode of toxic action is another part of our activities in the field. For a prerequisite for biologically based extrap- the chemical and pharmaceutical industry, olation from cells in culture or laboratory we offer both theoretical and experimental animals to humans, from high dose to low expertise for cooperations. dose, and from the reproducible situation of experimental systems to the heterogeneity of a human population. Efforts on dose- response relationships and mixture effects are based on experimental data but include elaborate statistical analysis as well as kinetic modeling. Schmid, U., Stopper, H., Schweda, F., Queisser, N., Schupp, N. (2008) Angioten- sin II induces DNA damage in the kidney. Investigated Compounds Cancer Res. 68(22):9239-9246.

The list of investigated compounds com- Walitza, S., Kämpf, K., Artamonov, N., prises a variety of chemical classes and Romanos, M., Gnana Oli, R., Wirth, S., Warnke, A., Gerlach, M., Stopper, sources. Exposure at the work place and H. (2009) No elevated genomic dam- in the environment include aromatic hy- age in children and adolescents with at- drocarbons and substituted derivatives, as tention deficit/hyperactivity disorder af- well as chlorinated and fluorinated chem- ter methylphenidate therapy. Toxicol Lett. 184(1):38-43. icals. Dietary exposure includes mycotox- ins (ochratoxin A, fumonisin B1), heat-de- Lutz, W.K. (2009) The Viracept (nel- rived products (acrylamide, furan), migrants finavir)–ethyl methanesulfonate case: a from polymers, phytoestrogens, as well as threshold risk assessment for human ex- different types of fat and their (per)oxidation posure to a genotoxic drug contamination. Toxicol. Lett. 190: 239-242. products. For drugs, we focus on agents

for which the probability of side effects is SELECTED PUBLICATIONS Adler, M., Muller, K., Rached, E., Dekant, modulated by pharmacogenetic differences W. and Mally, A. (2009) Modulation of key and/or enzyme inhibition. Compounds with regulators of mitosis linked to chromosomal instability is an early event in ochra- estrogenic and antiestrogenic activity are toxin A carcinogenicity. Carcinogenesis 30, used primarily in connection with the inves- 711-719. tigation of epigenetic effects. Endogenous and unavoidable DNA-damaging agents Delatour, T., Mally, A., Richoz, J., Ozden, and processes that contribute to “sponta- S., Dekant, W., Ihmels, H., Otto, D., Gas- parutto, D., Marin-Kuan, M., Schilter, B. neous” tumor formation are also of interest. and Cavin, C. (2008) Absence of 2‘-de- Oxidative stress is considered a major factor oxyguanosine-carbon 8-bound ochratoxin in this respect. A adduct in rat kidney DNA monitored by isotope dilution LC-MS/MS. Mol Nutr Food Res 52, 472-482. 45 2.16 Institute of Pharmacology and Toxicology, Chair of Pharmacology

Mission portantly receptors for adrenaline and nor- Professor Dr. med. Martin J. Lohse and Structure adrenaline and for parathyroid hormone. (Head) In the past few years we have developed The Institute of Pharmacology and Toxicol- a variety of techniques to visualize recep- Versbacher St. 9 ogy comprises Chairs for Pharmacology tor activation and inactivation with the aid 97078 Würzburg (Prof. Lohse) and for Toxicology (Prof. Lutz). of new sensors and fluorescence microsco- Tel.: 0931/201-48400 The institute also houses research groups of py methods. This permits the direct study Fax: 0931/201-48539 the Rudolf Virchow Center that was funded of receptors and signaling mechanisms „at E-mail: [email protected] in 2001 and is chaired by Prof. Lohse. work“, and the analysis of the speed and lo- www.pharmakologie.uni-wuerzburg.de The chair comprises a total of 75 people, calization of cellular signals. We have shown 40 of whom are paid from grants. All re- extremely rapid (50 ms) activation of recep-

CONTACT DETAILS CONTACT Professor Dr. rer. nat. Antje Gohla search groups are devoted to the investi- tors and their direct cross-talk at the cell Tel.: 0931/201-48977 gation of molecular mechanisms of cellu- surface. Another discovery concerns signal- lar communication, their role for physiologi- ing by internalized receptors from intracel- Professor Dr. rer. nat. Moritz Bünemann cal functions and their potential to serve as lular sites. drug targets. In addition to standard bio- Professor Dr. Dr. Stefan Engelhardt chemical and molecular biology equipment, the chair has a SPF unit for the generation G-Proteins und Regulation of Ion Chan- of transgenic models as well as equipment nels for rapid microscopic imaging, for confocal, (M. Bünemann) 2-photon and TIRF microscopy, for electrophysiology and for cardiovascular physiol- Many ion channels are regulated by recep- ogy and histology. tors and G-proteins. We investigate the mo- The chair also provides a drug information lecular mechanism of this control, and use service for the university hospital and acco- fluorescence methods to visualize an entire modates the faculty‘s ethics committee. signaling chain from the receptor to the activation of the ion channel. Major Research Interests Phosphatases and Cellular Motility (A. Gohla; joint appointment with Rudolf Vir- Research in pharmacology is primarily con- chow Center) cerned with cell surface receptors for the stress hormones adrenaline and noradren- The cytoskeleton plays a fundamental role aline, and with related receptors that bin, for cell adhesion and motility, and is an im- for example, opiates, somatostatin and ad- portant drug target for cancer and cardio- enosine. These receptors are being inves- vascular disease. We have discovered a tigated with a large array of methods and novel class of human phosphatases that questions that range from the structures regulate cytoskeletal dynamics. Employ- of receptors and ligands to transgenic dis- ing primarily biochemical and cell biologi- ease models and studies on patient sam- cal methods, we study phosphatase inter- ples. Our research is funded by grants from action partners and substrates, and investi- the DFG, in particular the SFB487 and 688, gate the signalling pathways that determine the EU, the BMBF (Federal Ministry of Re- phosphatase activities downstream of ex- search), the Bavarian research Foundation tracellular cues. and others.

Mechanisms und Function of G-Protein-coupled Re- ceptors (M. Lohse, D. Calebiro C. Hoffmann, V.O. Nikolaev)

Communication between receptors occurs via hormones and neurotransmitters that are recognized by specific receptors, which constitute the Fig. 1: Visualizing receptor function: thyroid follicles from primary class of drug targets. a transgenic mouse expressing a fluorescent sensor for We investigate their func- cAMP change their fluorescence upon stimulation with tion and regulation in various thyroid stimulating hormone, TSH. Changes in color re- model systems, most im- flect the increase in intracellular cAMP.

46 Chronic heart failure is one we now want to try to develop a therapeutic of the main health prob- strategy based on cyclic peptides. lems of old age. Based on a mouse model of slow- ly developing heart failure we are searching for genes Teaching and mechanisms that contribute to heart failure and The Institute is responsible for teaching dilatation and may of- pharmacology and toxicology to students fer new therapeutic ave- in medicine, dentistry, biology and biomedi- nues. We have discovered cine. The focus is on general and clinical a number of pathways that pharmacology for medical students (5th, can lead to heart failure (β- 6th and 8th term) and pharmacy students adrenergic receptors, the (5th-8th term). We also play a key role in sodium/proton exchanger the conception of the new research orient- NHE1, the interleukin con- ed BSc/MSc curriculum in Biomedicine and verting enzyme ICE, the participate in the curriculum in Experimen- transcriptional regulator tal Medicine. We offer the full curriculum NAB1, the protein kinase for the medical specialties of pharmacology inhibitor RKIP, a newly dis- and clinical pharmacology. covered activation path- Fig. 2: MicroRNAs in the heart – demonstration of micro way for the protein kinases RNA21 in failing but not in non-failing heart. ERK1/2 as well as mutations in signaling and con- tractile proteins. We have also established a contribution of newly discovered micro RNAs in heart failure. Adenosine Receptors and their Ligands (K.-N. Klotz) Receptor-Antiodies in Heart Failure Adenosine is a ubiquitous mediator that (R. Jahns, in collaboration with the Depart- acts on cells via four different receptors. In ment of Medicine and Rudolf Virchow Cen- collaboration with chemists we develop se- ter) lective ligands for these receptors and investigate the principles of their specific rec- Over many years we have demonstrated the ognition. presence of antibodies against β1-adrenergic receptors in about a third of patients with chronic heart failure. These auto-an- Calebiro D, Nikolaev VO, Gagliani MC, de Mechanisms of Heart Failure and Car- tibodies reduce the chance of survival of Filippis T, Dees C, Tacchetti C, Persani L, diac Signaling these patients by 50%. We have now gener- Lohse MJ (2009) Persistent cAMP-signals (S. Engelhardt, joint appointment with Ru- ated a corresponding animal model by im- triggered by internalized G-protein-coupled dolf Virchow Center; K. Lorenz, J. Schmitt) munizing rats with receptor epitopes. In a receptors. PLoS Biol. 7:e1000172 project funded by the BMBF GoBio program Dorsch S, Klotz KN, Engelhardt S, Lohse MJ, Bünemann M (2009) Analysis of receptor oligomerization by FRAP microscopy. Nature Methods 6, 225-30

Lorenz K, Schmitt JP, Schmitteckert EM, Lohse MJ (2009) A new type of ERK1/2- autophosphorylation causes cardiac hypertrophy. Nature Medicine 15, 75-83.

Thum T, Gross C, Fiedler J, Fischer T, Kissler S, Bussen M, Galuppo P, Just S, Rottbauer W, Frantz S, Castoldi M, Sout- schek J, Koteliansky V, Rosenwald A, Bas-

SELECTED PUBLICATIONS son MA, Licht JD, Pena JT, Rouhanifard SH, Muckenthaler MU, Tuschl T, Martin GR, Bauersachs J, Engelhardt S (2008) MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 456, 980-4

Vilardaga JP, Nikolaev VO, Lorenz K, Zhuang Z, Lohse MJ (2008) Direct inhibi- Fig. 3: Demonstration of phosphatase action on cytoskeletal dynamics. The depletion of tion of G protein signaling by cross-confor- the phosphatase (AUM) by RNA interference stabilizes actin fibres (shown in green). mational switches between a2-adrenergic and m-opioid receptors. Nature Chemical 47 Biology 4, 126-131. 2.17 Institute of Forensic Medicine

Professor Dr. med. Christoph Meißner Mission Another research focus is forensic neuro- (Head) and structure pathology. Based on a method which is in routine use at the department of neuro- Versbacher St. 3 In 2008, the academic staff of the Insti- anatomy (Prof. Dr. H. Heinsen) at the Clinic 97078 Würzburg tute of Forensic Medicine at Würzburg Uni- and Polyclinic for Psychiatry, Psychosomat- Tel.: 0931/201-47020 versity consisted of two physicians and one ics and Psychotherapy, it is possible to as- Fax: 0931/201-47000 toxicologist as well as the head of the in- semble 3D images from gallocyanin-stained E-mail: [email protected] tsitute. Temporarily there was only one se- sections and to gain detailed insights which www.uni-wuerzburg.de/rechtsmedizin nior physician (Oberarzt), due to materni- thus far have been impossible to image. The ty leave of one physician. With the change targeted use of this method in certain nu- in leadership, under the new conditions of clear regions of Alzheimer brains, in sudden

CONTACT DETAILS CONTACT an attending physician (Chefarzt) contract, infant death syndrome (SIDS) and sudden another physician and a molecular biolo- unexpected death in epilepsy (SUDEP) is in gist were employed. Two of these academic the pipeline. staff, as well as two more technicians and a secretary are being financed through third- In collaboration with the department of neu- party means of the institute. The remaining ropathology (Dr. C. Monoranu) and the Clin- job capacity is oriented at the discipline’s ic and Polyclinic for Psychiatry, Psychoso- tasks of research, teaching and privileged matics and Psychotherapy (Prof. A.J. Fall- services of forensic medicine. gatter), a project combining clinical data with basic science in an ideal fashion has Forensic medicine services for the region been developed. Since a diagnosis of Al- Unterfranken (as well as bordering parts of zheimer’s disease can presently only be Oberfranken and Baden-Württemberg) are ascertained when the aetiology is well ad- done at the request of courts, district pros- vanced, better diagnostic options must be ecutors and police stations. The main tasks found. In the Polyclinic for Psychiatry, Psy- are the resolution of causes of death, clini- chosomatics and Psychotherapy the meth- cal forensic medicine including examination od of vagus-evoked potentials has been de- of the living and victims of physical violence, veloped and validated for early diagnosis on forensic analysis of traces, paternity analy- Alzheimer patients. Based on these clini- ses, and forensic-toxicologic analysis to de- cal data, the project is aiming for examina- termine causes of death and solve traffic tion of the brainstem of these patients, in accidents. particular morphological and molecular biological changes associated with oxidative stress. Evidence of cell-specific deletions of Major Research mitochondrial DNA due to oxidative stress Interests and altered patterns of gene expression in these regions could then serve as the start- Research in forensic medicine is to be de- ing point for innovative strategies in diag- veloped in a bipartite manner. On the one nostics and therapy. hand, it is essentially required to improve analytical methods and possibilities, in order to provide the authorities with material evidence for the solution of cases. On the Teaching other hand, a focus on research is impera- tive; this can represent an important mo- Teaching forensic medicine to medical stu- saic piece within the faculty, in order to un- dents involves a lecture series, laborato- dertake interdisciplinary research in times ries and seminars. In the lectures, topics of scarce resources. Over the years, an ex- include thanotology, various forms of vio- pertise has grown in forensic medicine such lence, forensic/molecular biology aspects, that useable results can be extracted from forensic toxicology, as well as ethical and very little and heavily degraded starting ma- medical-legal aspects. Students also learn terial – an expertise that can benefit other how to perform autopsies; here an expan- disciplines. sion of the practice-oriented teaching in small groups seems desirable. The practi- Preliminary experiments towards the im- cal skills that students can acquire for their provement of forensic methods have been later work in general practice are particu- performed, where, employing miniSTRs, larly emphasised in teaching. The distinc- even with degraded DNA and telogenic hair tion between self-harm and external harm (i.e. shed hair) results can be obtained. Telo- as well as the clinical analysis of domestic genic hair usually contains either no roots or violence are taught through a multitude of only rudimentary roots and frequently does case studies with extensive imagery. not allow routine DNA analysis work. External teachings include a well-attend-

48 Fig. 1: Isolation of immunohistochemically labelled single cells by means of a laser dissection microscope for molecular biological analysis of certain cell entities in Alzheimer’s disease. ed class for law students entitled “Foren- sic medicine for lawyers”. For legal interns (Rechtsreferendare), instructions on the effects of alcohol and drugs in traffic are also on offer, with a monitored drinking experiment. Furthermore, biology students can take the class “Forensic medicine for biologists”.

Bauer M, Patzelt D (2008) Identification of menstrual blood by real time RT-PCR: technical improvements and the practical value of negative test results. Forensic Sci Int 174:55-59.

Michel TM, Frangou S, Camara S, Thie- meyer D, Jecel J, Tatschner T, Zoechling R, Grünblatt E. (2008) Altered glial cell line- derived neurotrophic factor (GDNF) concentrations in the brain of patients with depressive disorder: a comparative postmortem study. Eur Psychiatry 23:413-20.

Oehmichen M, Wötzel F, Meissner C (2009) Hypoxic-ischemic changes in SIDS brains as demonstrated by a reduction in MAP2-reactive neurons. Acta Neuropathol (Berl) 117:267-274.

SELECTED PUBLICATIONS Walter T, Meissner C, Oehmichen M (2009) Pathomorphological staging of subdural hemorrhages: statistical analysis of posttraumatic histomorphological alterations. Leg Med (Tokyo) 11 Suppl 1: S56-62.

Oehmichen M, Gronki T, Meissner C, An- lauf M, Schwark T (2009) Mast cell reactivity at the margin of human skin wounds: an early cell marker of wound survival? Fo- rensic Sci Int 191: 1-5. 49 2.18 Institute of Pathology

Mission and was specifically developed to detect vari- Professor Dr. med. Andreas Rosenwald Structure ous chromosomal translocations in paraffin (Head) embedded tumor tissue. The Institute of Pathology is an academic Josef-Schneider-Str. 2 center with more than 90 employees in- 97080 Würzburg cluding 15 pathologists. The institute deliv- Therapeutic Relevance of CD56 Depen- Tel.: 0931/201-47776 ers clinical care including histological and dant Signalling Pathways in Ischemic Fax: 0931/201-47440 cytological diagnostic assessments of bi- Cardiomyopathy and Malignant Hema- E-mail: [email protected] opsies and other materials, as well as au- topoietic Neoplasias www.pathologie.uni-wuerzburg.de topsies. Specialized departments, e.g. for (S. Gattenlöhner) Neuropathology or Molecular Pathology, Professor Dr. med. Dr. h.c. Hans-Konrad CONTACT DETAILS CONTACT concentrate on specific diagnostic and sci- In the framework of this research area it Müller-Hermelink entific topics. The Institute of Pathology has was shown that the cell adhesion molecule (Head until 30. 9. 2008) a particular focus on diagnostic and scien- and signal transducer CD56 induces apop- tific aspects of hematopathology and con- tosis and inhibits the calcium transport in Professor Dr. med. Stefan Gattenlöhner stitutes one of six German reference cen- human heart cells and reduces contractility Tel.: 0931/201-47420 ters for lymph node pathology. The diagnos- in cardiac myocytes, whereas it functions tic expertise in this field and the scientific anti-apoptotic and pro-proliferative in ma- Professor Dr. med. Wolfgang Roggendorf achievements are internationally visible. lignant hematopoietic neoplasms via the Tel.: 0931/201-47429 NFκB pathway. Professor Dr. rer. nat. Dr. sc. nat. Edgar Serfling Major Research Tel.: 0931/201-47431 Interests Immunotherapy for Rhabdomyosarcoma and Rhabdoid Differentiated Tumors Research in Hematopathology and Con- (S. Gattenlöhner) sultation Center for Lymph Node Pathol- ogy Rhabdomyosarcomas (RMS) are the most (A. Rosenwald) common malignant soft tissue tumors in children that show a 5-year survival rate of The Reference Center for Lymph Node Pa- 5% in advanced stages. After identification thology operates as a national consulta- of the fetal acetylcholine receptor (fAChR) tion center and coordinates research ac- as a tumor-specific antigen in RMS, we es- tivities associated with prospective clinical tablished an anti-fAChR-based immuno- lymphoma trials including trials of the ‘Ger- therapy. In future investigations, a fully human study group for high-grade non-Hodg- man immunotoxin shall be generated and kin lymphomas (DSHNHL)’. Professor Ros- tested in Phase I clinical trials. enwald’s group has a major research focus on the molecular pathogenesis of malignant B- and T-cell lymphomas. Specifical- Transcriptional Control in T-Lymphocytes ly, high-throughput technologies including (E. Serfling) gene expression profiling and high-resolution genomics approaches are used to de- The Department of Molecular Pathology cipher molecular alterations in lymphoid contributed to the establishment of a new neoplasms. Recently, major studies were SFB/Transregio (Collaborative Research performed in mantle cell lymphomas and Center), TRR52, of the German Research diffuse large B-cell lymphomas. In follicu- Association (DFG) which started its work lar lymphomas, new molecular and clinical in July 2008 with the topic ‘Transcription- subgroups could be identified. al programming of individual T-cell populations’. Professor Serfling’s research is fo- Dr. Geissinger’s group is interested in the cused on the role of calcium/calcineurin molecular and immunophenotypic char- inducible nuclear factor of activated T-cell acterization of peripheral T-cell lympho- (NFAT) transcription factors in lymphocyte mas (PTCL). Recent projects identified a function and their proliferation and apopto- disturbed expression of the T-cell recep- sis. Main topics are the creation of mouse tor/CD3 complex and associated signalling lines for the conditional inactivation of the molecules in primary cutaneous, but also murine Nfatc1 gene, post-transcriptional in systemic CD30-positive lymphoprolifera- modifications of NFAT factors and the tran- tions. scriptional inactivation (and repression) of the murine Nfatc1 gene. Dr. Haralambieva and coworkers analyzed the biological and genetic heterogeneity of multiple myeloma by using a fluorescence Human Immunity to Cancer in situ hybridization (FISH) approach that (H.P. Vollmers)

50 Fig. 1: Three-dimensional presentation of the overexpression of CD56 (rot) in human heart muscle cells.

The experimental work of this research tion, the role of microcirculation and its im- group is focused on human innate immuni- pairment is being investigated in Alzheim- ty to cancer in which antibodies play an im- er’s disease. portant role. Several tumor-specific natural antibodies could already be identified and characterized. The antibodies are coded by distinct germ line genes, their targets be- Teaching ing post-transcriptionally modified carbohy- drate epitopes on tumor cell surface recep- The institute of pathology is responsible tors. Such tumor-specific modified epitopes for teaching pathology as part of the med- could be found on proteins such as CD55, ical curriculum of the Wuerzburg Medical CFR-1, GRP78 and TAF15. All tested anti- School. Specifically, 6 professors and addi- Leich E, Salaverria I, Bea S, Zettl A, Wright bodies remove malignant cells in vitro and tional teaching staff conduct lectures, semi- G, Moreno V, Gascoyne RD, Chan WC, in vivo by inducing apoptosis. In collabora- nars, practical classes (histology) and mac- Braziel RM, Rimsza LM, Weisenburger DD, tion with an Australian company, some of ropathologic case demonstrations (autop- Delabie J, Jaffe ES, Lister A, Fitzgibbon J, the identified antibodies are scheduled to sies). Additional courses for graduate stu- Staudt LM, Hartmann EM, Mueller-Her- enter clinical trials in 2010. The ongoing dents cover a wide range of specific sub- melink HK, Campo E, Ott G, Rosenwald A (2009). Follicular lymphomas with and scientific work is concentrated on the char- jects, techniques, and skills. Pathology lec- without translocation t(14;18) differ in acterization of the antibody epitopes and turers also participate in interdisciplinary gene expression profiles and genetic alter- the apoptotic pathways. teaching projects (e.g. interdisciplinary on- ations. Blood 114(4): 826-34. cology) and clinico-pathologic conferenc- Nayak A, Glöckner-Pagel J, Vaeth M, es for several hospitals and clinical depart- Schumann JE, Buttmann M, Bopp T, Neurooncology and neurodegeneration ments. Schmitt E, Serfling E, Berberich-Siebelt (W. Roggendorf) F (2009). Sumoylation of the transcription factor NFATc1 leads to its subnucle- The neurooncological focus of Professor ar relocalization and interleukin-2 repression by histone deacetylase. J Biol Chem Roggendorf’s research group is on ependy- 284(16): 10935-46. momas, a primary tumor of the central ner-

vous system that often occurs in childhood. SELECTED PUBLICATIONS Gattenlöhner S, Stühmer T, Leich E, Re- The clinical prognosis is very variable. Using inhard M, Etschmann B, Völker HU, Ros- enwald A, Serfling E, Bargou RC, Ertl G, molecular analyses on the gene expression Einsele H, Müller-Hermelink HK (2009). and genetic levels, characteristic genetic al- Specific detection of CD56(NCAM) iso- terations and gene expression profiles could forms by novel qRT-PCRs and antibodies be identified. In the field of neurodegenera- identifies aggressive malignant neoplasias with tumor progression. Am J Pathol. 174(4):1160-71. 51 2.19 Institute for Medical Radiation and Cell Research (MSZ)

Mission the cancer stem cell related factor Bmi1 as Professor Dr. rer. nat. Albrecht Müller and Structure crucial for the growth of NSCLC (Becker et (acting Head) al., PLOS One 2009; 4(1):e4230). The objective of the MSZ under the aegis Zinklesweg 10 of Prof. Ulf Rapp was to better understand 97078 Würzburg cancer with special emphasis on signaling Biochemistry Tel.: 0931/201-45848 pathways known to be disrupted in tumors. (U. Rapp) Fax: 0931/201-45148 In addition, in cooperation with pharmaceu- E-mail: [email protected] tical companies the MSZ was involved in The mitogenic cascade RAF/MEK/ERK plays www.uni-wuerzburg.de/strahlenkunde the development of small molecule inhibi- a central role in the regulation of cell prolif- tors and therapeutic vaccines. With the re- eration, differentiation, transformation and

CONTACT DETAILS CONTACT Professor Dr. med. Ulf R. Rapp tirement of Prof. Rapp the MSZ has seen a apoptosis. Over the past years we have fo- (Head until 31. 3. 2009) major change, which touched the scientific cused our research effort on the elucida- direction of the Institute as a whole. The fo- tion of molecular mechanisms involved in Professor Dr. rer. nat. Thomas Raabe cus shifted towards understanding various RAF activation. In detail, our team provid- Tel.: 0931/201-45841 aspects of regenerative stem cell biology. ed new insight into regulation of C-RAF ki- Two groups which were organized as part of nase by scaffold proteins 14-3-3 and pro- the department earlier because of the inti- hibitin. (Fischer et al., J. Biol. Chem. 2009, mate relationship between cancer and re- 284:3183). Additionally, our team uncov- generative stem cells are currently carrying ered new aspects in isoform specific regu- the scientific program. Prof. Müllers group lation and cellular function of A-RAF kinase. is analyzing gene expression programs in Using mass spectrometry we identified and mammalian embryonic and adult stem cells characterized a number of new phosphory- with a special emphasis on chromatin regulation sites in A-RAF (Baljuls et al., J. Biol. lation. Prof. Raabes group is studying signal Chem. 2008, 283:27239). Moreover, we transduction within the progenitor compart- were able to establish a new function of A- ment of the developing Drosophila brain. RAF in endocytosis and internalization of the The MSZ is working together with several cell receptors, which has been unknown so institutes of the faculties of medicine and far (Nekhoroshkova et al., PLOS One 2009; biology and is integrated in local and nation- 4(2):e4647). Of particular importance are al collaborative research centers. the new data on the interplay between RAF kinases and the apoptosis regulatory proteins IAP and BAD, which advance our un- Major Research derstanding of the mechanisms involved in Interests the regulation of apoptosis (Dogan et al., Nature Cell Biol. 2008,10:1447; Polzien et Tumor Genetics al., J. Biol. Chem 2009, 284:28004). (U. Rapp)

We have successfully used an in house de- Bacterial Tumor Therapy veloped mouse model system for non-small (U. Rapp, B. Bergmann) cell lung cancer (NSCLC) to study various aspects of cancer related genes in the The state of knowledge in tumor immunol- past. The system is based on the expres- ogy indicates that previous approaches can sion of an oncogenic form of the RAF ki- barely stimulate the innate immunity. Fur- nase, termed C-RAF BXB in specific cells thermore, they cannot bypass anti-immu- of the lung which leads to the development nological mechanisms located within the of adenomas within two weeks after birth tumor. Apparently, both aspects are impor- of transgenic animals. No progression of tant for the efficacy of a tumor vaccine. these tumors to metastasis has ever been The research group deals with the potential observed. As NSCLC is the most lethal hu- of attenuated intracellular bacteria as carri- man cancer due to its high rate of metas- er for specific tumour antigens. The immune tasis the dissemination of cancer cells from response against the tumor is enhanced by the primary tumor and the contribution of bacterial components thereby breaking the cancer associated genes to this process immune tolerance of the tumor. In a trans- has been in the focus of our studies. Our genic lung tumor model in mice vaccination most recent work employing the C-RAF BXB with recombinant attenuated Salmonella NSCLC system has led to the generation has been proven successfully to act thera- of the first conditional model for metasta- peutically. In addition, the fusion of a part of sis of NSCLC and identified a gene, c-MYC a bacterial toxin to the tumor antigen could that is able to orchestrate all steps of this further improve the efficacy of the orally ap- process (Rapp UR et al., PLoS One. 2009; plied live Salmonella based vaccine. A pros- 4(6): e6029.). A second project identified tate cancer vaccine based on the latter ap-

52 tations of the human RSK homologue are associated with mental retardation.

Teaching

With the renovation and equipment of our practical room, which was also paid in part from tuition fees, a significant improvement for hands-on training for medical, biomedical and biological students was achieved.

Fig. 1: The MSZ building. proach showed significant therapeutic ef- ic stem cells. Albrecht Müller is speaker of fects in the mouse model (Fensterle et al., the national DFG priority program 1356: Cancer Gene Ther. 2008, 15:85). In paral- Pluripotency and cellular reprogramming of lel, the platform technology could further be the BMBF-consortium: CB-HERMES (Cord improved by increasing the level of tumor Blood-Hematopoietic Stem Cells: Reliable antigen secretion (Hotz et al., Int. J. Med. Methods for ex-vivo ExpanSion) and he is Microbiol. 2009, 299:109). In cooperation member of the bioethics committee of the with Æterna Zentaris a Salmonella-based Bavarian state government. vaccine against prostate carcinoma is now in preparation for clinical study. Molecular Genetics Rapp UR, Korn C, Ceteci F, Karreman C, (T. Raabe) Luetkenhaus K, Serafin V, Zanucco E, Cas- Stem Cell Biology tro I, Potapenko T. MYC is a metastasis (A. Müller) In our group we take advantage of the ge- gene for non-small-cell lung cancer. PLoS netic model organism Drosophila in com- One. 2009; 4(6): e6029. Stem cells are rare but essential cell types bination with molecular and cell biologi- Dogan T, Harms GS, Hekman M, Kar- for development and tissue regeneration. cal approaches to elucidate mechanisms reman C, Oberoi TK, Alnemri ES, Rapp Research on stem cell biology and cellu- that control generation and differentiation UR, Rajalingam K. X-linked and cellular lar pluripotency is one of the most prom- of neuronal cells. Despite great anatomi- IAPs modulate the stability of C-RAF ki- ising research fields in human medicine. cal differences, vertebrates and inverte- nase and cell motility. Nat Cell Biol. 2008 Dec;10(12):1447-55. The possibility to reprogram cells into any brates share a number of highly conserved type of adult stem cells for the purpose of signalling pathways that control develop- Fensterle J, Bergmann B, Yone CL, Hotz cell replacement holds tremendous thera- mental processes. Thus studies in model C, Meyer SR, Spreng S, Goebel W, Rapp peutic promise and may circumvent ethical organisms can contribute to a better un- UR, Gentschev I. Cancer immunotherapy considerations concerning the derivation derstanding of human diseases of the cen- based on recombinant Salmonella enteri- ca serovar Typhimurium aroA strains se- of new human embryonic stem cells. The tral nervous system. We are investigating a creting prostate-specific antigen and chol- molecular pathways controlling pluripoten- number of mutations, which cause an al- era toxin subunit B. Cancer Gene Ther.

cy and cellular reprogramming are now only tered proliferation pattern of neural progen- SELECTED PUBLICATIONS 2008 Feb;15(2):85-93. beginning to be unraveled. The stem cell itor cells (Hovhanyan & Raabe, J. Neuro- Hovhanyan A, Raabe T. Structural brain biology group focuses on embryonic, he- gen. 2009, 23:42). A further focus of our mutants: mushroom body defect (mud): matopoietic and mesenchymal stem cells research lies on proteins of the p21-acti- a case study. J Neurogenet. 2009;23(1- and asks how global chromatin states guide vated kinase family and their involvement in 2):42-7. stem cell behavior (Dinger et al., Stem Cells morphogenetic processes during eye devel- 2008, 26:119; Obier & Müller, CTO 2009, opment (Menzel et al., Biochem. J. 2008, Dinger TC, Eckardt S, Choi SW, Camare- ro G, Kurosaka S, Hornich V, McLaugh- DOI: 10.1159/000240247). Also, we are 416:231). In collaboration with clinical re- lin KJ, Müller AM. Androgenetic embry- analysing the developmental potential of search groups we are analysing the function onic stem cells form neural progenitor mesenchymal and uniparental embryon- of the kinase RSK in synaptic plasticity. Mu- cells in vivo and in vitro. Stem Cells. 2008 Jun;26(6):1474-83. 53 2.20 Institute of Human Genetics

Mission the central gene of the vitamin K depen- Professor Dr. med. Thomas Haaf and Structure dent blood clotting cascade. Subsequent- (Head) ly, mutations in VKORC1 were recognized Human Genetics is an important area of as cause of warfarin-resistance in both hu- Biozentrum biomedicine with increasing impact on the mans and rodents. A knock-out of VKORC1 Am Hubland practice of medicine. Human Genetics in- in mice causes lethal spontaneous bleed- 97074 Würzburg vestigates evolution, structure, function, in- ings which can be prevented by oral substi- Tel.: 0931/31-88738 heritance and disorders of the human ge- tution of vitamin K. Fax: 0931/31-84069 nome. Results of these studies are applied In addition, the group has a long standing E-mail: [email protected] to genetic diagnosis, genetic counseling interest in the genetics of inherited mus- www.humgen.biozentrum.uni-wuerzburg.de/ and patient care. At the University of Würz- cle disorders, including the muscular dys-

CONTACT DETAILS CONTACT burg, human genetics is represented by a trophies, the myotonias, and malignant hy- Professor Dr. med. Holger Höhn basic science-oriented Chair (Prof. Haaf) perthermia. Clemens Müller-Reible serves (Head until 31. 3. 2008) and a Division of Medical Genetics (Prof. as a member of several European commit- Grimm) providing genetic services. Both tees on quality assurance in genetic diag- Professor Dr. rer. nat. Clemens R. Müller- chair and division participate in patient care nostics. Reible and teaching for students in the fields of Tel.: 0931/31-84063 medicine, biomedicine and biology. Located in the Würzburg Biocenter, the Institute be- Somatic cell genetics longs to the University of Würzburg School (D. Schindler) of Medicine. Genes that ensure genomic stability of somatic cells and thus safeguard against neo- Major plasia and premature ageing are of key in- Research Interests terest to this group. These so-called caretaker genes are involved in the recognition Epigenetics and reversal of DNA damage. They include, (T. Haaf) among others, ATM, NBN, RAD50, LIG4, NEHJ1, WRN, MCPH1 and the Fanconi Epigenetic information is not encoded by anemia (FA) family of genes. Most recently, the DNA sequence itself but by reversible the group participated in the identification modifications of DNA (methylation of CpG of three novel FA genes (FANCJ, FANCN and dinucleotides) and/or histones. In mam- FANCI). As a partner and interactor of one mals, the paternal and maternal genomes of the high-penetrance breast and ovar- undergo parent-specific methylation repro- ian cancer genes, BRCA2, biallelic muta- gramming in the germ line and early em- tions in FANCN play a significant role in the bryogenesis. Stochastic and/or environ- emergence of certain types of early child- mentally induced errors (epimutations) in hood tumors, apart from the predisposition this highly coordinated process may con- of monoallelic mutations for breast or ovar- tribute to human disease. We analyze the ian cancer. Collaborating with groups from effects of assisted reproductive technolo- Germany and abroad, the Schindler labora- gies on epigenetic reprogramming in mu- tory has made major contributions to cell rine and bovine germ cells/embryos as well genetic, epidemiological and functional as- as in human miscarriages and newborns. pects of FA and other caretaker gene syn- In another project we search for epigene- dromes including ataxia telangiectasia, the tic differences in the regulation of gene ex- Nijmegen breakage syndrome and related pression in human and non-human primate disorders. The group investigates protein brains. DNA sequence variations alone can- complexes (MRN complex, FA core com- not account for the enormous differences plex, and histone-fold complex) and path- between human and primate brain struc- ways (FA/BRC pathway for genomic main- ture/function and their cognitive abilities. tenance, non-homologous end joining and Epigenetic factors may form a main source homologous recombination repair) in which of phenotypic variation between individuals caretaker genes exert their functions. Im- and between species. pairments of these genes result in cell cycle arrest, chromosome breakage, increased cell death rates, cancer predisposition, and Molecular human genetics features of premature aging. Current efforts (C. R. Muller-Reible) are directed at identifying new members of the genomic maintenance gene networks, Using a positional cloning approach and elucidating their function, and studying their collaborating with Johannes Oldenburg (In- phenotypic effects in zebrafish models. stitute of Experimental Hematology, Bonn), the group was able to identify VKORC1 as

54 Cytogenetics and comparative genome research (M. Schmid)

Using classical and molecular cytogenetic methods, the group headed by Michael Schmid analyses mechanisms of chromosome evolution and chromosome pathology. Cooperating with Manfred Schartl (Insti- tute of Physiological Chemistry I), the group uses several model systems, including am- phibians, fish, birds and mammals to improve our understanding of chromosomal and genomic evolution in vertebrates. In addition, the group provides access to cytogenetic methods (including FISH, SKY and CGH) to a variety of other groups within the biocenter and the medical school. Mi- chael Schmid serves as editor or co-editor of a number of genetics journals and book series (Cytogenetic and Genome Research, Sexual Development, Molecular Syndro- mology, Genome Dynamics, and Mono- graphs in Human Genetics).

Teaching

The medical school curriculum includes a lecture course entitled “Clinical Human Ge- netics” which is taught in the 6th semester, together with a interdisciplinary course on “Disease prevention”. Medical students can choose human genetics as an elective during their rotating internships, with emphasis Farcas R, Schneider E, Frauenknecht K, on genetic diagnosis, dysmorphology and Kondova I, Bontrop R, Bohl J, Navarro B, genetic counseling. In addition to teaching Metzler M, Zischler H, Zechner U, Daser A, medical students, the Institute also offers Haaf T (2009) Differences in DNA methyl- courses to students of biomedicine and bi- ation patterns and expression of the CCRK ology, including laboratory courses in hu- gene in human and non-human primate cortices. Mol Biol Evol 26:1379-1389. man cytogenetics and human molecular genetics. Undergraduate biology students Nanda I, Schlegelmilch K, Haaf T, Schartl can choose human genetics as one of the M, Schmid M (2009) Synteny conserva- major subjects. Graduate students can ob- tion of the Z chromosome in 14 avian species (11 families) supports a role for Z tain their M.S. or Ph.D. degrees within one dosage in avian sex determination. Cyto- of the research groups of the Department. genet Genome Res 122:150-156.

Neveling K, Endt D, Hoehn H, Schindler D (2009) Genotype-phenotype correlations in Fanconi anemia. Mutat Res 668:73- 91.

SELECTED PUBLICATIONS Spohn G, Kleinridders A, Wunderlich FT, Watzka M, Zaucke F, Blumbach K, Geisen C, Seifried E, Müller CR, Paulsson M, Brüning JC, Oldenburg J. (2009) VKORC1 deficiency in mice causes early postnatal lethality due to severe bleeding. Thromb Haemost. 101:1044-1050.

Waltes R, Kalb R, Gatei M, Kijas AW, Stumm M, Sobeck A, Wieland B, Varon R, Lerenthal Y, Lavin MF, Schindler D, Dörk T (2009) Human RAD50 deficiency in a Ni- jmegen breakage syndrome-like disorder. Am J Hum Genet 84:605-616. 55 2.20.1 Division of Medical Genetics

Professor Dr. med. Tiemo Grimm Mission Center for Familial Breast and Ovary (Head) and structure Carcinoma (FBOC) (Speakers: Prof. Dr. T. Grimm, Medical Ge- Theodor-Boveri-Weg 11 As a subspecialty and application of hu- netics, and Prof. Dr. J. Dietl, Department of 97074 Würzburg man genetics, medical genetics involves Obstetrics and Gynecology, University Hos- Tel.: 0931/31-84076 the transfer of scientific insights from ba- pital) Fax: 0931/31-84434 sic human genetics research into the clin- The Center is a cooperative venture be- E-mail: [email protected] ic. In addition of genetic diagnostics and tween the Department of Human and Medi- www.humgen.biozentrum.uni-wuerzburg.de/ genetic counselling, hallmark features of cal Genetics and the Department of Obstet- med_genetik/ medical genetics are aspects of preventive rics and Gynecology and the Department of and predictive medicine. Medical genetics Radiology of the University Hospital. It takes

CONTACT DETAILS CONTACT deals with a large spectrum of inherited dis- care of patients and families affected by or orders, with focus on affected individuals, at risk of familial cancer of the breast and entire families, and the population at large. ovary. Services provides by the center in- Interaction with patients and their families clude genetic counselling, genetic testing, is established during the genetic counseling and provision of medical as well as pre- sessions. This includes the exploration of ventive care (e.g. mammography screen- family history, the physical exam of affected ings) (cf. contribution.5.2.6). The Würz- individuals, the collection of medical infor- burg FBOC center serves the entire region mation concerning the individual and family of northern Bavaria and is supported in part members, knowledge of syndromology and by the German Cancer Aid. congenital disorders, expertise in formal genetics and psychological aspects of disease in order to arrive at a correct genetic diag- Major Research nosis and provide adequate counselling. In Interests addition, medical genetics assures access to genetic testing for an ever increasing In terms of research activities, the Division number of inherited disorders and disease of Medical Genetics focusses on three main susceptibilities. The genetic counsellor is topics: (1) phenotypic, statistical and pop- responsible for the correct communication ulation genetic aspects of inherited neuro- and interpretation of genetic test results. muscular diseases, (2) epidemiology, pat- Overall guiding principles are patient auton- terns of inheritance and molecular genetics omy and ethical concerns. Diagnostic and of dyslexia, and (3) fundamental aspects of predictive genetic testing are embedded in formal and statistical genetics as they relate the counseling process. Comprehensive ge- to monogenic and polygenic diseases. netic services are provided by the Würzburg Center of Medical Genetics. The center includes the Department of Human Genetics Statistical and formal genetics of inher- (Chair: Prof. Dr. med. T. Haaf), the Division ited neuromuscular disorders of Medical Genetics (Head: Prof. Dr. med. (T. Grimm) T. Grimm), and a private practice located and operated within the Department of Hu- Risk calculations in medical genetics reman and Medical Genetics (PD. Dr. med. quire precision of genetic models underlying E. Kunstmann). As a general practicioner of the inheritance patterns of the respective human genetics, Dr. Kunstmann is fully ac- disorders. For example, mutation rates for credited with the public insurance system. X-linked disorders (such as muscular dys- trophies Duchenne / Becker) were shown to vary as a function of gender and muta- The Division of Medical Genetics includes tion type. Another research focus is on risk the following sections: calculations within the context of counseling implications of somatic and germ cell Center for muscular disorders of the mosaicism. German Society of Muscular Diseases Another example is the elaboration of a (Speakers: Prof. Dr. K. Reiners, Neurology, specialized genetic model for spinal mus- and Prof. Dr. T. Grimm, Medical Genetics; cular atrophy (SMA) which allows for rea- Coordinator: Dipl. Soz. Päd. Angelika Eiler) sonably precise risk calculations despite The Center for muscular disorders provides unclear or problematic molecular genetic diagnostic, counseling and social servic- testing results. es for patients and families affected by or at risk of muscle disease. It is operated in close cooperations with the Department of Neurology of the Würzburg University Hos- pital (cf. contribution 3.21).

56 Fig. 1: Organisational structure of the Würzburg Center of Medical Genetics.

Genetics of dyslexia Ethical aspects of Human Genetics (T. Grimm) (T. M. Schroeder-Kurth)

Dyslexia affects an estimated 5% of ger- Rapid developments in the area of prena- man primary and secondary school stu- tal and predictive genetic testing, including dents. Extensive family studies provide evi- the medical applications of genetic technol- Rudnik-Schöneborn S, Berg C, Zerres K, dence for familial clustering, including rare ogy (e.g. gene therapy; therapeutic cloning, Betzler C, Grimm T, Eggermann T, Eg- pedigrees suggestive of monogenic inheri- regenerative medicine, etc.) mandate ethi- germann K, Wirth R, Wirth B, Heller R tance. Whole genome mapping (collabo- cal guidlines. What shall we expect from, (2009). Genotype-phenotype studies in in- ration with the Max Planck Institute of Mo- and how shall we interpret the results of fantile spinal muscular atrophy (SMA) type lecular Genetics, Berlin) in a family with a the 1.000 Dollar genome which is on the I in Germany: implications for clinical trials and genetic counselling. Clin Genet. clear autosomal dominant inheritance pat- horizon? What is the role and what are the 76:168-178. tern of the dyslexia trait revealed a novel implications of human genetics within the dyslexia locus on human chromosome 4. emerging field of personalized medicine? Grimm T, Kress W, Meng G, Müller-Reible Using a large series of dyslexia families in These and other questions are discussed CR (2009) Muskeldystrophien Duchenne und Becker - Molekulargenetische Diag- whom linkage to chromosome 4 has not and dealt with on a national and europe- nostik und genetisches Modell. medgen been excluded we currently attempt to rep- an level in order to arrive at clinically use- 21: 327-331. licate these findings. If successful, candi- ful recommendations, guidelines and criti- date gene approaches will be used to iden- cal evaluations. Moenning A, Jäger R, Egert A, Kress W, tify the putative novel dyslexia gene. Wardelmann E, Schorle H (2009) Sus- tained platelet-derived growth factor receptor alpha signaling in osteoblasts results in craniosynostosis by overactivating

Disorders of premature closure of cra- Teaching SELECTED PUBLICATIONS the phospholipase C-gamma pathway. Mol nial sutures (craniosynostoses) Cell Biol. 29:881-891. (W. Kress) The Division of Medical Genetics provides Decker E, Stellzig-Eisenhauer A, Fiebig lectures, hands-on courses and discus- BS, Rau C, Kress W, Saar K, Rüschendorf Around 20 % of patients with premature clo- sion rounds for medical students, students F, Hubner N, Grimm T, Weber BH (2008). sure of cranial sutures belong to the catego- of biomedicine, and students of biology. In PTHR1 loss-of-function mutations in famil- ry of complex autosomal dominant cranio- addition, the Division provides clerkships ial, nonsyndromic primary failure of tooth eruption. Am J Hum Genet. 83:781-786. synostoses which include additional malfor- and internships during the clinical part of mations of the distal extremities. Underlying the medical curriculum. Students acquire Bergmann C, Fliegauf M, Brüchle NO, genetic alterations involve mutations in a theoretical and practical knowledge in es- Frank V, Olbrich H, Kirschner J, Scherm- variety of fibroblast growth factor receptors tablishing a genetic diagnosis, including as- er B, Schmedding I, Kispert A, Kränzlin B, Nürnberg G, Becker C, Grimm T, Girschick and transcription factors. Major efforts are pects of dysmorphology, syndromology, pre- G, Lynch SA, Kelehan P, Senderek J, Neu- directed at establishing genotype-pheno- and postnatal genetic testing using cytoge- haus TJ, Stallmach T, Zentgraf H, Nürn- type correlations, and at defining nosologic netic, cell genetic and molecular methods, berg P, Gretz N, Lo C, Lienkamp S, Schäfer subgroups by way of molecular analysis. and they acquire practical knowledge in ge- T, Walz G, Benzing T, Zerres K, Omran H netic counselling. (2008). Loss of nephrocystin-3 function can cause embryonic lethality, Meckel- Gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia. Am J 57 Hum Genet. 82:959-970. 3 University Hospital 3.1 Introduction

The University Hospital Würzburg compris- sion Medicine and Hematotherapy as well es 19 Clinics (for inpatients), 22 Policlinics as Institute for Clinical Biochemistry and (for outpatients), 4 Clinical Institutes as well Pathobiochemistry with Central Laboratory as 2 independent Chairs. Furthermore there in building A3/A4. are 6 affiliated Training Colleges of Health Care, which together offer more than 500 The other locations of the University Hos- apprenticeship training positions. pital are closely interlocked: “Kopfklinik” (Departments of Neurology, Neurosurgery, The University Hospital employs a total of Neuroradiology, Ophthalmology, Ear-, Nose- 4.237 full-time employees, among them and Throat-Surgery and Radiation Oncology 740 physicians, 1.210 nurses, 359 em- in building B1/B2), “Nervenkliniken” (De- ployees working as ancillary staff and 1.023 partments of Psychiatry, Psychosomatic and medical-technical employees. Psychotherapy for Adults as well as Children and Adolescents in area F), the Center of Interdisciplinary – and partially outreach Dentistry, Oral- and Maxillofacial Sur- collaboration is the focus of 16 Clinical gery in area G and the Departments of Centers: Comprehensive Cancer Center, Pediatrics, Obstetrics and Gynecology Center for Stem Cell Therapy, Breast Cen- as well as Dermatology and Venerology ter, Colon Center, Thorax Center, Cardio- in area C and D. vascular Center, Comprehensive Heart Fail- ure Center, Infarct Network, Trauma Cen- Among the constructional activities in the ter, Musculo-Scelettal Center, Center for future are the reconstruction of the ”Kop- Rheumatism, Transplant Center, Compre- fklinik”, and the construction of a „Mother- hensive Hearing Center, Center for Cleft, Child-Center”. With the existing infrastruc- Lip and Palate, Perinatal Center, Interdisci- ture, which has to be improved continuous- plinary Center of Palliative Care. The Center ly, the University Hospital will be prepared to for Interdisciplinary Clinical Research (IZKF) fulfill the challenges of a changing health- builds the bridge between clinical theoreti- care market and simultaneously will be able cal research and clinical research. to ensure a prosperous working environment for research and teaching. According to the official plan 2008, the University Hospital provides 1,461 hospital beds; the utilization rate of the 1,414 beds Professor Dr. med. Chr. Reiners having been set up was 97.4% with an av- Managing Medical Director erage resting time of 8.2 days. In the year 2008, 50,248 patients received inpatient treatment and a total amount of 411,046 care days were performed; additionally a total of 183,535 patients received outpatient treatment. Approximately 81% of all patients originate from the administrative regions of Lower-, Middle- and Upper-Fran- conia as well as from other parts of Bavaria. 12% of all patients come from the adjacent Baden-Wuerttemberg, the remaining 7% from the rest of Germany or from abroad.

The modern Health Care Center ZOM|ZIM, build up from the Centers of Operative Med- icine and Internal Medicine, combines the following institutions under one roof: De- partment of Anesthesiology, General-, Vis- ceral-, Vascular- and Pediatric Surgery (Sur- gical Clinic I), Department of Traumatology, Hand-, Plastical- and Reconstructive Sur- gery (Surgical Clinic II), Department of Tho- rax-, Heart- and Thoracic Vascular Surgery as well as the Department of Urology and Paediatric Urology in building A1/A2 and on the other hand Department of Internal Med- icine I, Department of Internal Medicine II, Department of Nuclear Medicine, Institute of Radiology, Institute of Clinical Transfu-

58 Fig. 1: Entrance hall of the Center of Internal Medicine (ZIM).

59 3.2 Department of Anaesthesia and Critical Care

students and residents the department runs in the field of anaesthesia, pain therapy, Professor Dr. med. Norbert Roewer a laboratory for the diagnosis of malignant palliative medicine, intensive care medicine (Head of the Department) hyperthermia. Malignant hyperthermia is a and cognate disciplines are generated. rare hereditary disorder, which might occur Oberdürrbacherstrasse 6 quickly and life-threatening during anaes- 97080 Würzburg thesia. Organ-Protection Tel.: 0931/201-30001 (M. Lange) Fax: 0931/201-30019 E-mail: Anaesthesie-Direktion@klinik. Major Research Volatile anesthetics not only induce an- uni-wuerzburg.de Interests esthesia, but also render organs resistant www.anaesthesie.uni-wuerzburg.de against ischemic damage. The intracellular

CONTACT DETAILS CONTACT Pain research mechanisms underlying anesthesia induced Professor Dr. rer. nat. Carola Förster (H. Rittner, A. Brack, G. Sprotte) reduction of ischemia/reperfusion injury are Tel.: 0931/201-30065 under intense investigation. The projects Different research groups focus on the performed by the research group aim to Professor Dr. med. Peter Kranke pathophysiology of the immunological sys- identify triggers, mediators and end-effec- Tel.: 0931/201-30116 tem and its role in the development and tors of anesthetic-induced pre- and post- chronification of pain, using approaches conditioning and to characterize their com- with chronic pain patients or experimental plex intracellular interaction in the heart and in-vitro and in-vivo techniques. the brain. Mission and Structure Intestinal hypomotility in ICU patients Acute lung injury (M. Herbert) (R. Muellenbach) The Department of Anaesthesiology annually performs anaesthesia for approximately ICU patients show a dysfunction of the in- Acute lung injuries in adults, caused by 26.000 surgical and diagnostic procedures testinal motility. Consequence of which may pneumonia, sepsis and multiple traumas in the various clinical departments including develop systemic inflammation and further still show a lethality of 40-60%. The key to orthopaedic cases (König-Ludwig-Haus). aggravation of the patients condition. With survive for patients is a ventilation strategy The pain centre and the outpatient depart- the help of experimental animal models the which allows the lung to recover and heal. ment of Anaesthesiology in each case ex- interdependency between drugs used in in- The choice of a ventilation profile with opti- hibit more than 9.000 patient contacts per tensive care and the motility of the intestine mal pressure amplitudes for the individual year of patients suffering from acute and is investigated. patient needs is of vital importance. With chronic pain. The department has an inter- the help of experimentally induced acute disciplinary Intensive Care Unit with 12 beds lung injury in pigs the influence of differ- for critically ill patients after major surgery Evidence Based Medicine ent ventilation modes and profiles on the or for those suffering from severe multiple (P. Kranke) inflammation and function of the lungs are traumas. Each intensive care bed is fully investigated. In patients the usages of high equipped with new state-of-the-art bedside “Evidence Based Medicine” tries to pro- oscillatory ventilation modes in combination monitoring and data management systems vide best up-to-date quality data for special with extracorporal lung assist devices in pa- as well as ventilators and all available sys- questions concerning the treatment of patients with acute lung injuries are scientifi- tems to treat all kinds of organ failure. tients. The facilitation of an evidence based cally accompanied. The department further consists of a section way of thinking and behaviour in the periop- for trauma and emergency medicine, which erative medicine is the aim of the research is responsible for clinical education as well group. For this purpose systematic reviews as research in this field of medicine.

The department provides as well a modern simulation centre for anaesthesia and emergency cases. An artificial patient, equipped with computer technology, allows the realistic training of routine anaesthetic procedures as well as the handling of rare emergency events.

The section “Scientific anaesthesiology” (chair: Mrs. Prof. Dr. rer. nat. C. Förster) allows the handling of scientific and clinical approaches in close collaboration with scientists and modern fundamental research techniques. Abb. 1: Translocation of opiod receptors to the cell membrane in neutrophils before (left) In addition to patient care and education of and after (right) stimulation.

60 Abb. 2: Morphological changes of the F-actin cytosceleton in microvascular brain endothelial cells without (A) and with (B) glucocorticoid treatment.

Blood-Brain-Barrier Intelligent diagnosis and monitoring (C. Förster) systems (J. Broscheit) Brain capillaries generate a tight barrier between the blood and the neurons in the The development of intelligent knowledge central nervous system (CNS). The so called based systems, which support the anaes- blood-brain-barrier (BBB) consists of endo- thesiologist during daily work, is the aim of thelial cells lining the brain capillaries. The this group. The research group is cooper- endothelial cells perform inter-cellular tight- ation with the Lehrstuhl IV, Künstliche In- junctions composed of members of the telligenz und Angewandte Informatik, Insti- claudin family. Several diseases of the CNS tuts für Informatik of the University of Würz- derange the BBB and result in diminished burg. expression of the claudin proteins. The scientific aim is the identification of molecular targets of steroids in the BBB and the un- Trauma emergency room management derlying signal transduction pathways. Ad- (T. Wurmb) ditional the molecular functions of different tight junction proteins of the BBB during the The initial diagnostic and therapeutic treat- CNS development are investigated. ment of polytraumatized patients is performed by a multidisciplinary medical staff Burek M, Förster CY (2009); Cloning team in the trauma emergency room. The and characterization of the murine clau- Microcirculation development of algorithms and operating din-5 promoter. Mol Cell Endocrinol. (C. Wunder) procedures to provide optimal support for 27;298:19-24. these patients at high risk are performed by Schuster F, Metterlein T, Negele S, Kranke The term microcirculation denotes the clinical investigations. P, Muellenbach RM, Schwemmer U, Roew- bloodflow in the smallest vessels and capil- er N, Anetseder M. (2008); An in-vivo laries. The perpetuation of the microcircu- metabolic test for detecting malignant hy- lation in the different organs is fundamen- perthermia susceptibility in humans: a pilot study. Anesth Analg. 107:909-914. tal for the function and metabolism of the different cell populations. The patho-physi- Schick MA, Isbary TJ, Schlegel N, Brugger ological coherences of the microcirculatory J, Waschke J, Muellenbach R, Roewer N, disturbances in the liver and the intestine Wunder C (2009) The impact of crystal- loid and colloid infusion on the kidney in during systemic inflammatory states and rodent sepsis. Intensive Care Med. 2009 shock are the aim of the investigated proj- Nov 5. [Epub ahead of print]. ects. The organ failure of the liver and / or the intestine is associated with a high mor- Stumpner J, Redel A, Kellermann A, Lotz tality. By means of small animal models and SELECTED PUBLICATIONS CA, Blomeyer CA, Smul TM, Kehl F, Roew- er N, Lange M (2009); Differential role of clinical studies the underlying mechanisms Pim-1 kinase in anesthetic-induced and of microcirculatory failure in the liver and in- ischemic preconditioning against myocar- testine and the potential therapeutic inter- dial infarction. Anesthesiology 111:1257- ference are investigated. 1264. Rittner HL, Hackel D, Voigt P, Mousa S, Stolz A, Labuz D, Schäfer M, Schaefer M, Stein C, Brack A (2009); Mycobacteria at- tenuate nociceptive responses by formyl peptide receptor triggered opioid peptide release from neutrophils. PLoS Pathog. 5(4):e1000362. Epub 2009 Apr 3. 61 3.3 Department of General, Visceral, Vascular and Pediatric Surgery (Surgery I)

Professor Dr. med. Christoph-Thomas Germer Mission Major Research (Head of the Department) and Structure Interests

Oberdürrbacher Str. 6 The Department of General, Visceral, Vas- New points of focus include some very in- 97080 Würzburg cular and Pediatric Surgery covers the teresting areas of surgical research. Proj- Tel.: 0931/201-31000 whole spectrum of services in all these sur- ects examine clinically relevant questions in Fax: 0931/201-31009 gical fields. The department has 132 beds, close cooperation with the fundamental re- E-mail: [email protected] including intermediate and intensive care search department. In addition to a modern www.zom-wuerzburg.de units. Six thousand surgical procedures are repertoire of analyses in cell and molecular performed every year. Specialized consulta- biology, protein chemistry and immunology, Professor Dr. med. Burkhard Höcht tions hours are available to patients: the projects are equipped with relevant ani- CONTACT DETAILS CONTACT Tel.: 0931/201-31071 mal models. For example, the anti-tumour • interdisciplinary tumour surgery effect of antibodies on human tumours is Professor Dr. rer. nat. Karin Ulrichs • oesophagus and gastric diseases being investigated in vivo in pre-clinical xe- Tel.: 0931/201-31700 • liver, gallbladder, and pancreas nograft models. Last year the Society of Ba- • endocrine diseases varian Surgeons (Vereinigung der Bayerisch- Professor Dr. rer. nat. Ana Maria Waaga-Gasser • gastrointestinal diagnosis en Chirurgen) honoured the achievements Tel.: 0931/201-31715 • endoscopy, proctology and endosonog- in this field with the Otto-Götze Prize. raphy • vascular and pediatric surgery Some of the project heads are also members of the Excellence Academy, a cooperation of the German Society of Surgery Clinical (Deutsche Gesellschaft für Chirurgie) and Services the German Research Foundation (DFG) that promotes young scientists. The proj- Oncological surgery is one of the major ects network within the university and also fields in the department. Centre of Intes- with many national and international groups. tinal Medicine, a certified, interdisciplinary One example is the joint project with the In- centre, was established two years ago. Pa- stitute for Molecular Infection Biology. This tients are treated according to the therapy project, funded by the Federal Ministry of guidelines of the tumour board. Special ex- Education and Research (BMBF), investi- pertise exists in the care of gastric, pancre- gates the special complex of problems of as and rectal cancer, primary and secondary hospital infections. Another example is a liver cancer, and thyroid cancer. cooperation on oncology with the Biocenter Würzburg, Chair of Physiological Chemistry The endocrinology unit treats the dysfunc- II (Prof. Dr. M. Eilers). Projects are also in- tion of parathyroid and adrenal glands with tegrated in research centres of the univer- minimally invasive thyroid surgery and mon- sity, such as the Interdisciplinary Centre for itoring of the recurrent laryngeal nerve. Clinical Research (IZKF) and the graduate schools (Graduiertenkollegs). The success The coloproctology unit offers therapies for of these projects can be seen in the third hemorrhoids, incontinence, constipation, party funding, patents, prizes, awards, and and complicated anal fistulas. Special ex- scholarships attained. Further information pertise also exists for the treatment of ab- on the following projects is available on the dominal wall hernias. Patients with morbid web site of the department: adiposity are cared for by an interdisciplinary team of surgeons, internists and psychologists (Würzburger Model). Clinical Studies (U. Dietz, Th. Meyer, J. Pelz, A. Thal- The pediatric unit provides the best of care heimer) for the full range of clinical pediatric needs. These include the operative care of premature births, treatment of birth defects, basic pediatric urology, and pediatric traumatology.

The vascular surgery unit treats abdominal aortic aneurysms with aorta-iliac bifurcation prostheses. Aorta and iliac vascular diseases are treated with endovascular procedures. Our surgeons are well experienced Fig.1: Many different in vitro and in vivo in femur crural artery bypass surgery and tests are part of a modern repertoire of carotid artery surgery. analyses.

62 total recovery from type 2 diabetes. We are presently working on joint projects on this topic with the Chair of Anatomy and Cell Bi- ology I (Prof. Dr. H. Koepsell) and the De- partment of Investigative Medicine, Ham- mersmith Hospital, Imperial College Lon- don, UK (Prof. CW le Roux).

Fig. 2: Minimally invasive evidence of human tumours in bowel (A) and liver (B) in Tissue Engineering xenograft models using bioluminescence (U. Dietz, Th. Meyer) imaging. Biocompatible materials are being tested to determine if they could replace the artificial materials presently used for treating large Studies in oncology (peritoneal carcinosis, congenital defects of the abdominal wall. rectal cancer), pediatric surgery (compres- The project “Adhesion of tumour cells on sion therapy for burns and scalds of chil- surgical sutures” examines modifications dren), and tissue engineering (two-compo- of sutures to prevent the adhesion of tu- nent nets) are currently in progress. mour cells.

Infection / Inflammation Transplantation-Immunology (U. Lorenz, N. Schlegel) (I. Klein, C. Otto, U. Steger, K. Ulrichs)

Surgical implant materials are being tested Different projects examine regulatory im- for their resistance to staphylococcus aure- mune cells in vitro and in vivo in several es- us infections. The project “Pathophysiology tablished animal models and how they in- of the intestinal barrier in the case of acute hibit immune responses. They play a very inflammation” examines the intercellular important role in transplantation medicine signalling pathway following the breakdown because they are involved in the formation of the intestinal barrier. This might lead to of graft-specific tolerance. They prevent the new pharmacological approaches to stabi- patient’s immune cells from destroying the lize the intestinal barrier. essential but foreign organ or graft. Sever- al projects deal with liver immunology because inhibitory responses often occur in Oncology the liver. Schatton T, Murphy GF, Frank NY, Yamau- (C. Otto, J. Pelz, U. Steger, A. Thalheimer, B. ra K, Waaga-Gasser AM, Gasser M, Zhan v. Rahden, A. M. Waaga-Gasser) Q, Jordan S, Duncan LM, Weishaupt C, Fuhlbrigge RC, Kupper TS, Sayegh MH, The development of tumours in the gastro- Teaching Frank MH. (2008) Identification of cells intestinal tract is being examined. Pre-clini- initiating human melanomas. Nature 451(7176):345-349. cal experimental models should lead to new All aspects of modern surgery are covered therapy concepts for cancer of the colon, in lectures and seminars in the advanced Thalheimer A, Schlemmer M, Bueter M, colorectal liver metastases, and peritone- education programme. The medical faculty Merkelbach-Bruse S, Schildhaus HU, al carcinosis. We are working in coopera- awarded the department the Albert-Kölliker Buettner R, Hartung E, Thiede A, Mey- er D, Fein M, Maroske J, Wardelmann tion with Prof. Dr. G. Schönfelder, Institute teaching prize for its outstanding teaching E. (2008) Familial gastrointestinal stro- of Pharmacology and Toxicology. Further commitment. Bedside teaching has been mal tumors caused by the novel KIT exon points of focus are the interaction between optimized to ensure a qualified practical 17 germline mutation N822Y. Am J Surg cancer cells and immune cells on a cellular training. An Interdisciplinary Training and Pathol. 32(10):1560-1565. and molecular level, and the metabolism of Simulation Centre (INTUS) was established Lorenz U, Hüttinger C, Schäfer T, Ziebuhr cancer cells. in the SkillsLab to give students more op- W, Thiede A, Hacker J, Engelmann S, portunities to improve their operating skills Hecker M, Ohlsen K. (2008) The alterna-

on training simulators under realistic condi- SELECTED PUBLICATIONS tive sigma factor sigma B of Staphylococ- Metabolic Disorders tions. Training courses for thyroid and mi- cus aureus modulates virulence in experimental central venous catheter-related in- (M. Bueter, C. Jurowich) crosurgery, laparoscopic operation proce- fections. Microbes Infect. 10(3):217-223. dures, as well as advanced training in gas- Type 2 diabetes mellitus is a common con- trointestinal diagnostics and endosonosco- Kim M, Reibetanz J, Boenicke L, Germer comitant disease in patients with adiposity. py are offered on a regular basis. CT, Jayne D, Isbert C. (2009) Quality of life Conservative therapies to treat morbid adi- after transperineal rectosigmoidectomy. Br J Surg. 97(2):269-272. posity are seldom successful. In contrast, different methods of bariatric surgery lead Gattenlohner S, Germer C, Muller-Hermel- to a marked improvement, and sometimes ink HK. (2009) K-ras mutations and cetux- imab in colorectal cancer. N Engl J Med. 63 360(8):835-836. 3.4 Department of Trauma-, Hand-, Plastic- and Reconstructive Surgery

Professor Dr. med. Rainer Meffert General cal outcome of subtalar joint dislocations as (Head of the Department) Information well as the outcome after operative treatment of distal radius fractures. In addition, Oberdürrbacher Str. 6 In the department of Trauma, Hand, Plas- there is a multi center study II of the spine 97080 Würzburg tic and Reconstructive surgery 18 medical group of the German society of traumatol- Tel.: 0931/201-37000 doctors are occupied. For the treatment gy. Moreover, we additionally examine the Fax: 0931/201-37009 of patients, 52 beds are available on our outcome of thoracal and lumbar spine frac- E-mail: [email protected] wards. Additional beds are available on the tures. Another prospective study deals with www.klinik.uni-wuerzburg.de/unfallchirurgie Intensive Care Unit and the Intermediate different surgical treatments of incomplete Care unit burst fractures of the thoracal and lumbar Professor Dr. med. Arnulf Weckbach spine and the influence of hydroxylapatit for CONTACT DETAILS CONTACT Tel.: 0931 201-37010 There is a close cooperation inbetween the the biological fusion in the treatment of ven- department of genereal surgery, the depart- tral monosegmental spondylodesis of un- ment of anaesthesiology and the institute of stable fractures of the thoraco-lumbar. Be- radiology in regard to the interdisciplinary sides, the use of DBM versus autologous treatment of patients. tricortical bone chips is examined.

Polytraumatized patients are first examined The focus of the experimental research was and treated in the modern shock room with also extended. Two of our research groups spiral CT. Other functional facilities as the are supported by the IZKF now. One of these central sterilisation, the operating theatres, groups examines the influence of VEGF165 the intensive care units and the physiother- on the experimentally induced musculo- apy facilities are of highest standard. More- skeletal trauma. Because of very promis- over, angiography, CT and MRI are avail- ing results they now also examine the influ- able. ence of another proangiogenic growth factor (CYR61) in coorperation with Prof. Schü- tze of the Department of Orthopaedics. Be- Care sides, the influence of CYR61 on skeletal muscle cells is examined. After approval by The different focuses of the department of the local ethics commitee muscle cells of Trauma, Hand, Plastic and Reconstructive patient´s are generated and cultured. Be- surgery are represented in different con- sides, the biocompatibility of silicone coat- sultation hours. These are nect to the gen- ed implants are examined. Since 2007 we eral consultation hour, one for spinal frac- have a set up for biomechanical testings. tures, pelvic fractures and problem frac- Projects enclose biomechanical testings of tures, Berufsgenossenschaft, for hand, for implants in hand surgery and e.g. for an- arthroscopy of the knee and shoulder as kle fractures with special respect to osteo- well as for joint replacement and for injuries porotic bones. In addition, different locking of the foot. Besides, there are consultation plates for fractures of the metacarpal bones hours for asthetic and plastic surgery. are tested.

The main focuses of our department are reflected in the statistics of more than 3000 operations per annum. These include about 180 interventions of the spine. About 60 interventions in the pelvic ring, 150 os- teosynthesis of long long bones and about 300 complicated joint injuries. We perform about 500 surgeries on the hand and 300 in plastic surgery. Within the scope of trauma network we treat about 100 polytraumatized patients interdisciplinary.

Major Research Interests

Our current clinical studies include a prospective randomerised study for the treatment of fractures of the clavicle, a retrospective study of complications of locking Fig. 1: Biomechanical testing of a new- plates in the treatment of proximal humerus ly developed angle-stable external ankle fractures. Additionally, we analyze the clini- plate.

64 Fig. 2: Experimen- tal fracture model to test angle-stable mini implants at the metacarpals.

Teaching

Education is divided into eduation of students as well as into teaching for our doctors on daily rounds and discussions. Since this semester the number of the weekly main lectures for students was doubled. At the end of the semester we have got a repi- titorium in which students are able to repeat the content of the semester with the help of patient related cases. In addition, there are two grand rounds every week. Twice per day indications are discussed. For students we offer a great variety of hospitations. Besides, we continously have foreign students visiting. The extensive teaching offer for the students also integrates clinical investigation courses, training periods with ‚bedside-teaching‘, weekly block training periods as well as different consultation hours. Every three months we organise an interdisciplinary polytrauma conference which is well accepted. Inhere, everybody can present their own subject related cases to be discussed.

Raschke MJ, Josten C, Gebhard F, Ruch- holtz S, Stöckle U, Meffert R, Zwipp H. University benchmarking. A current status analysis. Unfallchirurg. 2009 Oct;112(10):896-903.

Jakubietz RG, Jakubietz MG, Jakubietz DF, Koehler G, Zeplin PH, Meffert RH, Schmidt K. Ischial pressure sores: reconstruction using the perforator-based reverse flow musculocutaneous 180 degrees propeller flap. Microsurgery. 2009;29(8):672-5.

Jakubietz R, Grünert JG, Kloss DF, Meffert R, Schmidt K, Jakubietz MG. Aging and the appearance of the hand. Hautarzt. 2009 Mar;60(3):217, 220-5.

Wurmb T, Balling H, Frühwald P, Keil T, Kredel M, Meffert R, Roewer N, Brederlau

SELECTED PUBLICATIONS J. Polytrauma management in a period of change: time analysis of new strategies for emergency room treatment. Unfallchirurg. 2009 Apr;112(4):390-9.

Meffert RH, Frey SP, Jansen H, Ochman S, Raschke MJ, Langer M. Muscle strength quantification in small animals: a new transcutaneous technique in rabbits. J Or- thop Res. 2008 Nov;26(11):1526-32. 65 3.5 Institute of Transfusion Medicine and Haemotherapy

Professor Dr. med. Markus Böck Mission (Head) and Structure Teaching

Oberdürrbacher Str. 6 The Institute of Transfusion Medicine and • Main lecture “transfusion medicine” 97080 Würzburg Haemotherapy is localized at three posi- • Lecture “Blood group serology and trans- Tel.: 0931 201-31300 tions within the hospital area. It provides fusion therapy” Fax : 0931 201-31376 • a laboratory for blood group serology • Lecture “Immunohaematology” E-mail: [email protected] • a laboratory for HLA-typing • Lecture “Therapeutical and preparative www.transfusionsmedizin.uni-wuerzburg.de • a GMP-laboratory for modification and apheresis” cryopreservation of stem cell concen- • Lecture “Transfusion in difficult pa- trates tients”

CONTACT DETAILS CONTACT • a blood bank for supplying the university • Lecture “Production of blood compo- hospital with blood components nents” • a blood donation department • Lecture “Biology and function of red • a department for therapeutical aphere- cells” sis • Lecture “Transfusion therapy with and • a register for stem cell donors without red cells” • Lecture “Stem cell transplantation: from the donor to the transplant” Clinica • Lecture “The HLA-system” activities • Pracitcal training “Transfusion medicine and immunohaematology” The Institute of Transfusion Medicine and • Pracical training “Blood group serology” Haemotherapy supplies the university hospital of Wuerzburg with all required blood products, e.g. red cell concentrates, platelet concentrates and fresh frozen plasma. Additionally, it is competent for the production of autologous and allogenic stem cell concentrates for adult patients of the hospital. Beside immuno-haematological laboratory analyses (e.g. blood group serology, red blood cell cross match, antibody screening, antibody differentiation) the Institute of Transfusion Medicine and Haemothera- py provides HLA-testing for the patients of the hospital with serological and DNA-based methods. It is responsible for the search of compatible stem cell donors and organizes a stem cell donor registry for the national and international donor mediation. In addition, the Institute of Transfusion Medicine and Haemotherapy is specialized in the enforce- ment of therapeutical aphereses (e.g. plas- mapheresis, immunoadsorption, cell-apheresis). Furthermore, quality assurance in haemotherapy for the university hospital is one of the central functions of the institute.

Major Research Interest

Biochemical and functional comparison of different platelet concentrates

Platelet concentrates are obtained by apheresis or by buffy coat method. One of the research activities of the Institute of Trans- fusion Medicine and Haemotherapy is the biochemical and functional characterization and comparison of these two types of plate- Fig. 1: Platelets from a stored platelet let concentrates. concentrate.

66 Chuang W.Y., Ströbel P., Belharazem D., Rieckmann P., Toyka K.V., Nix W., Schalke B., Gold R., Kiefer R., Klinker E., Opitz A., Inoue M., Kuo T., Müller-Hermelink H.K., Marx A. The PTPN22gain-of-function+18 58T(+)genotypes correlate with low IL-2 expression in thymomas and predispose to myasthenia gravis. Genes & Immu- nity. ww.nature.com/doifinder/10.1038/ gene.2009.64.

Kapp M., Stevanovic S., Fick K., Tan S.M., Loeffler J., Opitz A., Tonn T., Stuhler G., Einsele H., Grigoliet U. CD8+ T-cell responses to tumor-associated antigens correlate with superior relapse-free survival after allo-SCT. Bone Marrow Transplanta- tion. 2009; 1-12.

Schöttker B, Feuchtinger. T, Schumm

SELECTED PUBLICATIONS M., Klinker E., Handretinger R, Einsele H., Stuhler G. Five-donors one recipient modeling a mosaic of granulocytes, natural killer and T cells from cord- blood and third-party donors. www.nature.com/clini- calparctice - doi: 10.1038/ncponc1105.

Kobsar A., Heeg S., Krohne K., Opitz A., Walter U., Böck M., Gambaryah S., Ei- genthaler M. Cyclic Nucleotide-Regulat- ed Proliferation and Differentiation Vary in Human Hematopoetic Stem Cells derived from Healthy Persons, Tumor Patients and Chronic Myelocytic Leukemia Pa- tients Stem Cells and Development 2008; 17(1): 81-92. 67 3.6 Department of Thoracic and Cardiovascular Surgery

and for patients requiring aortic surgery. In rently investigating the effect of CD28- an- Professor Dr. med. Rainer G. Leyh addition there is a tumour outpatient clinic tibodies on tolerance induction. The second (Head of the Department) for thoracic tumours. step will be the reversal of tolerance induction by CTLA4-antibodies. Furthermore, we Oberdürrbacher Str. 6 Within a radius of 100 kms we represent are preparing experimental studies to as- 97070 Würzburg the sole institution which offers the full sess the immunosuppressive properties of Tel.: 0931/201-33001 range of adult heart surgery including heart inhibitory blocking peptide (IBP, Dr. Lange Fax: 0931/201-33009 transplantation and simultaneous manage- in cooperation with PD Dr. Ritter from the E-mail: [email protected] ment of any kind of thoracic surgery includ- department of cardiology). IBP inhibits the www.htc-wuerzburg.de ing tracheal surgery. protein which is responsible for transferring calcineurin into the nucleus without the dra-

CONTACT DETAILS CONTACT Main areas of interest are total arterial re- matic side effects of classical calcineurin vascularization, beating heart bypass sur- inhibitors like cyclosporine A or tacrolimus. gery, reconstructive valve surgery includ- Knock-out- mice will serve as study animals ing DAVID-, YACOUB-procedures. In 2009 for Nrf-2 transcription factor and ist effect transapical/transfermoral minimally-inva- on oxidative stress. sive aortic valve replacements were introduced into routine clinical practice. This is a joint project with the Department of Cardi- Heart / lung transplantation ology. In selected patients we also offer the ROSS procedure. Over the last two years Drs. Sommer and Prof. Sinha have established a rat model A mobile heart-lung-machine (Lifebridge) for the induction of pulmonary ischemia-reis available for improved management of perfusion-injury (IR). Susceptability to infe- heart or lung failure patients. Such patients cetion and function of pulmonary mitochon- are transferred to our hospital through a dria during IR are determined. The influ- dedicated team from our department. ence of mitochondrial function on IR is unknown. Utilizing single-lung-transplantation Approx. 400 thoracic cases are performed the function of AMs, mitochondria and sur- per year. Main areas of interest are extra- factant during IR is examined. Isolated AMs pleural pneumonectomies for mesothelio- will be examined regarding their function ( ma and minimally-invasive procedures and phagocytosis, cytokine-secretion, NO-syn- laser resections. We are proud to offer the thesis). Resveratrol will be used to modify only laser system in the region. The laser these functions. The results are expected to enables us to perform cancer surgery with a improve the outcome after lung-transplan- maximum protection of healthy tissue. tation. The project is partly funded by the interdisciplinary center for clinical research In addition we cover the entire field of ar- Würzburg (IZKF). rhythmia surgery. Apart from pacemaker, ICD In addition the impact of volatile anesthetics and biventricular device implantations we on myocardial infarction in a mouse model routinely perform Mini-MAZE procedures for is examined in cooperation with the depart- the surgical treatment of atrial fibrillation. ment of anaesthesiology (Dres. Lange and Stumpner). Another cooperation with PD Dr. Mission Otto from experimental tumorimmunology and Structure Major Research (ETI) will examine mitochondrial function of Interests isolated tumor cells and the dependency of The department of Thoracic and Cardiovas- different tumors from glykolysis and oxida- cular Surgery is a 56-bed department with Cardiac surgery: tive phosphorylation. 3 operating theaters and its own 14 bed in- Ross operation tensive care/intermediate care unit. At present 20 physicians and 1 psychologist are By means of MR and CT-scanning we eval- Quality of life of surgeons working in this department. uate the impact of different implant techniques of the pulmonary autograft on post- This project is a cooperation with the Ger- Approximately 2000 procedures are per- operative RV function (Dr. Gorski, Dr. Som- man Society for Surgery (DGCh; Prof. Bauer formed annually covering the entire field of mer). Data from all Ross procedures are for- and PD Dr. Bohrer) adult heart and thoracic surgery. 950 pro- warded to the German Ross registry. cedures are open heart surgeries with extra- corporeal circulation. Neuropsychological studies and cardiac Transplant vasculopathy after heart surgery In 2007 an assist device program was es- transplantation tablished and the heart transplant program Studies on neuropsychological abilities with relaunched. Specialized outpatient clinics After establishing a heterotopic rat heart the computer-based test “TAP” have been provide care for transplant and VAD patients transplant model (Dr. Lange) we are cur- cmpleted and the results presented. In the

68 near future, the TAP will be compared with In addition we are proud to offer a new sem- the standard “paper and pencil” tests. We inar on „ethics in surgery“ starting in fall expect the TAP-data to be more reliable and 2007. robust. It would enable us to routinely examine cardiac surgical patients in a neuro- This department is the only one in the state psychological manner. Similar studies with of Bavaria which offers German board certi- patients undergoing transapical aortic valve fied training in cardiac surgery, cardiac sur- replacements are under way (Dr. Krannich) gical intensive care medicine and thoracic surgery within one department.

Prevention and therapy of deep sternal In 2010 we are planning to host two clini- wound infections (DSWI) cal fellows from Serbia and Tadjikistan, respectively. At present we are conducting a double- blind, randomized study with antibiotics-releasing felts (Gentacoll) regarding the incidence of DSWI. We are leading the inauguration of a working group (“wound management”) of the German society of Thoracic and Cardiovascular Surgery (DGTHG). We plan to establish a nationwide registry on DSWI and hope to deduct scientific guidelines for the prevention and therapy of DSWI (Dr. Schimmer)

Thoracic surgery

Predictive markers of non-small cell lung cancers and stem cells (Dr. M. Lazariotou). Establishment of a nationwide registry “malignant mesothelioma” (PD Dr. Bohrer), History of thoracic surgery at the Univer- sity Hospital Würzburg since 1945 (PD Dr. Bohrer) Outocme of patients with empyema (Dr. Aleksic I, Sommer SP, Kottenberg-Assenm- Hamouda) acher E, Lange V, Schimmer C, Oezkur M, Leyh RG, Gorski A. Cardiac operations in Surgery for pulmonary nodules an estab- the presence of meningioma. Ann Thorac Surg. 2009 Oct;88(4):1264-8. lished therapeutic approach. However, the psychological benefit of these procedures Schimmer C, Reents W, Berneder S, Ei- in patients with underlying benign or ma- gel P, Sezer O, Scheld H, Sahraoui K, Gan- lignant disease has not been investigated sera B, Deppert O, Rubio A, Feyrer R, at all yet. Therefore, the quality of life after Sauer C, Elert O, Leyh R. Prevention of sternal dehiscence and infection in high- thoracic surgery needs to be examined (Dr. risk patients: a prospective randomized Krannich, Dr. Bohrer, Dr. Neukam). multicenter trial. Ann Thorac Surg. 2008 Dec;86(6):1897-904.

Krannich JH, Herzog M, Weyers P, Lu- eger S, Faller H, Bohrer T, Lange V, Elert Teaching O, Leyh R. Patients‘ needs during hos- pitalization in a cardiac surgery unit be- All topics of cardiothoracic surgery relevant fore and after coronary artery bypass graft to the medical student are covered by a lec- SELECTED PUBLICATIONS surgery. Thorac Cardiovasc Surg. 2009 Feb;57(1):22-4. ture series and regular „bed-side“-teaching plus grand rounds. Since 2007 2-3 medi- Lange V, Renner A, Sagstetter MR, Laz- cal students spend two weeks in the depart- ariotou M, Harms H, Gummert JF, Leyh ment as part of a mandatory surgical rota- RG, Elert O. Heterotopic rat heart transplantation (Lewis to F344): early ICAM- tion. Final year medical students spend a 1 expression after 8 hours of cold isch- 16 week rotation in our department. emia. J Heart Lung Transplant. 2008 Sep;27(9):1031-5. A new weekly cardiology/cardiac surgery conference is a mainstay for the education Schimmer C, Sommer SP, Bensch M, Bohrer T, Aleksic I, Leyh R. Sternal clo- of our residents. sure techniques and postoperative sternal wound complications in elderly pa- 69 tients. Eur J Cardiothorac Surg. 2008 Jul;34(1):132-8. 3.7 Department of Urology and Paediatric Urology

Mission of patients the risk of biochemical progres- Professor Dr. med. Hubertus Riedmiller and structure sion within a 5-year period is approximate- (Head of the Department) ly 40%. The Department of Urology and Paediatric We evaluate the outcome of surgical tech- Oberdürrbacher Str. 6 Urology is a tertiary referral centre with two niques in high risk PCa in an european mul- 97080 Würzburg general wards (54 beds), intensive care unit ticenter study. Tel.: 0931/201-32001 (8 beds) with haemodialysis facility, a busy Fax: 0931/201-32013 outpatient clinic with uroradiology section, E-mail: [email protected] point-of-care lab and a research laboratory Identification of tumor supressors or www.urologie.uni-wuerzburg.de with an emphasis on molecular urooncolo- onco- microRNAs in prostate cancer gy. Three state-of-the-art operating theatres (B. Kneitz, M. Possner, M. Spahn)

CONTACT DETAILS CONTACT allow the surgical treatment of approximately 2.500 adults and 350 children and ado- The aim of our studies is to analyse the lescents with 2.500 conventional open and role of miRNAs for the development and laparoscopic procedures and more than progression of prostate cancer. Tumor tis- 1.800 endourologic interventions per year. sue from a European multicenter database The equipment comprises a multi-function is used for the analysis. Using microarrays unit for extracorporal shockwave lithotrip- and qRT-PCR miRNA analysis we detected sy, a computer-assisted (video)urodynamic specific miRNA signatures for prostate can- set-up, lasers of the most recent genera- cer (Figure 2). By bioinformatics and statis- tion and several ultrasound machines with tical analysis specific miRNAs were identi- colour-coded duplex sonography and tran- fied, which are linked to the development srectal probes. and progression of cancer. To study the molecular mechanisms of such miRNAs we are The surgical spectrum encompasses the currently studying the function of specific entire speciality of urology (high volume miRNAs in vitro. centre) with special expertise in urooncol- ogy (particularly orthotopic bladder substitution and continent cutaneous/heterotop- Aberrant expression of spindle check- ic urinary diversion following radical cystec- point genes in high grade prostate can- tomy, nerve-sparing; radical perineal and cer retropubic prostatectomy/nerve-sparing; (B. Kneitz) nephron-sparing surgery of renal cell cancer; polychemotherapy); paediatric urology To understand the role of aberrant expres- (correction of complex congenital malfor- sion of mitotic spindle checkpoint (MSC) mations), reconstructive urology (all types genes for the development of PCa we ana- of urinary diversion and conversion, recon- lysed the expression of two MSC genes. In struction of the whole urinary tract, ureteral addition we studied the effect of Bub1b hap- replacement, open urethral reconstruction, lo- insufficiency for induction of genomic in- complex fistula repair) including implanta- stability and resistance against therapeutic tion of artificial urinary sphincters and pe- agents in vitro. We could show that spindle nile prosthesis, urogynaecology and renal checkpoint genes are frequently down reg- transplantationen (cadaver and living relat- ulated in high grade PCAs. Our results sug- ed transplantation). gest that the expression of MSC genes may be helpful biomarkers and might be involved Major Research In- terests

Translational Prosatate Carcinoma Research Treatment of patients with high risk prostate cancer (M. Spahn, B. Kneitz)

The percentage of patients with high risk prostate cancer (PCa) (>T2c or PSA >20 ng/ml or Gleason score >8) is still significant (2003: 22%). In this group Fig. 1: MiRNA expression signature of Prostate cancer.

70 Identification of tumor- suppressor- und onco- microRNAs in bladder- and renal cell carcinoma. (B. Kneitz, A. Kocot, D. Vergho)

Fig. 2: Generation of a transgenic mouse model to inac- The aim of our studies is tivate mismatch repair activity in the prostate using the Cre- to analyse the role of miR- loxP system. NAs for the development and progression of bladder and renal cell can- in malignant progression of PCAs and failure cer. Using microarrays and qRT-PCR miRNA of treatment using cytotoxic agents. analysis we detected specific miRNA signatures for both cancer entities. By bioinformatics and statistical analysis specific miR- Impact of mismatch repair defects on NAs were identified, which are linked to the pathogenesis and prognosis of prostate development and progression of cancer. To cancer study the molecular mechanisms of such (B. Kneitz, M. Spahn) miRNAs we are currently studying the function of specific miRNAs in vitro. To answer the question what impact mismatch repair (MMR) defects play for PCa development we generated novel mouse models based on a prostate specific inac- Teaching tivation of the MMR system using the Cre- LoxP. This model will provide the opportunity Traditional teaching formats (lecture with to study the molecular and genetic mecha- clinical case presentation and live trans- nisms of the early development, progres- mission of surgical procedures from the sion and eventually metastasis of PCa and operating theatre; clerkships/electives) are will allow to functionally explore different offered along with integrated and interdis- therapies in vivo. ciplinary approaches. Participation in skills lab, e-learning-programmes, interdisciplin- E Avdievich, C Reiss, SJ Scherer, Y Zhang, Characterization of the humoral immune ary oncology (seminar and lecture), emer- SM Maier, B Jin, HH Jr, A Rosenwald, H response and identification of new diag- gency medicine, integrated seminars in Riedmiller, R Kucherlapati, PE Cohen, W nostic molecular marker in transitional tumor biology, interdisciplinary paediatric Edelmann and B Kneitz: (2008) Distinct cell carcinoma pathophysiology and courses in prevention, Effects of the Recurrent Mlh1G67R Mu- (P. Ardelt) epidemiology and biostatistics. Hos-pitation tation on MMR Functions, Cancer and Meiosis. Proc Natl Acad Sci. 2008 Mar in the operating theatre and outpatient clin- 18;105(11):4247-52. Intravesical immunotherapy with Mycobac- ic is possible throughout the en-tire aca- terium bovis Bacillus Calmette-Guerin (BCG) demic year. Spahn M, Vergho D, Riedmiller H. (2009). is the current standard of care against su- Iatrogenic recto-urethral fistula: perineal repair and buccal mucosa interposition. perficial high-grade transitional cell carci- BJU Int. 2009;103(2): 242-6. noma of the urinary bladder (carcinoma in situ, pT1G3). However, individual patient Spahn M, Kneitz S, Scholz CJ, Nico S, Rü- outcome is hardly predictable due to the diger T, Ströbel P, Riedmiller H, Kneitz B lack of serum markers. As a result, progres- (2009). Expression of microRNA-221 is progressively reduced in aggressive pros- sion to muscle-invasive bladder cancer and tate cancer and metastasis and predicts critical delay of treatments (such as neo- clinical recurrence. Int J Cancer. 2009, in

adjuvant combination chemotherapy and/or SELECTED PUBLICATIONS press. radical cystectomy) often occur. Ardelt PU, Kneitz B, Adam P, Reiss C, Ko- cot A, Fensterle J, Chen L, Pasqualini R, We identified a biomarker capable of mea- Arap W, Gerharz EW, Riedmiller H.(2009). suring immune response induced by BCG Reactive antibodies against bacillus and therefore predicting the outcome of this Calmette-Guerin heat-shock protein-65 therapy: Antibody production against M. bo- potentially predict the outcome of immunotherapy for high-grade transitional cell vis BCG HSP-65 can serve as a serolog- carcinoma of the bladder. Cancer 2009 ical marker for the predictive outcome of in press. BCG-immunotherapy. Subsequent studies will determine the value of this candidate Spahn M, Kocot A, Löser A, Kneitz B, Riedmiller H (2009). Last Resort in Com- marker to modify BCG-mediated treatment plex Urinary Incontinence: Bladder Neck for individual bladder cancer patients. Closure and Continent Vesicostomy - Long Term Results and Comparison of Different 71 Techniques.“ Urology, 2009, in press. 3.8 Department of Orthopaedics

Professor Dr. med. Maximilian Rudert Mission Major Research (Head of the Department) and Structure Interests

König-Ludwig-Haus The Orthopaedic Department König-Lud- The Orthopaedic Center for Musculoskeletal Brettreichstr. 11 wig-Haus is a top level hospital for the treat- Research is located in a 600 sq. m labora- 97074 Würzburg ment of musculoskeletal diseases and inju- tory space (S1, S2, radioactivity) with one Tel.: 0931/803-1102 ries. The hospital is operated by the district location at Brettreichstrasse 11 and anoth- Fax: 0931/803-1109 of Unterfranken. Integrated are the Chair of er at Röntgenring 11. The Center is support- E-mail: [email protected] Orthopaedics and the Outpatient Clinic for ed by the District of Unterfranken. It is fund- www.orthopädie.uni-wuerzburg.de Orthopaedics of the University Hospital, as ed by the German Research Society (Clini- well as the Orthopaedic Center for Musculo- cal research Unit KFO 103, DFG Research

CONTACT DETAILS CONTACT Professor Dr. med. Franz Jakob skeletal Research. The Chairman of the De- unit FOR 793, several single projects), the Tel.: 0931/803-1580 partment, one full Professor of Osteology, German Ministry of Research BMBF (BMBF- 6 Associated Professors and 22 Residents Konsortium Osteopath, BMBF-Verbundpro- are taking care of the patients and teach- jekt Präeklampsie), the Ministry of Econ- ing. The hospital has 140 beds and in 4 op- omy (EXIST Phase I), the European Union erating theatres more than 4.100 surgical (EU-Konsortien ADIPOA und VASCUBONE), procedures are performed each year. The the IZKF of the University of Würzburg, the University Outpatient Clinic provides care for Arthrose Hilfe e. V. and the Research Fund about 13.500 patients a year. The König- of the State of Bavaria (Research consor- Ludwig-Haus also runs its own x-ray depart- tium cell-based regeneration of the mus- ment and physiotherapy. culoskeletal system and age, FORZEBRA), as well as several industrial cooperation. Specialities in the treatment of orthopaedic The number of positions funded is 25 (as patients are of 2009). • Arthroplasty of the Hip, Knee, Shoulder, Elbow and Tumor Prostheses • Shoulder and Elbow Surgery Key Issues in Research • Sports Medicine • Biology of Mesenchymal Stem Cells (F. • Ankle and Foot Surgery Jakob, R. Ebert, B. Mentrup, P. Benisch, • Pediatric Orthopaedic Surgery B. Klotz, N. Raijmaakers, S. Müller-Deu- • Spine Surgery bert, L. Seefried) • Tumor Surgery • Molecular Orthopaedics and Cell Biology • Orthopaedic Rheumatology (N. Schütze, T. Schilling, R. Laug, Sim- • Arthroscopy of the Knee, Shoulder, El- one Hilpert, A. Noll, K. Schlegelmilch) bow and Ankle • Tissue Engineering, Regenerative Med- • Osteology (metabolic and degenerative icine, Translation in Cell Therapy (U. diseases with a special focus in osteo- Nöth, L. Rackwitz, R. Hallinger, M. We- porosis and malignant bone disease) ber, M. Rudert) • Gene Therapy in Musculoskeletal Dis- eases (A. Steinert, P. Prager, N. Arm- Orthopaedic consulting is offered for several bruster, C. Weber) other hospitals and centers for disabled. • Molecular and Classical Biomechanics (F. Jakob, L. Seefried, S. Müller-Deu- The Orthopaedic Center for Musculoskele- bert, A. Steinert, M. Hoberg) tal Research is an interactive platform be- • Fracture Healing in Trauma and Osteopo- tween basic science, translational research rosis (KFO 103 in Cooperation with KFO and clinical implementation of innovative 102 Berlin; FOR 793) therapeutic strategies. The main research topics are mesenchymal stem cell biology and the development of cell-based therapeutic strategies for the regeneration of mesenchymal tissues, such as bone, cartilage, tendons and ligaments. The Center supports the representation of the chair in the field of Orthopaedic Surgery concerning research and teaching. The Head of the Center, Prof. Dr. Franz Jakob, is also the speaker of the Interdisciplinary Musculosk- eletal Center Würzburg MCW, which plays an important role in the development of a Fig. 1: Tumor prostheses of the hip after new research branch at the university. resection of a metastasis of the proximal femur due to a bronchial carcinoma.

72 niques and orthopaedic technical devices and corselets • Clinical ward Rounds, x-ray discussions, orthopaedic colloquia • Molecular Aspects of Bone Diseases – Genes and Cell Biology • Molecular Methods for osteology in basic science • Integrated Seminar on the Molecular Ba- sis of Musculoskeletal Diseases • TecFun Technology of Operation Materi- als

Fellowships The ortopaedic department König-Lud- wig-Haus hosts fellows from all over the world. Dedicated fellowshops are the SI- COT (Societé Internationale de Chirurgie Orthopédique et de Traumatologie) Wuer- zburg Travelling Fellowship (3 Month) and Fig. 2: Electrospinning of collagen type I fibers for tendon and ligament replacement. the Wuerzburg-Assiut SICOT Fellowship (6 Month). Each year also fellows from the ASG (Austrian-Suisse-German) Fellowship • Particle Disease and Infektion of Pros- • Special Orthopaedic Pediatric Surgery, and the German Travelling Fellowship visit theses (B. Baumann, N. Schütze) Spine and Foot Surgery (P. Raab, V. Ettl) Würzburg for one week. • Tumor Surgery and Modern Brachythera- • Clinical Studies on Osteoporosis (F. Ja- py (M. Rudert, P. Raab, M. Lüdemann) kob, L. Seefried, S. Goebel) • Special Techniques in Shoulder Joint Re- • Pain Research in Orthopaedics (S. Goe- construction (S. Goebel) bel) • Tissue Engineering of the Meniscus (M. Rudert, M. Hoberg, A. Steinert) • Nanofiber Technology and Electrospin- ning (L. Rackwitz) Teaching • Autologous Chondrocyte Transplantation ( U. Nöth, L. Rackwitz, A. Steinert, M. • Course in clinical examination tech- Rudert, T. Barthel) niques for operative and conservative • Application of mesenchymal stem cells orthopaedics for the therapy of Femoral Head Necrosis • Lectures in Basics of Orthopaedics (also and Osteoarthritis (M. Rudert, L. Rack- accompanying the practical course) witz, U. Nöth) • Practical Course in Orthopaedics (bed- Rudert M, Burgkart R, Gradinger R, Re- • Endoprosthesis of Hip and the Knee (U. Nöth, side teaching in small groups, demon- chl H. (2009) Chirurgie der Weichteilsar- M. Hoberg, M. Lüdemann, M. Rudert) strations in physiotherapy, plaster tech- kome im Bereich der Extremitäten. Chirurg 80:194-201.

Limbert C, Ebert R, Schilling T, Path G, Benisch P, Klein-Hitpass L, Seufert J, Ja- kob F. (2009) Functional Signature of Hu- man Islet-derived Precursor Cells compared to Bone Marrow-derived Mesenchy- mal Stem Cells. Stem Cells Dev 6 (E-pub ahead of print).

Schilling T, Küffner R, Klein-Hitpass L, Zim- mer R, Jakob F, Schütze N. (2008) Micro- array analyses of transdifferentiated mesenchymal stem cells. J Cell Biochem. 103: 413-433.

Nöth U, Steinert AF, Tuan RS. (2008)

SELECTED PUBLICATIONS Technology insight: adult mesenchymal stem cells for osteoarthritis therapy. Nat Clin Pract Rheumatol 4:371-380. Fig. 3: Signatur of different mesenchymal stem cells from bone marrow stroma of the femoral head (hBM-MSC) in contrast to mesenchymal Progenitors associated with pan- Steinert AF, Palmer GD, Pilapil C, Nöth creatic islets (hIPC). Besides the differential expression of different key receptors and U, Evans CH, Ghivizzani SC. (2009) En- transcription factors the cells show a „positionell memory“ based on their HoxA-expres- hanced in vitro chondrogenesis of prima- sion (from Limbert et al. 2009). ry mesenchymal stem cells by combined gene transfer. Tissue Eng Part A 15:1127- 1139. 73 3.9 Department of Obstetrics and Gynaecology

Per annum, approximately 2,200 opera- Research Project „Tumour immune es- Professor Dr. med. Johannes Dietl tions, 1,500 deliveries, 5400 DRG cas- cape“ (Head of the Department) es, 22,000 outpatient therapies (of which (J. Wischhusen, S. Häusler, A. Chandran, 3500 were chemotherapies) have been M. Junker, A. Seida, M. Ossadnik) Josef-Schneider-Str. 4 performed. Centres of the clinic are: The 97080 Würzburg interdisciplinary treatment of gynecological With funding from the IZKF, a junior research Tel.: 0931/201-25251 cancers, including breast (certified breast group could be established on the field of Fax: 0931/201-25406 centre), the centre for hereditary breast and tumour immunology. Particular attention is E-mail: [email protected] ovarian cancer, the treatment of urinary in- paid to members of the TGF-β superfamily www.frauenklinik.uni-wuerzburg.de continence and pelvic floor dysfunction, (M. Junker), as TGF-β promotes migration, care of risk pregnancies and infertility treat- invasion and angiogenesis and contributes

CONTACT DETAILS CONTACT ment including in vitro fertilisation. to “immune escape“. In a GSLS-funded collaborative project with the Max-Planck-In- stitute in Munich, immunoregulatory func- Major Research tions of TGF-β-inducible miRNAs are inves- Interests tigated (A. Chandran).

Fetomaternal interface In close association with the junior research (U. Kämmerer, L. Rieger, S. Segerer, J. Di- group, another project investigates the im- etl) munomodulatory function of the ectonucle- otidases CD39 and CD73 in the tumor mi- Haemochorial placentation in humans still croenvironment (S. Häusler). represents an unique situation: the fetus, which can be considered as a semiallogenic A further focus is placed on the explora- transplant is not rejected, even though fetal tion of the immunogenic properties of can- trophoblast cells are found in close contact cer stem cells (joint DFG-funded project BE to maternal immune cells. Factors providing 1394/9-1 together with Prof. Jürgen Beck- this adequate microenvironment for the es- er from the Department of Dermatology). tablishment of peripheral tolerance are cy- This lead to the discovery of a new „immune tokines, growth factors and hormones. escape“ mechanism which could be highly relevant for the treatment of HER2-positive breast cancer with Trastuzumab (F. Reim, Investigation of impact and function of J. Wischhusen). thrombopoietin (TPO) in human pregnancy decidua In order to screen for better tumour mark- (S. Segerer, U. Kämmerer, J. Dietl) ers, miRNA profiles are investigated in pe- Mission ripheral blood from ovarian cancer patients and Structure A new “first applicant” programme by the and age- and sex-matched healthy con- IZKF Wuerzburg promotes the investigation trols. This project i spart of a cooperation The Woman’s Hospital (bed capacity of 84, of the role of the growth factor thrombo- with the newly founded Heidelberg-based 33 doctors, 102 nurses, 14,5 midwives, poietin on the fetomaternal interface. Thus, biotech company Febit and is sponsored by 6 assistant medical technicians) has two analysis of interactions between fetal and funds for the promotion of the biotech area obstetrical and three gynecological wards, maternal cells at the feto-maternal inter- (S.Häusler. J. Wischhusen). 5 labour and delivery rooms and a Level I face should further elucidate the physiolog- Perinatal Centre with six neonatal intensive- ic control of the invasive growth of the pla- care beds, three operating rooms of most centa by the maternal immune system. Studies on function and prognostic modern standards, an operating room for value of LASP in the dissemination of caesarean sections, an intermediate-care Cooperating as a clinical research group breast and ovarian cancer unit, outpatient clinics for gynecology and (KFO 124, cooperation with the department (PA. Hönig, M. Kapp, U. Kämmerer) obstetrics, gynaecological oncology, breast of dermatology, J. Becker), we investigate cancer, dysplasias of the cervix, child and placentation as a tumor model. In project 4 LIM and SH3 domain protein (LASP) is an adolescence gynecology, urogynecology, of KFO 124 the interaction of invasive fetal actin-binding protein that plays a role in cel- endocrinology and reproductive medicine, trophoblast cells with maternal uterine im- lular migration. In a study in collaboration prenatal diagnostics. There are laboratories mune cell populations are investigated. The with the institute of clinical biochemistry for endocrinology, cytology and reproductive function of the immune cells under the in- (E. Butt), we try to analyze the expression medicine with andrology. Programs include fluence of mediators specific for pregnancy of LASP in breast cancer metastases in or- a midwifery school. In the women’s clinic are is evaluated and the trophoblast cells are der to elucidate a possible significance of also department of the Clinic for Radiation investigated with regard to their features this protein in tumour progress. Cell culture Therapy (external radiation; brachytherapy) similar to tumor cells (with focus on matrix studies investigate the function of LASP and the Institute of Radiology (mammogra- metalloproteases). in the biology of tumour cells. The project phy, vacuum biopsy) and the Department of is funded by the Deutsche Krebshilfe (No Anaesthesiology (pain ambulance). 107706).

74 Molecular analysis of gamete interaction and the influence of uropathogenic Fig. 1: Developement of the embryo from microbes on fertility the oocyte to the blastocyst. a) intracyto- (C. Rennemeier, C. Albert) plasmatic sperm injection (ICSI) of a spermatozoa in metaphase II oocyte. b) fertil- Infertility in men and women is frequent- ized oocyte, c-f) early stages of the devel- ly associated with genital contaminations opement of the embryo. caused by various microorganisms. The molecular basis of this correlation remains still elusive, and little attention has been paid on potential direct influences of commensal or uropathogenic microbes on hu- New GnRH antagonists in the treatment man gametes. Since many microorganisms of gynaecological malignancies and tri- are known to release distinct communi- ple negative breast cancer cation signalling molecules in substantial (J. Engel, A. Hönig) amounts, we raised the question whether such molecules can directly affect human GnRH seems to act as a local growth fac- gametes. Our studies revealed that signal- tor in a variety of tumours. GnRH antago- ling molecules employed by the opportunis- nists show anti-tumour efficacy in vitro and tic human pathogens Candida albicans and in vivo, but it remains unclear whether atyp- Pseudomonas aeruginosa elicit multiple ical GnRH I- or GnRH II-receptors mediate detrimental effects on human spermatozoa. these effects. „Peptidomimetic“-GnRH an- In a beginning project we investigated the tagonists, whose advantage lies in the oral interaction of uterine dendritic cells (DCs) bioavailability, represent a new pharmaco- with human spermatozoa and the influence logic strategy. With the help of in vitro tu- of seminal plasma on this interaction. mour models of endometrium, ovarian and tripel negative breast cancer, the effect of these new non-peptidic GnRH antagonists in terms of their effectiveness and mecha- Teaching nism of action is investigated. The curricular teaching in Obstetrics and Gynaecology consist of a main lecture (8th The AKT-pathway as a therapeutic target semester), seminars, clinical visits (9th se- in gynecological and breast cancers mester) and a practical training (10th se- (J. Engel, A. Hönig) mester). Additionally, a „Skills Laboratory“ Krockenberger M, Dombrowski Y, Weidler focuses on practical aspects of the subject. C, Ossadnik M, Hönig A, Häusler S, Voigt The AKT-pathway is overactivatedin various With gynaecological models and case stud- H, Becker JC, Leng L, Steinle A, Weller M, Bucala R, Dietl J and Wischhusen J. Mac- and seems to hold a key position in malig- ies, students learn to deal with clinical situ- rophage migration inhibitory factor (MIF) nant transformation by regulating a multi- ations and to handle diagnostic equipment. contributes to the immune escape of ovar- tude of actions, such as proliferation, resis- The training is complemented by a number ian cancer by downregulating NKG2D. J tance to apoptosis and chemotherapy and of interdisciplinary subjects like ethics, pre- Immunol, 180(11):7338-48, 2008. cell metabolism. Thus, proteins such as AKT ventive medicine, emergency medicine, in- Reim F, Dombrowski Y, Ritter C, Buttmann in PI3K, which are in different positions in fectious diseases, tumour biology and on- M, Häusler S, Ossadnik M, Krockenberg- that pathway are highly promising targets cology. For doctors in private practice, we er M, Beier D, Beier CP, Dietl J, Becker in cancer therapy. In endometrial cancerrs organize regular interdisciplinary conferenc- JC, Hönig A, Wischhusen J. Immunose- for instance AKT is frequently overactivated es as part of the perinatal centre. lection of breast and ovarian cancer cells with trastuzumab and NK cells: Selective by loss of its suppressor PTEN. In ovarian escape of CD44high/ CD24low/HER2low cancers overactivation of AKT is associated breast cancer stem cells. Cancer Res. with resistance to chemotherapy. It could 69(20):8058-66, 2009. be demonstrated, that AKT-inhbitor perifo- sine displays substantial anti-tumor activity Rennemeier C, Frambach T, Hennicke F,

SELECTED PUBLICATIONS Dietl J, Staib P. Microbial quorum-sensing in models of human ovarian and endome- molecules induce acrosome loss and cell trial cancers and shows additive effects with death in human spermatozoa. Infect Im- platinum derivatives. These results have mun 2009, 77: 4490-4497. been the basis for project which is funde by Schally AV, Varga JL, Engel JE. Antagonists IZKF from January 2010, aiming at investi- of growth-hormone-releasing hormone: an gating the AKT-pathway in ovarian cancers emerging new therapy for cancer. Nat Clin with special regard to immunemodulatory Pract Endocrinol Metab 2008, 4: 33-43. effects (B-131-N). Segerer SE, Müller N, van den Brandt J, Kapp M, Dietl J, Reichardt HM, Rieger L, Kämmerer U. Impact of female sex hormones on the maturation and function of human dendritic cells. Am J Reprod Immu- 75 nol. 2009 Sep;62(3):165-73. 3.10 Department of Pediatrics

Dr. F. Deinlein, PD Dr. M. Eyrich, Dr. B. Win- infants with bronchopulmonary dysplasia Professor Dr. med. Christian P. Speer FRCP kler), cardiology (Dr. J. Wirbelauer), pulm- (BPD), as well as in children with asthma. (Edin.) (Head of the Department) onology / cystic fibrosis / sports medicine Specifically, this project studies the inverse (Prof. Dr. H. Hebestreit), gastroenterology gene regulation of transforming growth fac- Josef-Schneider-Straße 2 (Dr. A. Dick), nephrology (Dr. A Beissert, Dr. tor ß and connective tissue growth factor 97080 Würzburg B. Wiewrodt), endocrinology (Dr. K. Ergez- as potential new mechanism in the patho- Tel.: 0931/201-27830 inger), diabetes (Dr. R. Wössner), neurope- genesis of BPD. Fax: 0931/201-27833 diatrics / social pediatrics (Prof. Dr. H.-M. E-mail: [email protected] Straßburg), immunology / infectiology (Prof. www.kinderklinik.uni-wuerzburg.de Dr. J. Liese, MSc), rheumatology (Prof. Dr. Reconstitution of the immune system J. Liese, MSc), and others. Patients of all after stem cell therapy Professor Dr. med. Matthias Eyrich CONTACT DETAILS CONTACT pediatric age groups ranging from prema- Tel.: 0931/201-27640 ture infants up to adolescents are treated After the start of the stem cell transplan- for the entire spectrum of pediatric diseases tation unit in 2005, the reconstitution of Professor Dr. med. Helge Hebestreit on the wards as well as in outpatient clin- the immune system after transplantation Tel.: 0931/201-27889 ics. The Children’s Hospital is in close co- of highly purified hematopoietic stem cells operation with pediatric neurosurgery, pe- beyond HLA-barriers has been studied. The Professor Dr. med. Johannes Liese, MSc diatric surgery, urology / pediatric urology, objective of this project is to optimize es- Tel.: 0931/201-27731 and the hospitals for dental, oral, and fa- tablished immunotherapeutic approaches cial therapy. Every year, around 6500 pa- such as the transfusion of donor lympho- Professor Dr. med. Paul-Gerhard Schlegel tients are treated as inpatients and 15000 cytes in order to enhance the antileucemic Tel.: 0931/201-27888 as outpatients. effect of stem cell transplantation. Another aspect of the studies related to the recon- Professor Dr. med. Hans-Michael Straßburg stitution of the immune system is the in- Tel.: 0931/201-27734 Major Research teraction of human peripheral blood stem Interests cells with notch-ligands and the resulting differentiation of lymphoid cells. The great Inflammation in acute and chronic lung importance of this scientific focus is under- disease of premature infants and new- lined by the installation of an endowed pro- borns. fessorship for experimental and clinical cellular therapy financed by the “Elterninitia- The aim of this long-term project is to ana- tive für leukämie- und tumorkranke Kind- lyze pathophysiological mechanisms in or- er Würzburg e.V.”. Prof. Dr. Matthias Eyrich der to establish new strategies for preven- has been appointed for this position in De- tion and therapy for this disease. Among cember 2009. other projects, studies are conducted to analyze the influence of prenatal inflammation on the development of regulatory T-lymphocytes in the fetal thymus, to evaluate the interaction between sur- factant protein A and transforming growth factor ß as a novel mechanism to regu- Mission late inflammatory and fibros- and Structure ing reactions in the lungs, and to characterize the effects of The Children’s Hospital of the University of steroids and interleukin 6 on Würzburg (staff: 59.45 MD`s, 163.5 nurs- the gen expression of surfaces, 34.75 technicians / administrative staff) tant protein B and the Jak/ comprises 115 beds including a pediatric- Stat signal pathway. neonatal intensive care unit (12 beds) and a neonatal intensive care unit (12 beds) in the perinatal centre (obstetrics and gynecol- Characterization of “airway ogy). The Children’s Hospital is divided into remodelling” processes in Fig. 1: Following 5 days of differentiation in the pres- the following functional sections: neonatol- chronic pulmonary inflam- ence of the cytokines GM-CSF and IL-4, dendritic cells ogy (Prof. Dr. C. P. Speer, Dr. E. Frieauff, PD matory reactions phagocyte fluorescence-labelled synthetic particles. Dr. S. Kunzmann, Dr. W. Thomas, Dr. J. Wir- Maturation is achieved with TNFα and IL-1ß. The par- belauer, Dr. R. Wössner), pediatric intensive The purpose of this set of stud- ticles are used to visualize the ability of the cells to care (Prof. Dr. C. P. Speer, Dr. E. Frieauff, ies is the molecular character- phagocyte. In clinical application, tumor antigens are PD Dr. S. Kunzmann, Dr. W. Thomas, Dr. ization of transmitters that are used instead of the synthetic particles which will be pre- J. Wirbelauer), oncology / haematology / involved in pulmonary remod- sented by the dendritic cells to the immune system of stem cell therapy (Prof. Dr. P.-G. Schlegel, elling processes in premature patients with brain tumors.

76 nation programs. In clinical studies, data on rics, pediatric pulmonology are qualified to safety, immunogenity and effectiveness of train MDs in their respective subspecialties. vaccines are gathered in cooperation with The Children’s Hospital organizes regular- pediatricians. ly clinical rounds and educational seminars for pediatricians on a regional and national level. In addition, every year scientific meet- Pathogenesis of rheumatoid diseases ings and symposia are organized in Würz- and immunodeficiency burg, e.g. every 3rd year the international Fig. 2: Ventilation of the lungs visualized symposium “Recent Advances in Neonatal by magnetic resonance spectroscopy us- Several research projects entailing basic Medicine“ with participants from more than ing oxygen as contrast medium. The im- research and clinical studies investigate 50 nations. Outside of the United States ages are generated by subtracting maps pathomechanisms of inflammatory proof America this symposium represents the acquired during breathing of room air and cesses in rheumatological diseases (juve- largest scientific forum for neonatology. pure oxygen. Left panel: normal homog- nile rheumatism, chronic non-bacterial os- enous ventilation in a healthy individual; teomyelitis) and hypophosphatemia, and right panel: inhomogeneous ventilation evaluate therapeutic options. Furthermore, with ventilation defects in the right lung in patients with compromised defense against a female patient with cystic fibrosis. infections are studied to identify the pathophysiological defects in immunity.

New cellular therapeutic concepts for Magnetic resonance imaging tech- brain tumors niques for examination of the lungs

Within a newly founded European network, This interdisciplinary project in coopera- innovative cellular therapeutic concepts to tion with Prof. Dr. M. Beer (Institute of Ra- treat malignant brain tumors are tested diology) and Prof. Dr. P. Jakob (Biophysics) and refined for the use in patients. One of assesses the value of low- and high-field these approaches, for example, is based on MRI scans of the thorax for the diagnosis of the combined application of patient-specif- pathological changes in the lungs and for ic dendritic cells (loaded with patient´s tu- the functional evaluation of ventilation and mor antigens) and tumor-specific cytotoxic perfusion (figure 2). T cells. To set the stage for clinical studies, extensive validation procedures for the Eyrich M, Wiegering V, Lim A, Schrauder manufacturing of dendritic cells and tumor- Exercise testing methodology and train- A, Winkler B, Schlegel PG (2009) Immune specific T-cells in our own GMP-facility fol- ing effects in healthy children and in function in children under chemotherapy lowing all legal demands are under way (see children with chronic diseases for standard risk acute lymphoblastic leu- Figure 1). These new techniques strength- kemia - a prospective study of 20 paediatric patients. Br J Haematol, 147:360- en the established neurooncological focus Several studies evaluate the preventative 370. of the Children´s Hospital, which has host- effects of physical activity in healthy chil- ed the German center of the pediatric brain dren, and the positive effects on patients Hebestreit H, Kieser S, Junge S, Ballmann tumor study for many years. In this study, with chronic diseases. Furthermore, the M, Hebestreit A, Schindler C, Schenk T, the primary therapy for children with me- mechanisms possibly underlying a reduced Posselt HG, Kriemler S (2009) Long-term effects of a partially supervised condition- dulloblastomas, ependymomas and supra- exercise capacity and involved in the basics ing program in cystic fibrosis. Eur Respir J tentorial primitive neuroectodermal tumor is for the beneficial effects of exercise are in- Jul 30. [Epub ahead of print]. evaluated and refined. vestigated. The validity of exercise testing for diagnosis and follow-up of therapeutic Morbach H, Girschick HJ (2009) Do B cells play a role in the pathogenesis of ju- effects is determined in other studies. venile idiopathic arthritis. Autoimmunity. Epidemiology and prevention of pediat- 42: 373-5. ric infectious diseases

SELECTED PUBLICATIONS Straathof KC, Rao K, Eyrich M, Hale G, In several studies, the effects of vaccina- Teaching Bird P, Berrie E, Brown L, Schlegel PG, Goulden N, Gaspar HB, Gennery AR, Lan- tion programs on the epidemiology of infec- dais P, Davies EG, Brenner MK, Veys P, tious diseases such as varicella, influenza, The Children’s Hospital of the University of Amrolia P (2009) Haematopoietic stem pneumococcal infections and pertussis and Würzburg offers several courses for medical cell transplantation with antibody-based their acceptance are evaluated in children students. Students have repeatedly evalu- minimal intensity conditioning: a phase 1/2 study. Lancet 374(9693):912-920. and adolescents. Regional surveillance ated the main lecture in pediatrics regular- programs which have been established in ly as one of the best courses in the faculty Thomas W, Seidenspinner S, Kramer BW, close cooperation with pediatricians in pri- of medicine. Prof. Dr. C. P. Speer is autho- Kawczynska-Leda N, Chmielnicka-Kopac- vate practices and pediatric hospitals such rized to fully train MDs in pediatrics, as well zyk M, Marx A, Wirbelauer J, Szymankie- as the “Bavarian Varicella Project” (BaVari- as in neonatology and pediatric intensive wicz M, Speer CP (2009) Airway concentrations of angiopoietin-1 and endostatin Pro) provide valid epidemiological data to care. The heads of the sections for pediat- in ventilated extremely premature infants evaluate the impact and success of vacci- ric haematology and oncology, neuropediat- are decreased after funisitis and unbalanced with bronchopulmonary dysplasia/ 77 death. Pediatr Res 65:468-473. 3.11 Department of Internal Medicine I

Mission mally invasive stent-based implantation of Professor Dr. med. Georg Ertl and Structure aortic valves was established. More than (Head of the Department) 300 high frequency- or cryo-ablations are The Department of Internal Medicine I (DIM performed per year. In cooporation with the Oberdürrbacher Str. 6 I) includes six divisions of internal medicine Department of Cardiac Surgery more than 97080 Würzburg in research, teaching, and patient care: 150 cardiac pace maker systems and 110 Tel.: 0931/201-39001 Endocrinology, Emergency- and Intensive ICDs were implanted. Several specialized Fax: 0931/201-639001 Care, Cardiology / Angiology, Nephrology, outpatient clinics cover the whole spec- E-mail: [email protected] and Pneumology. trum of cardiology: general cardiology, aor- www.klinik.uni-wuerzburg.de/deutsch/einrich- Excellent conditions for clinical research, tic valve disease, heart failure, adults with tungen/kliniken/MedizinischeKlinikundPo- teaching, and patient care through closest congenital heart disease, psycho-cardiolo- liklinikI/content.html CONTACT DETAILS CONTACT interdisciplinary contact have emerged from gy, arrhythmias, ICD and pacemaker. the move of the Department to the Centre The DIM I runs a state of the art intensive Professor Dr. med. Bruno Allolio of Internal Medicine (Zentrum Innere Med- care ward with 24 beds and an emergency Tel.: 0931/201-39020 izin, ZIM) mid-year 2009. ward with 12 beds in addition to the emergency room. The intensive care ward coor- Professor Dr. med. Christiane Angermann The Division of Endocrinology is in charge dinates the Infarct Network Mainfranken - Tel.: 0931/201-70460 of the ward specialized in endocrinology/di- founded in 2007 - which manages 600 pa- abetology and cares for more than 5000 tients with acute coronary syndrome per Professor Dr. med. Peter Josef Schanzen- outpatients. Since 2003 the Division of En- year. bächer docrinology has become the international Tel.: 0931/201-39181 reference centre for the adrenal carcinoma; in 2008/2009 more than 170 patients Major Research Professor Dr. med. Christoph Wanner were cared for this very rare disease. An in- Interests Tel.: 0931/201-39030 terdisciplinary centre for obesity was established in cooperation with the Department Endocrinology of Surgery. (B. Allolio, M. Fassnacht)

Nephrology does more than 5000 hemodi- A major research focus of the team consists alysis and peritoneal dialysis treatments per of translational and clinical studies in adre- year. Beside the care for hospitalized pa- nal tumors (particularly adrenocortical car- tients in a core unit, there are several out- cinoma). The German Adrenocortical Carci- patient clinics including the (1) low clear- noma Registry and the first randomized in- ance clinic, (2) the vasculitis clinic, (3) the ternational therapeutic study in advanced Fabry disease clinic (a national reference adrenal carcinoma (FIRM-ACT-Study) are center) and the (4) transplant clinic for post coordinated by Prof. Allolio and PD Dr. Fass- kidney transplantation care. In 2008/9, nacht with the support of Deutsche Kreb- more than 60 transplants (including living shilfe (German Cancer Aid) and BMBF. In donors) could be realized. basic and clinical studies, new diagnostic and therapeutic targets as well as targeted The Division of Pneumology cares for in- therapies for adrenal carcinoma are evalu- patients with bronchial carcinoma, severe ated. In a Max-Eder research group of the pneumonia, severe COPD or interstitial German Cancer Aid, headed by PD Dr. M. lunge disease. In the special pneumology Fassnacht, immune-therapeutic approach- outpatient clinic chemotherapies are per- es in adrenal tumors and – in a sub-project formed in patients with bronchial carcinoma of the clinical DFG research group „Tumor and patients are cared for with interstitial Microenvironment“ - the role of glucocor- lunge diseases, sarcoidosis, severe asthma ticoids for tumor immune response are ex- and alpha-1-antitrypsin-deficiency. A cen- amined. tre for pulmonary hypertension was recently established. The Pneumology is a central A second focus, initiated by Prof. Allolio and part of the interdisciplinary Thorax-Centre Dr. Hahner jointly with the Department of Mainfranken. Nuclear Medicine, aims at developing and implementing new radioactive tracers for The Division of Cardiology performed more adrenal imaging. This research is support- than 3000 invasive procedures in 3 cathe- ed by both the Sander-Stiftung (founda- terization laboratories, including 1000 per- tion) and the IZKF (Interdisciplinary Center cutaneous coronary interventions. In addi- for Clinical Research). tion, catheter based implantations of closure devices in patients with atrial septal Moreover, several “investigator-initiated“ defects and persistently open foramen ova- studies on acromegaly, hyponatremia and le are performed. In cooperation with the adrenal insufficiency are currently carried Department of Cardiac Surgery the mini- out. As part of an initiative for a German

78 and humans, modelling of cardiac microcir- Taking together the cardiovascular research culation, cellular and molecular processes in Würzburg is characterised by interdisci- in the vascular system. Heart failure: heal- plinary basic science, translational and clin- ing and remodelling after myocardial infarc- ical projects with the focus on heart failure tion in animal models and using imaging and cell-cell-interactions. techniques. Several aspects are investigated: platelet function, clotting system (A. Schäfer); oxidative stress (J. Widder), micro Research in Nephrology RNAs, ischemia perfusion injury (J. Bauer- (C. Wanner) sachs, S. Frantz), role of receptor antibodies during development of heart failure (R. The clinical topic is the identification of pre- Fig. 1: 123I-Iodmetomidat SPECT in a 68 Jahns); role of calcineurin (O. Ritter); vas- dictors for sudden cardiac death and risk year old patient with adrenocortical carci- cular activity (J. Bauersachs, A. Schäfer, factors for cardiac and vascular disease in noma with metastasis of kidney and liver J. Widder); platelets/coagulation and their Type 2 diabetics with chronic kidney dis- (A) and a 55 year old patient with an en- influence on cardiovascular function (A. ease. The questions are answered in large docrine inactive adrencortical carcinoma Schäfer, J. Bauersachs); pulmonary hyper- multicenter randomized trials and cohort (B). tension together with the Division of Pul- studies. Currently, the biobank of the com- mology (H. T. Pelzer). pleted 4D study – Die Deutsche Diabetes Conn Registry, patients with primary aldo- Dialyse Studie – is delivering useful results steronism are prospectively evaluated to Current translational projects (R. Jahns): in that respect. The SHARP study (Study on assess long-term outcome. Our Interdisci- therapeutic cyclopeptides in autoimmune Heart And Renal Protection) will come to plinary Obesity Center has become the ba- mediated heart failure; BMBF program an end in 2010 and is managed in coop- sis for a number of preclinical and clinical (Gründungsoffensive Biotechnologie, Go eration with the University of Oxford. 1,789 studies. Finally a number of multicenter Bio), 2007 founding of the company Corim- patients with impaired kidney function are studies initiated by different pharmaceuti- mun; 2009 completion of preclinical study taken care of by the coordinating centre for cal companies in the field of diabetes melli- and current phase I study in humans. clinical studies (ZKS). Research questions tus, hyponatremia, thyroid cancer, osteopo- about the progression of rare renal diseas- rosis, and neuroendocrine tumors are car- Current clinical projects (only investiga- es (e.g. M. Fabry) are being approached by ried out. tor initiated studies): biomaterial bank (R. prospective cohort studies. The transplanta- Jahns, S. Störk), 3D- and tissue doppler tion unit with their patients is integrated into echocardiography, storage heart diseas- a large multinational observational study Cardiology/Angiology es (Morbus Fabry together with nephrolo- (PORT study). The coordinating centre of (G. Ertl, J. Bauersachs) gy, Morbus Friedreich together with Neurol- the KfH foundation of preventive medicine ogy) and aortic stenosis (F. Weidemann, W. is being set up and is in charge of compre- Various teams investigate molecular mech- Voelker); heart failure – study selection with hensive cohort studies. A randomized con- anisms, imaging and treatment of heart principal investigator at DIM I (S. Störk, C. trolled trial has been initiated by investiga- failure and hypertrophy of the heart using Angermann, R. Jahns, G. Ertl): handheld tors of the academic hospital of Coburg and a broad array of in vitro and in vivo tech- BNP-study: echocardiography and BNP has offered co-chair function to Würzburg niques: Among others, experimental stud- testing in primary care. INH-interdisciplinary in the EPIC-CKD trial. In preclinical studies of the heart, cultured cardiomyocytes network heartfailure) – intervention study of ies, pathomechanisms of the damage and and endothelial progenitor cells, isolated nurse based disease management. MOOD- recovery of ischemic acute renal failure are platelets and vessels are performed. These HF study: serotonin reuptake inhibition with studied in different mouse models with oxi- investigations already yielded potential new escitalopram in patients with chronic heart dative stress and regulation of eNOS being therapeutic approaches. Results from ex- failure and depression as a comorbidity. taken into consideration. Further examina- perimental studies are transferred into clin- Prospective cohort-study rheumatism and tions in cooperation are carried out for the ical studies and patient care. Professor Ertl heart. Ethics HF: etiology/pathogenesis, regulation of transport proteins for organic is vice spokesman of the “Kompetenznetz prevalence and pathophysiological impor- anions OAT1 and OAT3. Herzinsuffizienz” and the special research tance of B1 auto-antibodies in heart failure, program SFB 688 as well as speaker of the acute myocardial infarction and myocardi- Review Board (Fachkollegium) “Medicine” tis. Pacemaker-ICDs (W. Bauer, O. Ritter): Pneumonology Working Group and of the Section “Heart and Circulation” role of new sensors; development of new (M. Schmidt, H.-T. Pelzer) of the DFG. He holds main responsibility for MRI-suitable pacemaker probes. Platelets the integrated research and treatment cen- (A. Schäfer, J. Bauersachs) role of plate- Basic research: Investigation of recruitment tre (IFB) “Prevention of heart failure and its lets in acute coronary syndrome, predictors and homing of blood fibrocytes to lung, and complications” which will be established in of clopidogrel non-responsiveness, vascular the role of fibroblasts and myofibroblasts in 2010 in Würzburg and is supported by the activity, endothelial progenitor cells (J. Bau- the exacerbation of idiopathic lung fibrosis. ministry of research and education. ersachs, T. Thum): in patients with coronary Animal model of chronic thromboembolic arterial disease and other cardiac diseas- pulmonary hypertension in cooperation with Current research projects in basic science: es endothelial function and circulating pro- the institute of physiology (K. Schuh). Electrophysiology of the heart on several genitor cells are investigated. Angiology (J. levels, especially cardiac sodium channels Baulmann): several multicenter studies re- Clinical research: Radiochemotherapy of (S. Maier). MRI-Imaging of the heart and garding vascular stiffness were initiated and non-small-cell lung cancer, molecular tar- cardiac biophysics (W. Bauer) in rodents coordinated from Würzburg. geted therapy of lung cancer. Palliative

79 treatment of terminal lung disease. Devel- Drechsler C, Krane V, Ritz E, März W, Wan- ner C. Glycemic Control and Cardiovascular opment of the Würzburg Lung Embolism Events in Diabetic Hemodialysis Patients. Registry. Multicenter vasodilative treatment Teaching Circulation 2009;120:2421-2428. study of chronic thromboembolic pulmonary hypertension (CTEPH). About 850 undergraduate clinical students Fassnacht M, Kreissl M, Weismann D, Allo- lio B 2009 New targets and therapeutic ap- participate in courses in Internal Medicine proaches for endocrine malignancies. Phar- each semester. In the 5th Semester, stu- macol Ther. 123(1):117-41. Interdisciplinary projects dents train in the basics of history taking and physical examination in the Skills Lab Fraccarollo D, Widder JD, Galuppo P, Thum T, Tsikas D, Hoffmann M, Ruetten H, Ertl G, Interdisciplinary research is of particular sig- with simulators and real patients. The stu- Bauersachs J. Improvement of left ventricu- nificance in the clinical and scientific areas dents´ skills are then tested in a standard- lar remodeling by the endothelial nitric ox- of the Department of Medicine I. Such in- ized clinical situation in a so-called OSCE ide synthase enhancer AVE9488 after ex- teractions are reflected in the numerous (Objective Structured Clinical Examination). perimental myocardial infarction. Circulation 118 (2008), 818-827. projects which are processed jointly by sev- In the 6th and 7th Semester, the main lec- eral teams within the Department and the ture and the clinical course in internal medi- Hahner S, Stuermer A, Kreissl M, Reiners C, University Hospital, but also within the Uni- cine take place. In the 10th Semester, stu- Fassnacht M, Haenscheid H, Beuschlein F, versity together with research groups of oth- dents join a “14day-on-the-ward-training”, Zink M, Lang K, Allolio B, Schirbel A 2008 SELECTED PUBLICATIONS 123I-Iodometomidate for molecular imag- er faculties. Some exemplary projects are followed by a one year internship (“Prak- ing of adrenocortical CYP11B enzymes; J listed here: tisches Jahr”) during the 11th and 12th Se- Clin Endocrinol Metab 93(6):2358-65. - M.Fabry: nephrology, cardiology mester. With about 3,000 hours of teach- - Heart failure projects: cardiology, endo- ing per semester, internal medicine is a Jazbutyte V, Arias-Loza PA, Hu K, Widder J, Govindaraj V, von Poser-Klein C, Bauersachs crinology, nephrology, human genetics, major subject in the medical curriculum. J, Fritzemeier KH, Hegele-Hartung C, Ney- psychiatry, psychology, pharmacology, The results in the nationwide exams are ex- ses L, Ertl G, Pelzer T. Ligand-dependent neurology cellent: Würzburg ranks first among all 36 activation of ER beta lowers blood pressure - Cardiac MR tomography: cardiology, ra- medical schools. Teaching for both medi- and attenuates cardiac hypertrophy in ovari- ectomized spontaneously hypertensive rats. diology, physics, chemistry, nuclear med- cal departments is organized by a teaching Cardiovasc Res. 2008; 77:774-781. icine coordinator and a secretary. The teaching - Development of molecular/cellular con- coordinator’s tasks are also to improve and Jung PH, Rieber J, Störk S, Hoyer C, Erhardt trast agents: cardiology, chemistry, phys- test the quality of teaching, to further devel- I, Nowotny A, Voelker W, Weidemann F, Ertl G, Klauss V, Angermann CE. Effect of con- ics, nanotechnology, nuclear medicine, op active teaching techniques, to increase trast application on interpretability and diag- Dept. of Medicine II the validity and reliability of students´ tests, nostic value of dobutamine stress echocar- - New imaging techniques for adrenal tu- the improvement of students´ basic skills diography in patients with intermediate cor- mors: endocrinology, nuclear medicine in physical examination and history taking, onary lesions: comparison with myocardial fractional flow reserve. Eur Heart J. 2008 - Interdisciplinary training and simulation faculty development and the promotion of Oct;29(20):2536-43. center (INTUS): multiple hospitals and e-learning. The teaching coordinator is also institutes in charge of students counselling und coop- Krane V, Winkler K, Drechsler C, Lilienthal J, eration with students` representatives. März W, Wanner C. Effect of atorvastatin on inflammation and outcome in patients with The Department of Medicine I together with type 2 diabetes mellitus on hemodialysis. the Institute for Clinical Biochemistry super- Kidney Int 2008;74;1461-1467. vises the special research grant SFB 688 “Cardiovascular Cell-Cell-Interaction“ (see Weidemann F, Herrmann S, Störk S, Nie- mann M, Frantz S, Lange V, Beer M, Gat- p. 140) and is involved in the DFG Clinical tenlöhner S, Voelker W, Ertl G, Strotmann Research Group KFO 124 „Tumor microen- JM. Impact of myocardial fibrosis in patients vironment“ (see p. 189). In addition, clini- with symptomatic severe aortic stenosis. cians and scientists of the department are Circulation. 2009 ;120(7):577-84. active in the several research centers (e.g. Weidemann F, Niemann M, Breunig F, Her- cardiovascular centre, interdisciplinary cen- rmann S, Beer M, Störk S, Voelker W, Ertl tre for clinical research, interdisciplinary tu- G, Wanner C, Strotmann J. Long-term ef- mor centre, centre for infection research). fects of enzyme replacement therapy on fabry cardiomyopathy: evidence for a better With the support of the ministry of research outcome with early treatment. Circulation. and education in 2010 the integrated re- 2009 3;119(4):524-9. search and treatment centre (IFB) “Preven- tion of heart failure and its complications” Thum T, Gross C, Fischer T, Fiedler J, Just S, Rottbauer W, Bussen M, Galuppo P, will be established in 2010 in Würzburg. Frantz S, Castoldi M, Muckenthaler M, This centre brings together several interdis- Soutschek J, Koteliansky V, Rosenwald A, ciplinary research projects within the fac- Bauersachs J, Engelhardt S. MicroRNA-21 ulty of medicine and beyond, and will play contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. a central role for cardiovascular research in Nature 456 (2008), 980-4. Würzburg.

80 3.12 Department of Internal Medicine II

Professor Dr. med. Hermann Einsele Mission Day Clinic for Psychosomatic Medicine (Head of the Department) and Structure (building C2)

Oberdürrbacher Str. 6 The „Medizinische Klinik und Poliklinik II der The hospital is divided into the following de- 97080 Würzburg Universität Würzburg“ (41 physicians, 74 partments: Tel.: 0931/201-40001 nurses, technical staff comprising 44 mem- Hematology/Oncology (Prof. Dr. R. Bargou) Fax: 0931/201-640001 bers) is located in the city of Würzburg: ZIM Gastroenterology (Prof. Dr. M. Scheurlen) E-mail: [email protected] (Center for Internal Medicine) and „Luitpol- Immunology/Rheumatology (Prof. Dr. H.-P. www.klinik.uni-wuerzburg.de/medizin2 dkrankenhaus“. Tony) Infectious Diseases (Prof. Dr. H. Klinker) Professor Dr. med. Ralf Bargou Section of Psychosomatics (Prof. Dr. H. CONTACT DETAILS CONTACT Tel.: 0931/201-40014 Zentrum für Innere Medizin (ZIM) Csef) 1. Center for Stem Cell Transplantation Professor Dr. med. Herbert Csef 1. Interdisciplinary Oncology – Phase-I/II On an inpatient basis, our hospital is spe- Tel.: 0931/201-40060 Unit cialised in the diagnosis and therapy of all 2. Department of Infectious Diseases kinds of internal. Moreover, we provide con- Professor Dr. med. Michael Scheurlen (Center for Infectious Diseases DGI), siliary service for other hospitals in Würz- Tel.: 0931/201-40201 comprising Infectious Disease-ward burg and its environs. We especially focus “Schottmüller” and outpatients’ de- on the following domains: partment for infectious diseases 3. Rheumatology ward (Behring) (1) Diagnosis and therapy of hematologic 4. Department of Gastroenterology in- neoplasias (MDS, leukemia, lympho- cluding ward “Romberg” and the out- ma, myeloma), including high-dose patients’ department for gastroentero- chemotherapy and both autologous logic diseases and allogeneic stem cell transplantation. (2) Diagnosis and therapy of solid tumors, Department for Endoscopy and Sonog- including the use of novel drugs and raphy immunotherapy. – Interdisciplinary tu- morboards, interdisciplinary tumorsur- 5. Laboratories for immunology and In- gery, interdisciplinary ambulatory Unit fectiology/Therapeutic Drug Monitor- for tumortherapy. ing (3) Innovative stem cell transplantation programme (2nd large programme in Luitpoldkrankenhaus Germany) with new transplantation procedures (cord blood programme, 6. Outpatients’ department for the ther- haploidentical stem cell transplanta- apy of haematological and oncological tion) and optimized control of com- diseases (from January 2010) plications (immunotherapy of infections, T cell therapy, bispecific antibodies, immunotherapy of residual tumor cells)

Fig. 1: Phase I study in NHL.

81 (4) Early Clinical Trial Unit: Use of novel cytostatics, novel antibodies, antibody constructs; immunotherapeutic treatment of lymphoma, myeloma, leukemia, and solid tumors (gastrointestinal tumors in particular) (5) Care for and therapy of patients suffering from acute and chronic infectious diseases (with focus on HIV and chronic infectious liver diseases, evaluation of new drugs, phase II-IV studies) (6) Diagnosis and therapy of rheumatic Fig.2: Combined CBT/Haplo-SCT + Third inflammatory joint diseases, including Party T-Celltherapy. the use of novel drugs, immunotherapy, phase II-II studies (7) Diagnosis and therapy of systemic in- (7) DFG CRU 216: Characterization of on- flammatory diseases (vasculitis, colla- cogeneic signaling pathways in multi- genosis…) ply myeloma and identification of ther- (8) Diagnosis and therapy of immune defi- apeutic target structures (Einsele/Bar- ciencies (CVID, drug-induced immune gou) deficiencies) (8) EU FP6 MANASP: Development of (9) Diagnosis and therapy of patients suf- novel management strategies for in- fering from acute and chronic, benign vasive aspergillosis (Koordinator: Ein- and malignant diseases of the gut and sele) liver, including invasive endoscopy (9) EU FP7 NanoII: Nanoscopically-guid- (10) Diagnostic and therapeutic gastroin- ed induction and expansion of regula- testinal and biliary endoscopy tory hematopietic cells to treat auto- (11) Therapy of patients with psychoso- immune and inflammatory processes matic diseases (e.g. anorexia nervo- (Einsele) sa) and patients with functional or so- (10) Development of molecular and immu- matoform disorders. Crisis interven- nologic therapy approaches in non- tion and psychotherapeutic interven- Hodgkin lymphoma (AG Knop, Bar- tion in cancer patients gou) (11) Phase-I unit for the realization of innovative therapy approaches in hemato- Major Research oncologic patients and in patients with Interests solid tumors. (12) In vivo Imaging in models of graft ver- Hematology / Oncology sus host disease (GVHD) and immunologic anti-tumor response (group (1) Cellular (gene-modified T cells, tumor Beilhack) antigen-specific T cells, γδ T-lympho- (13) Identification of markers for the pre- cytes) and humoral (antibody-based) diction of a looming graft versus host immunotherapy of malignant diseas- disease (GVHD) (group Beilhack) es (groups Bargou, Kunzmann, Topp, (14) Immunoreconstitution after alloge- K. Kahle, P. Langmann, D. Schirmer, U. Grigoleit, Beilhack) neig stem cell transplantation (AG Lenker, D. Keller, A. Helle, H. Klinker, W. Heinz: (2009) Simultaneous determina- (2) Function and specificity of human γδ Seggewiss) tion of voriconazole and posaconazole T-lymphocytes (group Kunzmann) (15) Tyrosine kinase inhibitors and their concentrations in human plasma by high- (3) Alterations in tumor metabolism as tar- effects on different immune cells (T performance liquid chromatography. Anti- get for therapeutic intervention in ma- cells, NK cells, DCs)(AG Seggewiss) microb Agents Chemother 53: 3140-3142 lignant diseases (group Kunzmann) (16) Novel strategies in allogeneic stem cell T. Berg, V. Weich, G. Teuber, H. Klinker, (4) Characterization of pathogene-specif- transplantation (cord blood transplan- B.Möller, J. Rasenack, H. Hinrichsen, ic immunity and its use in immuno- tation, haploidentical stem cell trans- G. R. Pape, U. Spengler, P. Buggisch, H. therapeutic strategies (AG Topp) plantation) (Einsele/Stuhler/Mielke) Balk, M. Zankel, K. Neumann,, C. Sar- (5) Characterization of signaling pathways (17) DC-vaccination and T cell therapy razin, S.Zeuzem: (2009) Individualized Treatment Strategy with Peginterferon Alfa- in activated T cells and their inhibition against infectious and malignant dis- 2b (Peg-IFN α-2b) Plus Ribavirin Accord- for the treatment of GvH. (AG Stuhler/ eases (AG Grigoleit/Einsele) ing to Early Viral Kinetics in Hepatitis C Vi- Grigoleit) (18) Development of vaccination strat- rus (HCV) Type 1-Infected Patients. Hepa- (6) Regulation of viral T cell immunity egies against HCMV infections (AG tology 50: 369-377 through co-stimulation of artificial an- Grigoleit) tigen-presenting cells and soluble fac- (19) Selective allodepletion of GVHD-in-

SELECTED PUBLICATIONS tors (AG Grigoleit/Stuhler) ducing T cells as a method for opti-

82 mizing therapy in allogeneic stem cell (7) Drug monitoring of antiretroviral Bargou, R., Leo, E., Zugmaier, G., Klinger, transplantation (AG Mielke) agents M., Goebeler, M., Knop, S., Noppeney,R., (20) Optimization of therapy with taxans on (8) Uridine pharmacokinetics Viardot, A., Hess, G., Schuler, M., Einsele, the basis of pharmacokinetic, phar- (9) Systemic antifungal therapy of inva- H., Riethmüller, G., Brandl, C., Wolf, A.., macodynamic and pharmacogenetic sive fungal infections Kirchinger, P., Klappers, P., Schmidt, M., knowledge in patients with solid tu- (10) Therapeutic drug monitoring of azole- Reinhardt, C., Baeuerle, P., Kufer, P.: Tu- mor regression in cancer patients by very mors; Screening, prophylaxis, and antifungal agents low doses of a T cell-engaging antibody. therapy of chemotherapy-induced pe- Science, 321(5891): 974-7, 2008. ripheral neuropathy (AG Mielke) Psychosomatics Beilhack, A., Schulz, S., Baker, J., Beil- hack, G. F., Nishimura, R., Baker, E. M., Landan, G., Herman, E. I., Butcher, E. C., Rheumatology / Clinical Immunology (1) Psychooncology and Psychoneuro- Contag, C. H. and Negrin, R. S., (2008) immunology. Palliative medicine and Prevention of acute graft-versus-host dis- (1) Modulation of the B cell repertoire in medical ethics. ease by blocking T-cell entry to secondary autoimmune diseases (2) Psychosomatic diseases of the gas- lymphoid organs. Blood 111: 2919-28. (2) Immunoreconstitution in immunologic trointestinal tract (e.g. irritable bowel Chatterjee, M., Rancso, C., Stühmer, T., diseases syndrome, IBS) and of the cardiovas- Eckstein, N., Andrulis, M., Gerecke, G., Lorentz, H. Royer, H.D., Bargou, R.C. (3) Development of the B cell system in cular system (e.g. stress and myocar- SELECTED PUBLICATIONS autuimmune diseases dial infarction). The Y-box binding protein YB-1 is associated with progressive disease and medi- (4) Transcriptional regulation of the low- (3) Psychological state, psychosocial fac- ates survival and drug resistance in mul- affinity receptor for IgE(CD23) tors and quality of life in longterm-sur- tiple myeloma. Blood, 111: 3714-3722, (5) Pathologic immunoregulation in lupus vivors after stemcell transplantation 2008. erythematodes (LED) Mezger M, Steffens M, Beyer M, Manger C, Eberle J, Toliat MR, Wienker TF, Ljung- man P, Hebart H, Dornbusch HJ, Einsele Gastroenterology Teaching H, Loeffler J. (2008) Polymorphisms in the chemokine (C-X-C motif) ligand 10 are as- (1) Molecular diagnostics in hereditary The „Medizinische Klinik und Poliklinik II“ of- sociated with invasive aspergillosis after allogeneic stem cell transplantation and gastroenterological tumors fers numerous courses for medical students influence CXCL10 expression in monocyte- (2) Cognitive, emotional, and somat- and for postgraduate professional educa- derived dendritic cells. Blood 111: 534-6. ic symptoms in patients with chronic tion. Prof. Dr. H. Einsele is certified trainer hepatitis C infection and antiviral infor the whole field of Internal Medicine. In Knop, S; Gerecke, C; Liebisch, P; Topp, terferon therapy addition, authorized training and education MS; Platzbecker, U; Sezer, O; Vollmuth, C; Falk, K; Glasmacher, A; Maeder, U; Ein- (3) Computer-based subgroup analysis for is available for the following specialties (2 sele, H; and Bargou. RC. Lenalidomide quality control and data generation in years each): Prof. Dr. H. Einsele (Hematol- (Revlimid®), adriamycin and dexametha- (4) gastroenterological sonography using ogy/Oncology), Prof. Dr. M. Scheurlen (Gas- sone (RAD) in patients with relapsed and standardized electronical patient files troenterology), Prof. Dr. H.-P. Tony (Rheu- refractory multiple myeloma: A report from the German Myeloma Study Group DSMM (5) Molecular, cytogenetic and functional matology) and Prof. Dr. H. Klinker (Infec- (Deutsche Studiengruppe Multiples Mye- characterization of colorectal, neuro- tious Diseases). The hospital organizes nu- lom). Blood, 113:1160-71, 2009. endocrine, and hepatocellular carci- merous advanced training courses and sci- noma entific meetings for both physicians and Kraus MR, Schäfer A, Schöttker K, Keicher (6) Antimicrobial activity of human colon patients. Often, patient organizations are C, Weissbrich B, Hofbauer I, Scheurlen M (2008). Therapy of interferon-induced de- epithelial cells, considering in particu- involved in planning and realization of the pression in chronic hepatitis C with citalo- lar cathelicidin events. pram: a randomised, double-blind, place- (7) LL-37 bo-controlled study. Gut 57:531-536. (8) Nutritional Medicine: Investigation of Schäfer A, Scheurlen M, Seufert J, Keich- novel functional carbohydrates for the er C, Weißbrich B, Rieger P, Kraus MR prevention of inflammatory and neo- (2010). Platelet serotonin (5-HAT) levels plastic intestinal diseases as well as in interferon-treated patients with hepati- diabetes mellitus tis C and its possible association with interferon-induced depression. J Hepatol 52:10-15.

Infectious Diseases Schöttker B, Feuchtinger T, Schumm M, Klinker E, Handgretinger R, Einsele H, (1) Antiretroviral therapy in HIV-infection Stuhler G: (2008) Five donors - one recipient: modeling a mosaic of granulocytes, (2) HIV-proteasinhibitor-plasma concen- natural killer and T cells from cord-blood trations and resistance development and third-party donors. Nature Clin Pract (3) Pharmacokinetic interactions of anti- Oncol May;5(5):291-5. retroviral drugs (4) Antiviral treatment strategies in chron- Reimer P, Rüdiger T, Geissinger E, Weiss- inger F, Nerl C, Schmitz N, Engert A, Ein- ic viral hepatitis B and C sele H, Müller-Hermelink HK, Wilhelm M. (5) Pharmacokinetics of ribavirin Autologous Stem-Cell Transplantation As (6) HCV/HIV coinfection First-Line Therapy in Peripheral T-Cell Lym- phomas: Results of a Prospective Multi- 83 center Study. J Clin Oncol. 2008 Nov 24. 3.12.1 Division of Molecular Internal Medicine

Professor Dr. rer. nat. Harald Wajant Mission of ‘targeting domains’ that interact with tu- (Head) and Structure mor specific structures facilitates the designated local activation of TNF receptors with- Röntgenring 11 The scientific focus of the division of Mo- out causing systemic side effects. 97070 Würzburg lecular Internal Medicine lies on basic bio- Tel.: 0931/201-71000 medical research and applied clinical in- Fax: 0931/201-7107 vestigations in molecular immunology and Research Group: Death Receptors E-mail: [email protected] oncology. Allocation of personnel includes (D. Siegmund) www-i.klinik.uni-wuerzburg.de/deutsch/ein- a scientific research position and part time richtungen/kliniken/MedizinischeKlinikundPo- secretary. Further, a transitory scientific po- Death receptors, a subgroup of the TNF re- liklinikII/abteilungfrmolekulareinneremedizin/ sition (Rotationsstelle) is available for clini- ceptor family that includes CD95, TRAILR1 CONTACT DETAILS CONTACT content.html cians of the Department of Internal Medi- and TRAILR2, were initially studied, be- cine II to temporarily pursue full time re- cause of their strong apoptotic effects. Over search that fits into the framework of the the last years, we and others could show, division. This initial option for scientific re- however, that these receptors can also ac- search is aimed to enable scientifically in- tivate pro-inflammatory signaling pathways. terested clinicians to acquire preliminary re- This is especially apparent in cells that are sults offering a chance to achieve indepen- resistant towards death receptor-induced dent external funding. The various research apoptosis. As inflammation can enhance projects of the division of Molecular Internal metastasis and angiogenesis of tumor cells, Medicine are currently funded by: it is possible that initial anti-tumoral effects • the German Research Foundation of death receptors are turned into mecha- • the Mildred Scheel Foundation for Can- nisms of tumor promotion in apoptosis re- cer Research sistant tumor cells. Research efforts, within • the German José Carreras Leukaemia- this group, are aimed to characterize pre- Foundation e.V. cise conditions, when stimulation of death • Wilhelm Sander-Stiftung receptors leads to enhanced metastasis • the Wyeth company and and aggressive tumor growth. Further, the • the Interdisciplinary Centre for Clinical basic molecular mechanisms of pro-inflam- Research of the University of Würzburg matory signal transduction by death receptors are also investigated. Major Research Interests Research Group: Co-operation of TNFR1 and TNFR2 The research activities of the division are focused on ligands of the tumor necrosis TNF, the name giving cytokine of the entire factor (TNF) family and their corresponding ligand family, occur as a transmembrane receptors. Ligands and receptors of the TNF and a soluble protein. The two forms of TNF family are of central importance for immu- differ in their capacities to activate TNFR1 noregulation and also control programmed and TNFR2. Both TNF receptors can induce cell death (apoptosis) in a variety of physi- in a cell type-specific manner the produc- ological and pathophysiological situations. tion of their own ligand TNF and show coun- The development of therapeutic useful re- teracting, but also synergistic effects de- combinant TNF ligand variants and clinical- pendent on the cell type.The precise cellu- ly relevant aspects of TNF receptor signal lar effects of TNF depend therefore on TNF- transduction are investigated in three re- receptor expression, cell type, extracellular search groups. conditions and, importantly, on the form of TNF that was used for receptor stimulation (Fig. 1). In this research group, the regula- Research Group: Therapeutic Fusions tory principles that cause the exceptional Proteins complexity of TNF signaling are investigated at the molecular level. Some ligands of the TNF family stimulate the immune system or trigger apoptosis. The potential therapeutic applications of Teaching these properties, however, are limited due to the serious side effects that are usually Courses, colloquia, seminaries und lectures associated with systemic activation of TNF related to the research topics of the divi- receptors. The research group develops fusion are offered for students of Biology and sion proteins of TNF ligands that become Medicine. only robustly activated after binding to membrane-associated antigens. Utilization

84 Fig.1: TNFR1 and TNFR2 are functionally linked in a highly complex manner. Activation of TNFR2 by transmembrane TNF leads to degradation of the adapter protein TRAF2 Wyzgol A, Müller N, Fick A, Munkel S, Grigoleit GU, Pfizenmaier K, Wajant H. (1a,b). Because this protein is important for TNFR1-induced activation of the proinflam- (2009) Trimer stabilization, oligomeriza- matory transcription factor NF-kappaB and recruitment of anti-apoptotic cIAP proteins tion, and antibody-mediated cell surface into the TNFR1 signaling complex (2a,b’), cells are sensitized toward TNFR1-mediated immobilization improve the activity of sol- cell death. Stimulation of TNFR1 by soluble TNF can induce NF-kappaB-dependent ex- uble trimers of CD27L, CD40L, 41BBL, pression of endogenous TNF (2a-2d). In its membrane-bound form, it activates TNFR2 and glucocorticoid-induced TNF receptor ligand. J. Immunol. 183:1851-1861. and sensitizes cells again for TNFR1-induced apoptosis, as described above (2e). An- other NF-kappaB target gene is TRAF1 (2a-c). TRAF1 forms heteromeric complexes Wicovsky A, Salzmann S, Roos C, Ehren- with TRAF2 and prevents its degradation by TNFR2 (2d’). TRAF1 can therefore disaffect schwender M, Rosenthal T, Siegmund D, TNFR2-mediated enhancement of TNFR1-induced apoptosis. Further, TRAF1 does also Henkler F, Gohlke F, Kneitz C, Wajant H. (2009) TNF-like weak inducer of apopto- enhance TNFR2-induced non-apoptotic signal transduction (3a-3c), which contributes sis inhibits proinflammatory TNF receptor- both to induction of TRAF1 and transmembrane TNF. 1 signaling. Cell Death Differ. 16:1445- 1459.

Wicovsky A, Henkler F, Salzmann S, Scheurich P, Kneitz C, Wajant H. (2009) Tumor necrosis factor receptor-associated

SELECTED PUBLICATIONS factor-1 enhances proinflammatory TNF receptor-2 signaling and modifies TNFR1- TNFR2 cooperation. Oncogene 28:1769- 1781.

Berg D, Stühmer T, Siegmund D, Müller N, Giner T, Dittrich-Breiholz O, Kracht M, Bargou R, Wajant H. (2009) Oligomerized tumor necrosis factor-related apoptosis inducing ligand strongly induces cell death in myeloma cells, but also activates proinflammatory signaling pathways. FEBS J. [Epub ahead of print].

Egberts JH, Cloosters V, Noack A, Schniewind B, Thon L, Klose S, Kettler B, von Forstner C, Kneitz C, Tepel J, Adam D, Wajant H, Kalthoff H, Trauzold A. (2008) Anti-tumor necrosis factor therapy inhibits pancreatic tumor growth and metastasis. Cancer Res. 68:1443-1450. 85 3.13 Institute of Clinical Biochemistry and Pathobiochemistry - Central Laboratory (IKBZ)

Professor Dr. med. Ulrich Walter Mission tion with vasopharm biotech, the status of (Head of the Institute) and Structure VASP phosphorylation was established as the most specific laboratory parameter for Oberdürrbacher Str. 6 The institute was founded in 1995 at the measuring of ADP receptor (P2Y12) inhibi- 97080 Würzburg conclusion of a DFG-funded (1989–1995) tion by antiplatelet drugs such as Clopido- Tel.: 0931/201-45001 Clinical Research Unit, was later merged in grel and Prasugrel. Fax: 0931/201-645000 2001 with the Central Diagnostic Labora- E-mail: [email protected] tory, and now consists of the: In 2009, the BMBF network project SARA www.ikbz.de a) Department of Clinical Chemistry / Lab- (Systems biology of prostaglandin and ADP oratory Medicine and Hemostaseology P2Y12 receptor signaling pathways) was Professor Dr. rer. nat. Michael Zimmer including an outpatient hemostasis clin- funded within the framework of the BMBF CONTACT DETAILS CONTACT Tel.: 0931-3293619 ic and the research initiative “Systems biology in med- b) Department of Clinical Biochemistry and icine” (coordinator: Prof. Albert Sickmann, Pathobiochemistry (Chair, Professorship Dortmund; project leaders of the medical of Clinical Molecular Biology and addi- subproject C ”Functional analysis of throm- tional groups), bocytes”: Dr. Jörg Geiger and Prof. Ulrich which conduct research, teaching and pa- Walter). The goal of the BMBF project (see tient care. With respect to clinical duties, report of the SARA project) is to obtain a the division of Clinical Chemistry & Labora- comprehensive understanding of platelet tory Medicine (directed by Dr. med. U. Stei- function regulation in healthy as well as dis- gerwald) is responsible for the major labo- eased states. ratory diagnostics of hospitalized and ambulatory patients of the university medical An additional group in the institute (PD Dr. center (ca. 4 million patient laboratory anal- Elke Butt) investigates the biological role of yses/year). Affiliated with this division is an the human protein LASP-1 in growth and outpatient clinic specialized in disorders of metastasis of different cancers, with the the hemostasis system. prospect of establishing LASP-1 as a prognostic marker for the metastatic potential of tumour cells. The work is supported by Major Research the German Cancer Foundation. An addi- Interests tional research domain is the characterization of cyclic nucleotides and their effector The major objective is elucidation of patho- proteins. physiological, genetic, and diagnostic aspects of important cardiovascular diseases (thrombosis, bleeding disorders, cor- Clinical Molecular Biology Group onary artery disease, stroke, heart failure (M. Zimmer) etc.) by investigating platelet and coagulation cascades in murine and human model This group is interested in the genetics of systems, also using systems biological ap- cardiac diseases and cardiomyopathies. proaches. Research projects are support- Currently, it investigates the pathogenesis ed by the DFG/SFB 688 (www.sfb688.de), of a dilative cardiomyopathy caused by a BMBF, foundations, and industry. novel disease gene. Other research areas focus on laminopathies which result from haploinsufficiency of the lamin A/C gene, Departments of Clinical Biochemistry mutational diagnostics of DCM genes, and and Laboratory Medicine (U. Walter)

The central research focus is the investigation of inter- and intracellular signal transduction pathways that are involved in the inhibition of platelets, especially the NO/ cGMP/PKG/VASP (vasodilator-stimulated phosphoprotein) signal transduction pathway and its cross-talk with pathways stimulated by platelet agonists such as vWF, thrombin and ADP. This project (guided by Drs. Stepan Gambaryan and Sabine Hert- erich) is part of the SFB688 (Director: Prof. Dr. med. U. Walter) and was prolonged by Fig. 1: Activating (ADP, vWF) and inhibitory the DFG in July 2009 for another 4 years (NO/cGMP/PKG/VASP) pathways in plate- (see also SFB 688 report). In coopera- lets (SFB 688, TP A2).

86 cavernous malformations (CCM1, CCM2, CCM3) which are a predispositon for inherited forms of hemorrhagic stroke. Dr. Felbor is now professor in the Institute of Human Genetics, University of Greifswald (www. medizin.uni-greifswald.de/humangen).

Vascular Biology Group (B. Nieswandt) This group evaluated defects in platelet receptors and signalling pathways using genetically altered murine model systems with the goal of developing novel antithrombotic strategies. In December 2008, Prof. Bern- hard Nieswandt became chairman of the Department of Experimental Biomedicine at Fig. 2: (A) Electron microscopy of resting the University of Wuerzburg (www.virchow. and adherent platelets. (B) Immunofluo- uni-wuerzburg.de/forschung). rescence images of LASP (red) and F-actin (green) in resting and adherent human platelets [Traenka, Butt et al. (2009) Thromb. Haemostasis 102:520-528]. Teaching

The institute offers lectures, seminars and practical courses, as well as active partici- the development of high-throughput SNP- pation in research projects, within the ar- typing using mass spectrometry. eas of clinical biochemistry and pathobiochemistry, and laboratory medicine, to undergraduate and graduate students of med- Metabolic Syndromes and Vascular Dis- icine, biology, pharmacy, and chemistry, in- eases cluding those in the MD-/PhD-program and (J. Schneider) the International Graduate School of Life Sciences (GSLS). The director of the in- In October 2009, Dr. Jochen Schneider (di- stitute (Prof. Ulrich Walter) is also Medical abetologist and endocrinologist) joined the Director of the Training School for Medical institute after returning from Washington Technical Assistents (www.mta-schule.uni- University, St. Louis Mo., USA. His research wuerzburg.de). focuses on non-traditional risk factors for Poppe H; Rybalkin SD; Rehmann H, Hinds the metabolic syndrome, vascular disease TR, Tang X-B, Christensen AE, Schwede F, Genieser HG, Bos JL, Doskeland SO, and chronic inflammation, in particular cell- Beavo JA, Butt E (2008) Cyclic nucleotide specific (dys)function of the ß3-integrin ad- analogs as probes of signaling pathways. hesion molecule. Nat. Methods 5, 277-278.

Gambaryan S, Kobsar A, Hartmann S, In 2009, three leaders of research Birschmann I, Kuhlencordt PJ, Müller-Es- groups left the institute after receiving terl W, Lohmann SM, Walter U. (2008) professorships: NO-synthase-/NO-independent regulation DFG/SFB Junior Research Group (T. Ren- of human and murine platelet soluble gua- né) The DFG-funded junior research group nylyl cyclase activity. J. Thromb. Haemost. 6:1376-1384. investigated the contact activation pathway stimulated by coagulation factor XII (Hage- Benz P.M., Blume C., Moebius J., Oschatz mann-Factor) as an attractive target for C., Schuh K., Sickmann A., Walter U., Fell- novel antithrombotics, as well as the mo- er S.M., Renné T. (2008) Cytoskeleton assembly at endothelial cell-cell contacts is lecular regulatory mechanisms of endothe- regulated by �II-spectrin-VASP complexes. J lial barrier function. Dr. Thomas Renné is

SELECTED PUBLICATIONS Cell Biol, 180,205-19. now Professor of Clinical Chemistry in the Department of Molecular Medicine and Lewandrowski U, Wortelkamp S, Lohrig Surgery at the Karolinska Institute in Stock- K, Zahedi RP, Wolters DA, Walter U, Sick- mann A (2009). Platelet membrane pro- holm (www.ki.se). teomics: a novel repository for functional research. Blood. 114, E10-E19. BayGene Program “Vascular Genet- ics” (U. Felbor) The independent BayGene van der Meijden PEJ, Munnix ICA, Au- ger JM, Govers-Riemslag JWP, Cosemans professorship of vascular genetics held by J, Kuijpers MJE, Spronk HM, Watson SP, Prof. Ute Felbor focused on the pathogen- Renne T, Heemskerk JWM (2009) Dual esis and molecular diagnostics of cerebral role of collagen in factor XII-dependent thrombus formation. Blood. 114: 881- 87 890. 3.14 Department of Dermatology, Venereology and Allergology

Mission Major Research Professor Dr. med. Eva-Bettina Bröcker and Structure Interests (Head of the Department) The department offers the entire spectrum Tumor biology and tumor immunology Josef-Schneider-Str. 2 of conservative dermatology and dermato- 97080 Würzburg logic surgery in patient care, research and This continuing main field of research ad- Tel.: 0931/201-26351 teaching. Residents can obtain a full spe- dresses several aspects of the biology of Fax: 0931/201-26700 cialisation in dermatology and venereol- cutaneous tumors within the scope of the E-mail: [email protected] ogy; additional professional qualifications Clinical Research Group KFO 124 (http:// www-i.klinik.uni-wuerzburg.de/deutsch/einrich- include allergology, dermatohistology, me- www.tumor-microenvironment.de/index. tungen/kliniken/haut/content.html dicinal tumor therapy and proctology. Apart htm) and various third-party funded proj-

CONTACT DETAILS CONTACT from the head of the department, 4 profes- ects listed as follows: Professor Dr. med. Henning Hamm sors of dermatology and 1 associate profes- • Tumor stem cells in skin tumors (J. C. Tel.: 0931/201-26738 sor have been working in research and edu- Becker, R. Houben) cation during the period under report. The • Molecular pathogenesis of Merkel cell Professor Dr. med. PhD Jürgen C. Becker department has 9 senior physicians, 2 fur- carcinoma (J.C. Becker, R. Houben) Tel.: 0931/201-26396 ther specialists in dermatology and 19 as- • Melanoma immunology (D. Schrama) sistant doctors. In research projects, 7 nat- • Melanoma genetics, chemoresistence ural scientists are employed on regular po- und preclinical testing of innovative ther- sitions or on third-party funds. The depart- apies (S. Ugurel-Becker) ment comprises the following divisions: • Genesis and molecular diagnostics of melanoma (J. C. Becker, S. Ugurel-Beck- • General outpatient clinic and consulta- er, E.-B. Bröcker) tions for specific skin diseases, outpa- • Apoptotic signal pathways in epithelial tient clinic for private patients cutaneous tumors (T. Giner) • Day clinic • Influence of polymorphisms on melano- • Wards for general dermatology, derma- ma prognosis (J. C. Becker, S. Ugurel- tooncology , dermatosurgery and private Becker, D. Schrama, E.-B. Bröcker) patients • Cell migration (P. Friedl, J. Storim) • Operation theatre • Stroma of Basal Cell Carcinoma (E.-B. • Outpatient clinic for allergology Bröcker, H. Kneitz) • Outpatient clinic for phototherapy • Aberrant signal transduction in Merkel • Dermatohistology, immunofluorescence Cell Carcinoma ( J.C.Becker, R.Houben) • Laboratory for dermatologic infectiology • Research laboratories Immunology and inflammation

Focuses of clinical interest • Interaction between T-lymphocytes and keratinocytes in dermatitis (A. Traut- • Dermatooncology (J.C. Becker, E.-B. mann, A. Kerstan) Bröcker, A. Gesierich, S. Ugurel-Becker) • Immunotherapy with wasp venom as • Allergology and eczematous skin dis- model for therapeutic immune modula- eases (A. Trautmann, J. Stoevesandt, A. tion in humans (A. Trautmann, A. Ker- Kerstan) stan) • Autoimmune skin diseases (E.-B. Bröck- • Interaction of T-cells with dendritic cells er, S. Benoit, J. Stoevesandt) and target cells (P. Friedl) • Hair diseases (H. Hamm, A. Kerstan), hyperhidrosis (H. Hamm) • Dermatologic surgery (G. Weyandt, A. Genodermatoses Gesierich) (H. Hamm) • Phlebology und proctology (G. Weyandt) • Pediatric dermatology (H. Hamm) Clinical and genetic characterization of • Dermatologic infectiology (A. Kolb-Mäur- genodermatoses in cooperation with the er) German Network for Ichthyoses and Relat- • Dermatohistology (E.-B. Bröcker, H. ed Cornification Disorders, the German Net- Kneitz, A. Kerstan) work Epidermolysis Bullosa and the department of dermatology, University of Maas- tricht, the Netherlands (BMBF).

88 Fig. 2: Appearance of the same patient’s scalp after harvesting (A), 6 days later (B), and 12 weeks later (C).

Fig. 1: Donor site (A) and split-skin graft of the scalp with 0.3 mm thickness (B).

Teaching

The entire field of dermatology, venereology, Armbruster N, Trautmann A, Bröcker EB, allergology and dermatooncology is taught Leverkus M, Kerstan A. (2009) Suprabasal to medical and dental students in lectures spongiosis in acute eczematous dermati- and practical courses. The department is tis: cFLIP maintains resistance of basal ke- also involved in the interdisciplinary educa- ratinocytes to T-cell-mediated apoptosis. J. tion of medical students and in the degree Invest Dermatol. 129:1696-702. program biomedicine. Main topics of doc- Hofmann UB, Voigt H, Andersen MH, toral theses derive from the research proj- Straten PT, Becker JC, Eggert AO. (2009) ects listed above. Identification and characterization of survivin-derived H-2Kb-restricted CTL epitopes. Eur J Immunol. 29:1419-1424.

Houben R, Schrama D, Becker JC. (2009) Molecular pathogenesis of Merkel cell carcinoma. Exp Dermatol. 18:193-198.

Hofmeister-Mueller V, Vetter-Kauczok CS, Ullrich R, Meder K, Lukanidin E, Broeck- er EB, Straten P, Andersen MH, Schra-

SELECTED PUBLICATIONS ma D, Becker JC. (2009) Immunogenec- ity of HLA-A1-restricted peptides derived from S100A4 (metastasin 1) in melanoma patients. Cancer Immunol Immunother. 58:1265-1273.

Weyandt GH, Bauer B. Berens N, Hamm H, Broecker EB (2009). Split-skin graft- ing from the scalp: the hidden advantage. Dermatol Surg. 35:1873-1879. 89 3.15 Institute of Radiology

and outpatients at the University Hospital 0.33 seconds has the potential to allow Professor Dr. med. Dietbert Hahn is the treatment of diseases of the vascu- non-invasive cardiovascular imaging. Thus, (Head of the Institute) lar and the bilary system. With the help of a focus of cardiovascular imaging research modern interventional radiology it is possi- is the non-invasive imaging of the heart and Oberdürrbacherstr. 6 ble to dilate vessels with balloon catheters coronary arteries, evaluating novel imaging 97080 Würzburg and metal stents in nearly every part of the techniques for coronary artery stenosis, as- Tel.: 0931/201-34000 body, avoiding the risks of an operation. sessment of myocardial infarction, diag- Fax: 0931/201-634001 The section of Pediatric Radiology offers nosis of acute chest pain, and congenital E-mail: [email protected] state-of-the art imaging including conven- cardiovascular disorders. Ongoing research burg.de tional X-rays with a strong focus on radiation projects include quantification of coronary www.uni-wuerzburg.de/radiologie protection, ultrasound and magnetic reso- artery calcifications and CT coronary angi-

CONTACT DETAILS CONTACT nance imaging. Main topics of the section ography. Professor Dr. med. Meinrad Beer of Pediatric Radiology are radiation pediatric Tel.: 0931/201-34883 urology, oncological diagnostic, diagnostic of skeletal age and pediatric malformation. Whole-body imaging using magnetic The Institute of Radiology offers a postgrad- resonance imaging and computed to- uate training in Radiology including the sub- mography specialities Pediatric Radiology and Neuro- (M. Beissert, M. Weininger, T. Pabst) radiology. Whole-body imaging using state-of-the art magnetic resonance imaging and comput- Major Research ed tomography offers new diagnostic possi- Interests bilities. In oncology whole-body imaging has the potential to allow a new level of flexibil- Basic Research and clinical investiga- ity, accuracy and speed to acurately stage tion of abdominal organs using MRI patients. Another focus of our research in- (F. Wendel, H. Neubauer, T. Pabst) cludes the evaluation of available imaging methods for the diagnosis of different on- Basic research and clinical investigations cological diseases. in the field of abdominal organ diagnosis are performed at the Institute of Radiology with the aim of introducing diffusion weight- MRI of the human lung ed imaging (DWI) in clinical routine. Special (M. Beer, M. Beissert, H. Köstler, T. Pabst, topics are the evaluation of the liver, kidney M. Oechsner, C. Ritter, A. Stäb, C. Wirth) and gastrointestinal tract. The characterisa- Mission tion of masses in the liver and the kidney, Techniques for morphological (under free and Structure as well as functional aspects are investigat- breathing) and functional (with and without ed in several studies. Special topics are the contrast agents) assessment of lung paren- The Institute of Radiology is responsible for evaluation of DWI in M. Crohn and colorec- chyma are developed with a main focus on the entire modern radiological diagnostic tal cancer. techniques for oxygen enhanced ventilation at the University Hospital of Würzburg. Two imaging. Patients with acquired interstitial professors, 13 senior staff radiologists, 20 as well as congenital diffuse lung diseas- residents and scientists as well as 53 tech- Basic Research and clinical investiga- es are studied. Moreover, diffusion-weight- nicians work together to ensure modern dition of pathologics of facial skull and ed (DWI) and late enhancement (LE) imag- agnostic imaging within the clinic. The Insti- neck using MRI ing is tested for a possible characterization tute of Radiology includes a section of Neu- (F. Wendel, T. Pabst) of pulmonary macro- and micro anatomic roradiology and of Pediatric Radiology. With structure. 4 Spiral-CT scanners and 7 MRI systems, Basic research and clinical investigations in which are available for emergency patients the field of diagnosing pathologics of facial 24 hours a day, more than 60.000 people skull and neck are performed at the Insti- Cardiac MR-Imaging are examined each year. A main emphasis tute of Radiology with the aim of introducing (M. Beer, H. Köstler, W. Machann, C. Ritter, in medical diagnostics is modern sonogra- diffusion weighted imaging (DWI) in clinical D. Stäb, A. Weng) phy. Thus more than 30.000 in- and outpa- routine. Special topics are the evaluation of tients are examined at the University Hos- the clinical value of DWI for investigation of Main focus is the development of new imag- pital each year with 6 high end ultrasound neoplastic masses in the oropharynx, head ing strategies for non-invasive primary diag- systems. A further main topic in diagnos- and neck region. nosis of coronary artery disease (CAD) and tic imaging and preventive medicine is the for the detection/exclusion of secundary verification of lesions of the breast, using cardiomyopathy. Besides the acquisition of mammography, sonography and MR-mam- Cardiac computed tomography morphologic and functional parameters our mography. In order to exclude cancer each (M. Beissert, M. Weininger) special interest is the detection of meta- year about 8.000 women undergo exami- bolic changes with 31P-MR-Spectroscopy nations at the Institute of Radiology. A fur- The availability of high-end multi-slice CT (fig. 1). Supported by a DFG-grant, main ther main task in medical attention for in- scanners using fast rotation times of up research in functional imaging is based on

90 Interventional Radiology (R. Kickuth, C. Ritter, J. P. Goltz)

The main investigational topics of the sub- division of Interventional Radiology are the Misago-II-Registry (SFA stenting), the evaluation of the technical and clinical outcome of port catheter systems of the forearm, the evaluation of the causalities for the explantation of port catheter systems of the forearm, and a feasibility study with regard to I-Guide-Kappa supported punctures, drain- ages, and fluid collection aspirations. Fig. 1: Short axis slice of a rest perfusion examination of the heart (left) and corresponding perfusion map (right) with absolute quantification of perfusion showing a 75% trans- mural perfusion defect of the anterior wall (arrows) in a high grade LAD stenosis. Teaching

Continuing medical education is regularly the development of high-resolution imaging optimal X-ray applications are developed in offered for radiologists in private practice, techniques for the determination and abso- co-operation with another hospital (PD Lan- senior radiologists, fellows and residents. lute quantification of cardiac perfusion (fig. gen). Supported by a grant, possible inter- In addition colleagues from other depart- 2). In this context, we advance MR tech- actions between pulmonary and musculo- ments are trained in several diagnostic pro- niques for the quantitative examination of skeletal symptoms are investigated using a cedures. endothelium-derived vasoreaction. Further- special designed MR-compatible ergometer more, innovative MR contrast agents are for assessment of muscular metabolism. applied. In addition, we focus on functional cardiac real-time and free-breathing MR imaging. MR Mammography (H. Köstler, A. Roth)

Pediatric Radiologie One of the major aims of our work on the (M. Beer, C. Wirth) 3T-MR-machine is the non-invasive evalu- Beer M, Wagner D, Myers J, Sandstede J, ation of different breast-diseases with the Köstler H, Hahn D, Neubauer S, Dubach Aims are development and clinical applica- MR-mammographie. The main focus lies on P, J. Effects of exercise training on myo- tion of high-resolution whole body MR tech- the developement of high-resolution MR- cardial energy metabolism and ventricular niques for assessment of inflammatory and techniques to detect smallest carcinomas/ function assessed by quantitative phos- oncologic diseases as well as inborn errors DCIS at the earliest possible stage without phorus-31 magnetic resonance spectroscopy and magnetic resonance imaging in of musculo-skeletal metabolism. Non-inva- any exposure to radiation. New acquisition dilated cardiomyopathy. Am. Coll. Cardiol. sive determination of renal function is an- strategies for magnetic resonance images 51, 1883-1891 (2008). other research topic in collaboration with like the diffusion weighted sequences have the Children´s Hospital of Philadelphia been developed and investigated systemat- Herbert Köstler. Christian Ritter, Michael Lipp, Meinrad, Beer, Dietbert Hahn, Jörn (Prof. Darge). The role of high-resolution ically. All these techniques are being devel- Sandstede. Comparison of different con- ultrasound is evaluated for assessment of oped for clinical use (fig. 3). trast agents and doses for quantitative MR neonates. Also for neonates and for young myocardial perfusion imaging. J. Magn. infants, interactive teaching programs for Reson. Imaging, 28, 382 - 389 (2008). New MR acquisition methods Martin Blaimer, Marcel Gutberlet, Pe- (H. Köstler, M. Beer, M. Gutberlet, C. Rit- ter Kellman, Felix A Breuer, Herbert Kös- ter, A. Roth) tler, Mark A Griswold, A virtual coil concept

SELECTED PUBLICATIONS for improved parallel MRI employing con- By developing of density weighted MR ac- jugate symmetric signals.Magn. Reson. Med., 61, 93 – 102 (2009). quisition in a project funded by the Deutsche Forschungsgemeinschaft the MR image Markus Oechsner, Matti Mühlhäusler, quality (resolution, signal to noise ratio) of Christian O. Ritter, Markus Weininger, Mat- MR can be improved. Density weighted MR thias Beissert, Peter M. Jakob, Mein- imaging is applied to MR real time imaging rad Beer, Dietbert Hahn, Herbert Köstler. Quantitative Contrast-Enhanced Perfusion of cardiac function and perfusion as well as Measurements of the Human Lung Using to 3D MR mammography for detection of the Prebolus Approach. J. Magn. Reson. carcinomas and therapy control. Imaging, 30, 104 - 111 (2009).

Weininger M, Lauterbach B, Knop S, Pabst T, Kenn W, Hahn D, Beissert M. Fig. 2: MRI of breast cancer of the left Whole-body MRI of multiple myeloma: side using a 3T whole body system. comparison of different MRI sequences in assessment of different growth patterns. 91 Eur J Radiol. Feb;69(2):339-45 (2009). 3.15.1 Division of Neuroradiology

Professor Dr. med. László Solymosi CT, a most up-to-date 3T magnetic reso- Neurooncology (Head) nance (MR) scanner with multi-channel (M. Warmuth-Metz, C. Várallyay) und –nuclear support operated exclusively Josef-Schneider-Str. 11 by the department and two 1.5T MR scan- The division acts as the neuroradiological 97080 Würzburg ners operated in alternation with the radio- reference site to all German multi-centric, Tel.: 0931/201-34790 logical department. pediatric neurooncological studies. Stag- Fax: 0931/201-34803 ing according to the different stages of dis- E-mail: a-neuroradiologie@neuroradiologie. Staff: 3 senior physicians, 5.5 residents, ease is the basis for treatment recommen- uni-wuerzburg.de 9.5 medical technicians, 3 third-party dations. Reference staging is an inclusion www.neuroradiologie.uni-wuerzburg.de funded residents and 4 research assistants criterion in most of the pediatric brain tu- (part-time). mor studies. New international treatmentD

CONTACT DETAILS CONTACT concepts are discussed together withC the Due to the regrettable shortage of neurora- reference centers. In this context internaA - diological departments in Germany, our in- tionally agreed guidelines for the imagingB in stitution accommodates a large and steadi- children with brain tumors have been devel- ly increasing number of patients from far oped and agreed upon. MR-examinations beyond the catchment area of the Univer- are evaluated to assess the therapy of ex- sity Hospital per se. perimental gliomas and novel MR contrast agents. Third-party funded. Interventional neuroradiology (i.e. endovascular treatment of aneurysms, arteriovenous malformations, intracranial neoplasms Pediatric Neuroradiology as well as of stenoses and occlusions of su- (M. Warmuth-Metz) pra-aortic vessels) constitutes a main focus of the department. The number of treated Close collaboration with the Pediatric Neu- cases is among the highest in Germany. The rosurgery in the diagnosis and treatment of Stroke-Unit supplies additional diagnostic CNS neoplasms, spinal and vascular mal- and therapeutic tasks. Further emphasis formations. is placed on neurooncology (i.e. diagnostic evaluation of CNS tumors together with the pediatric, neurosurgical and neurologi- MR Imaging of Neuromuscular Diseas- cal specialties). Close collaboration with the es Pediatric Neurosurgery and the Department (C. Várallyay) of Pediatrics characterizes the second diagnostic focus of pediatric neuroradiology. Animal experiments and clinical studies on A quite unique feature of the department the detection of peripheral nerve injuries pertains to the neuroradiological diagnostic and denervated muscles. evaluation of peripheral nerve injuries and myopathies which attracts patient referrals from all over Germany. Pre-surgical func- MR-Diffusion Imaging tional MR imaging is performed for surgical (A. Bartsch) targeting and prior to cochlear implantaton to limit the surgical risks and to increase the Development of new analysis methods for predictable benefits, respectively. MR-diffusion data to establish white matter

Mission Major Research and Structure Interests

The independent Division of Neuroradiology Neuroimaging is integrated into the Head Clinic of the Uni- (A. Biller, C. Várallyay) versity Hospital Würzburg and was founded in 1977. All modern diagnostic exams and This focus is funded by an endowed profes- therapeutic interventions available to the sorship assigned to Dr. Várallyay in conjunc- neuroradiological specialty are practiced at tion with the Department of Neurology. Here, the technically highest standard. The follow- new innovative contrast media are investigating equipment is linked into the PACS: a ed in inflammatory and regenerative process- modern digital imaging system for X-ray di- es of the central as well as peripheral nervous agnostics, a multifunctional X-ray imaging system. Furthermore, prospective studies are system with fluoroscopy and DSA capabil- conducted on brain regeneration after toxic ity, a multislice CT scanner, a biplane digi- insults (such as from alcohol) and on the oc- tal subtraction angiography system with flat currence of specific neuropsychological defi- Fig. 1: Areas of brain volume gain induced panel technology, “large display” and Dyna- cits in the course of various procedures. by abstinence from alcoholism.

92 The division organizes regular teaching and training events with national and international neuroradiological lecturers. Its staff is constantly active in various in- and out-of- house courses (such as refresher programs at the annual Convention of German Radi- ologists and regular neuroradiological training for the Bavarian Medical Association) and organizes or instructs various courses at the international level (such as the FSL & Freesurfer Courses or the Clinical FMRI Course on the Human Brain Mapping Con- ference).

Neuroradiological reference site for all Ger- man multi-centric therapy studies of pediatric brain tumors. Various international studies on malignant brain tumors (glioblastomas, pontine gliomas). International (worldwide) therapy studies on cerebral aneurysms (detachable coils, bioactive coils, stents, “flow diverter”).

Participation on therapy studies of inflammatory CNS diseases.

Fig. 2: Aneurysm in the posterior brain circulation before (A, B) and after (C, D) emboli- Bendszus M, Ladewig G, Jestaedt L, Mis- zation by platinum coils and stent. selwitz B, Solymosi L, Toyka K, Stoll G. Gadofluorine M enhancement allows more sensitive detection of inflammatory CNS integrity (e.g. Tract Based Spatial Statistics) mations and highly-vascularized tumors in lesions than T2-w imaging: a quantitative and establishing and testing of diffusion international and national studies. Optimi- MRI study. Brain 2008;131:2341-52. tractography under aversive conditions. zation of embolization materials and -tech- Biller A, Bartsch AJ, Homola G, Solymosi niques. Third-party funded. L, Bendszus M. The effect of ethanol on human brain metabolites longitudinally Functional MR-Imaging characterized by proton MR spectroscopy. J Cereb Blood Flow Metab. 2009;29:891- (A. Bartsch) Interventional Neuroradiology – Vessel- 902. recanalizing Therapies In cooperation with the Depts. of Neurosur- (L. Solymosi) Stingele R, Berger J, Alfke K, Eckstein gery, ENT, Neurology and Psychiatry. DFG- HH, Fraedrich G, Allenberg J, Hartmann (German Research Council) funded sub- Improvement of the effectiveness of vessel M, Ringleb PA, Fiehler J; SPACE investigators, Bruckmann H, Hennerici M, Jansen project in the Clinical Research Group on recanalization. Examination of pharmaco- O, Klein G, Kunze A, Marx P, Niederkorn K, ADHD. Characterization and quantifica- logical and mechanical recanalization. Di- Schmiedt W, Solymosi L, Zeumer H, Hacke

tion of neuronal resting-state networks by agnostics and interventional treatment of SELECTED PUBLICATIONS W. Clinical and angiographic risk factors fMRI. Mapping prior to neurosurgical resec- vasospasms after subarachnoidal hemor- for stroke and death within 30 days after carotid endarterectomy and stent-protect- tions and cochlear, brainstem and midbrain rhages. ed angioplasty: a subanalysis of the SPACE implants. Examination of the effects of a study. Lancet Neurol 2008;7:216-22. series of electroconvulsive therapies and acute alcohol ingestions on the brain. FMRI Várallyay CG, Muldoon LL, Gahramanov S, and quantified perfusion in malignant brain Teaching Wu YJ, Goodman JA, Li X, Pike MM, Neu- welt EA. Dynamic MRI using iron oxide tumors. nanoparticles to assess early vascular ef- The division participates in the university fects of antiangiogenic versus corticoste- education of students by conducting lec- roid treatment in a glioma model. J Cereb Interventional Neuroradiology – Vessel- tures and courses within the radiological Blood Flow Metab. 2009;29:853-60. occlusive Therapies and neuroradiological teaching. The head Warmuth-Metz M, Bison B, Dannemann- (L. Solymosi) of the division is authorized to full neurora- Stern E, Kortmann R, Rutkowski S, Pietsch diological training (3 years). T. CT and MR imaging in atypical teratoid/ Endovascular treatment of vascular malfor- rhabdoid tumors of the central nervous system. Neuroradiology 2008;50:447-52. 93 3.16 Department of Nuclear Medicine

Professor Dr. med. Christoph Reiners the use in small animals. It facilitates, after (Head of the Department) co-registration with small animal-PET and In the field of PET-diagnostics, F-18-FDG –SPECT, a correlation of anatomical with is routinely used for patient care and clini- Oberdürrbacher Str. 6 functional imaging. cal studies; for diagnosis of brain tumors 97080 Würzburg and prostate cancers, F-18-Fluorethyltyro- Tel.: 0931/201-35001 sine and F-18-Fluorethylcholine respective- Fax: 0931/201-635000 Diagnosis and Therapy of Thyroid Dis- ly are available. For non-invasive diagnosis E-mail: [email protected] orders of neuro-endocrine tumors, Ga-68-DOTA- burg.de (Chr. Reiners, J. Biko, F. Verburg, P. Sch- TOC has been established as somatostatin- www.klinik.uni-wuerzburg.de/nuklearmedizin neider) receptor-ligand for PET.

CONTACT DETAILS CONTACT Professor Dr. rer. nat. Samuel Samnick The main focus of the clinical research is A special focus in oncology is development, Tel.: 0931/201-35079 thyroid cancer, for which in, cooperation pre-clinical and clinical assessment of ra- with the Comprehensive Cancer Center, a diotracers for imaging adrenocortical can- regional incidence registry is kept. A close cer (together with the department of endo- Major Research collaboration exists with partner institution crinology). Here the SPECT tracer I-123- Interests in Minsk, Belarus, and Nagasaki, Japan, to Metomidate as well as the PET-tracer I- improve the diagnosis, therapy and after- 124-Metomidate could be successfully es- Experimental Nuclear medicine - Radio- care of radiation induced thyroid cancer in tablished in the framework of a study spon- chemistry/Radiopharmacy children. The department regularly partici- sored by Wilhelm-Sander-Stiftung in more (S. Samnick, A. Schirbel) pates in drug approval studies of new med- than 100 patients. On a compassionate ications for the treatment of thyroid carci- use basis, patients with untreatable met- The research group is in charge of the devel- noma (i.e. rhTSH, ZD6474, XL184, E7080 astatic adrenocortical cancer are treated opment of innovative radiopharmaceuticals and Sorafenib). The department of nuclear with I-131-Metomidate (Fig. 2). In paral- for imaging and therapy in nuclear medi- medicine participates in (and is partially in lel, the spectrum of radiopharmaceuticals cine. Probes are evaluated pre-clinically in- charge of) several international epidemio- for radionuclide therapy has been actual- vitro (e.g. in primary human cell-cultures), logical studies of iodine deficiency induced ly broadened. For patients with neuroen- as well as in-vivo, by using small animal im- thyroid disorders. In addition, a cooperation docrine tumors and other neoplasias with aging (small animal PET and SPECT). The with Su Yat-Sen University of Guangzhou, over expression of hormone receptors, the most promising tracers then are being fur- China, exists concerning longitudinal stud- receptor directed radionuclide therapy with ther medically assessed in cooperation ies for optimization of radioiodine therapy in Y-90 DOTATOC and Lu-177-DOTATATE are with clinical partners (please refer to sub- thyrotoxic patients. effective treatment options. ject areas oncology, cardiology and neurology-psychiatry). IZKF, Deutsche Krebshilfe, BMBF as well as DFG sponsor the radio- Medical Physics/Radiation Safety Cardiology pharmaceutical developments and the clin- (M. Laßmann, H. Hänscheid, S. Schlögl) (M. Kreißl, R. Lorenz) ical evaluation of new radiopharmaceuticals in the framework of SFB 688. The main point of interest is the field of At the department of nuclear medicine, internal dosimetry for radionuclide thera- the influence of the normal reference data py. Currently, new imaging procedures like base on the automated analysis of myocar- Pre-clinical imaging SPECT/CT and PET using nonstandard ra- dial perfusion studies was systematically (M. Kreißl, M. Laßmann, A. Schirbel, S. dionuclides are being evaluated for do- assessed and the process was further opti- Samnick) simetry and are implemented into clinical mized. The effect of physical stress on car- practice. In this context, particularly radio- diac function has been investigated in pa- Small animal PET, as well as animal SPECT nuclides are of interest, which can be used tients with coronary artery disease (CAD). are both non-invasive imaging modalities, for dosimetry in radionuclide therapy (i.e. I- Furthermore, tracers for imaging matrixme- which are being employed in-vivo to evalu- 124, Y-90, Lu-177). talloproteinases, which are known to play ate the new radiotracers developed by the a crucial role in CAD and the inflammatory radiochemistry-radiopharmacy group in co- A further focus of research is the meth- processes after myocardial infarction, are operation with other groups from IFB or SFB odological development of 3D-ultrasound also being developed. 688 and IZKF. Subjects of study are tumor and high resolution multi-pinhole-scintig- response to different chemotherapy regi- raphy for small organs (thyroid) and small mens, regulation of cardiac metabolism in animals. Additionally, the research group is Neurology/Psychiatry/Child- and Youth type II diabetes, remodelling after myocar- operating a whole body counter as an offi- Psychiatry dial infarction as well as the role of trans- cial recording point of the State of Bavaria (R. Lorenz, K. Nerlich, A. Schirbel) membranprotease fibroblast-activation- for the incorporation monitoring in persons protein α for wound healing and the fibrose who are occupationally exposed to radia- Together with the department of neurology, reaction after infarction in animal models. tion. transcranial ultrasound was compared with In addition, small animal PET studies are dopamine transporter scintigraphy in pa- performed in stroke and neurotrauma-mod- tients with Parkinson’s disease and atypical els. Oncology Parkinson syndromes. In children and ado- (R. Lorenz, M. Kreißl, P. Schneider, A. Schir- lescents with attention deficit hyperactivity In addition, 3D ultrasound was adapted for bel, S. Samnick) disorder, the effect of medical treatment on

94 Biodosimetry (K. Hempel, M. Laßmann, R. Lorenz, K. Nerlich)

In close cooperation with the Bundeswehr Institute of Radiobiology the induction, persistence and disappearance of DNA-damages are being studied using induced gamma-H2AX-foci after radiation exposure to I- 131. As a model, the in-vivo exposition of Fig. 1: Coronal small animal PET images mononuclear peripheral blood cells of pa- of a mouse implanted with prostate carci- tients with differentiated thyroid carcinoma noma cells (arrows). The tumor shows a in- after ablation treatment with I-131 (activ- creased glucose metabolism as visualized ities of more than 3 GBq) is being used. by a strong accumulation of [18F]-Fluoro- In comparison to physical dosimetry, thhe desoxyglucose whereas choline uptake im- induction, persistence and the disappear- aged with [18F]-Fluoroethylcholine is lower. ance of radiatin-induced gamma-H2AX and Tumor angioneogenesis may be assessed 53BP1 foci I-131 therapy of patients with using [68Ga]-NOTA-RGD. differentiated thyroid carcinoma is studied as a model for protracted, continuous, internal whole-body irradiation. dopamine transport was assessed. For the diagnosis of dementia, an automated para- Teaching metric image analysing procedure was in- Kobe C, Dietlein M, Franklin J, Markova J, troduced and evaluated in corticobasal de- In a project funded by the „Virtuelle Hoch- Lohri A, Amthauer H, Klutmann S, Knapp mentia. schule Bayern“, the department of nuclear WH, Zijlstra JM, Bockisch A, Weckesser M, Lorenz R, Schreckenberger M, Bares R, medicine - together with the institute for In- Eich HT, Mueller RP, Fuchs M, Borchmann formatics IV – optimizes an interactive pro- P, Schicha H, Diehl V, Engert A Positron Neuromuscular-Skeletal System gram for teaching medical students. emission tomography has a high negative (P. Schneider, H. Hänscheid) predictive value for progression or early relapse for patients with residual disease after first-line chemotherapy in advanced- The quantification of bone mineral content is stage Hodgkin lymphoma. Blood. 2008 strongly related to force producing muscles. Nov 15;112(10):3989-94. The densitometric measurement methods also allow assessment of bone strength, Elisei R, Schlumberger M, Driedger A, Reiners C, Kloos RT, Sherman SI, Haugen which is one of the main research focuses. B, Corone C, Molinaro E, Grasso L, Leb- In this context, methods were developed to oulleux S, Rachinsky I, Luster M, Lass- further assess the properties of the neuro- mann M, Busaidy NL, Wahl RL, Pacini F, muscular system in humans. These meth- Cho SY, Magner J, Pinchera A, Ladenson PW. (2009) Follow-up of low-risk differen- ods were ceded to the university to file for

SELECTED PUBLICATIONS tiated thyroid cancer patients who under- patents. In addition, field studies have been went radioiodine ablation of postsurgical carried out to test these methods as predic- thyroid remnants after either recombinant tive parameters of fall risk. human thyrotropin or thyroid hormone withdrawal. J Clin Endocrinol Metab 94: 4171-9.

WHO/REMPAN-Centre Hahner S, Stuermer A, Kreissl M, Rein- (Chr. Reiners, R. Schneider, M. Laßmann) ers C, Fassnacht M, Haenscheid H, Beus- chlein F, Zink M, Lang K, Allolio B, Schir- bel A. (2008). [123 I]Iodometomidate for The WHO/REMPAN-Centre was accredited molecular imaging of adrenocortical cyto- in 2005. Its key activities are the organi- chrome P450 family 11B enzymes. J Clin sational improvement of the medical treat- Endocrinol Metab. 93: 2358-65. ment of radiation accident patients in Ger- many, the administration of a radiation ac- Hänscheid H, Lassmann M, Luster M, Kloos RT, Reiners C. (2009) Blood do- cident data base as well as training and ed- simetry from a single measurement of the ucation in medical radiation accident man- whole body radioiodine retention in pa- agement (http://www.rempan.de). As one of tients with differentiated thyroid carcino- the Regional Centres for Radiation Protec- ma. Endocr Relat Cancer 16: 1283-9. tion, the department is responsible for the Samnick S, Romeike BF, Lehmann T, Isra- treatment of patients exposed in occupa- el I, Rübe C, Mautes A, Reiners C, Kirsch tional radiation accidents. CM. (2009) Efficacy of systemic radionuclide therapy with p-131I-iodo-L-phenyl- alanine combined with external beam photon irradiation in treating malignant glio- 95 mas. J Nucl Med 50: 2025-32. 3.17 Department of Radiation Oncology

Professor Dr. med. Michael Flentje cal basis data for a computerised treatment Fig. 1. Example (Head of the Department) planning. Planning, dose calculations and for the respirato- the calibration of the treatment units are ry movement of a Josef-Schneider-Str. 11 carried out by the section of medical phys- lung tumour dur- 97080 Würzburg ics. About 2200 patients (mainly ambula- ing radiation (blue Tel.: 0931/201-28891 tory) are treated annually. By means of the line). By means of Fax: 0931/201-28396 day ward it is possible to avoid hospitali- tracking and re- E-mail: [email protected] sation also in more intensive parts of the spective counter- treatment (concurrent chemotherapy, treat- measures the movement was reduced sig- ment of acute side effects). In addition to nificantly (red curve). the typical spectrum of radiation therapy,

CONTACT DETAILS CONTACT special techniques are offered like intra and extracranial radio surgery, total body irradiation before stem cell transplantation, contact irradiation for tumours of the eye and Glioblastoma multiforme is the most ag- interstitial brachytherapy of tumours in the gressive primary brain tumor in adults. head and neck, prostate, abdominal tu- Standard therapy consists of surgical re- mours, and tumours of the extremities af- section followed by radiotherapy (RT) which ter implantation of catheters or permanent significantly prolongs survival. Chemother- seeds. apy added to RT is used as concurrent or adjuvant treatment. Although more long- Major Research term survivors have been reported after Interests combined chemoradiotherapy, its success is limited in patients who develop chemo- Development of highly conformal treat- resistance. ment techniques A number of anticancer agents are known to synergistically enhance the cytotoxicity of The realisation of an optimal dose concen- ionizing radiation (IR). Among them are sev- tration in the tumour forms a major part eral camptothecin (CPT) derivatives, a novel of the research effort. The development of class of anticancer drugs directed against stereotactic techniques in the region of the DNA topoisomerase I (topoI). CPT, a plant body, the development of inverse planning alkaloid isolated from Camptotheca acu- techniques using intensity modulation and minata, is a potent antitumor drug with a dynamic multi leaf collimators and integra- broad spectrum of antitumor activity. CPT, tion of time dependent changes (intra- and however, failed through brief phase I/II clini- interfractional) are part of this. cal trials in the early 1970s because of its excessive toxicity. Nevertheless renewed interest in CPT has come from the identifica- Medical physics tion of its only known molecular target, DNA topoI, and the elucidation of the mecha- Research concerns image guided radiother- nism of its action. apy, optimisation and adaptation of dose Our radiobiological laboratory (2 scientists, distributions and dosimetry. Topics are: pa- 2 technicians, 2 grant positions) is appro- tient positioning, image registration, track- priately equipped to carry out basic research Mission ing of moving targets and movement com- of the biological effects of ionizing radiation and Structure pensation, dose calculation on image data in human cells. sets from cone-beam-CT, calculation of the In order to enhance the cytotoxicity of ra- The clinic for radiotherapy (18 physicians, accumulated dose in the presence of tu- diation, CPT, an inhibitor of DNA topoisom- 9 medical physicists, 19 radiographers, 16 mour movements, development of recipes erase I, was added to the cultured glioma nurses) uses 5 modern linear accelerators for optimisation and adaptation of intensi- cell lines before irradiation (IR). We found (including IGRT with an in room cone beam ty modulated radiotherapy, dose measure- that CPT enhanced the radiotoxicity in U87- CT), a short distance X-ray unit and after- ment and dose calculation in inhomoge- MG and SNB-19 cell lines if cell and colony loading units for remote controlled radioac- neous bodies and for small fields. The aims counts were used as the end-points (Fig. tive inserts. Patients are treated in a poli- are effective sparing of organs at risk and 3). In contrast, pre-treatment with CPT of clinic department, in a ward with 20 beds increase of the tumour control rate, hence U373-MG, GHE and GaMG cell lines did in the Kopfklinikum and in a day ward with a higher accuracy and safety of treatment not enhance cytotoxicity of IR in terms of 10 treatment places. Over that, the ward with ionizing radiation. cell and colony counts but accelerated DNA for palliative care of the university hospi- damage repair assessed by Rad50 foci. CPT tal is linked to our department. Spiral-CT, treated glioma cells revealed at least two ultra sound and a user connection to the Preclinical testing of DNA Topoisomer- subpopulations with respect to the expres- Institute of diagnostic radiology, especial- aseI-targeted radiotherapy of different sion of histone �H2AX, a marker of DNA ly related to MR-tomography for treatment human glioblastoma cell lines double-strand breaks. Combined CPT-IR planning provide the anatomical and physi- treatment followed by 30 min repair exert-

96 tional and international therapy studies for head and neck tumours and lung cancer. Major contributions concern randomized studies for organ preservation in Larynx/hy- popharynx Cancer (Delos 2) and in concurrent radiochemotherapy in advanced lung cancer (GILT-CRT). A quality circle for Unter/ Oberfranken as well as the radiation safety board (§ 83 StrSCHV) of Bavaria is chaired by the director of the department.

Fig. 2: Dose distribution for a prostate case achieved with IMRT technique: B: Adapta- tion to anatomical changes with translations only, C: complete re-planning, D2: controlled adaptation of the original technique.

ed stronger effects on γH2AX expression in the case of U87 and SNB cells than either treatment alone. Because of the importance of topoI for the cytotoxicity of CPT, we additionally analyzed the expression levels of topoI in exponentially growing glioblastoma cell cultures by flow-cytometry. We found that the untreated U87 cells showed the highest expression of topoI Meyer J., Wilbert J., Baier K., Gucken- (mean  460 a.u.), followed berger M., Richter A., Sauer O., Flentje M. by SNB cells (337 a.u.). The (2007) Positioning accuracy of cone-beam other three lines (U373, GHE computed tomography in combination with a HexaPOD robot treatment table. Int. J. and GaMG) showed much low- Radiat. Oncol. Biol. Phys. 67:1220-1228. er background levels of topoI ranging between 160-180 a.u. Guckenberger M., Wilbert J., Krieger T., The failure of CPT to enhance Richter A., Baier K., Meyer J., Flentje M. (2007) Four-dimensional treatment plan- the radiotoxicity of glioma ning for stereotactic body radiotherapy. U373-MG, GHE and GaMG cell Int. J. Radiat. Oncol. Biol. Phys. 69:276- lines in terms of cell and colony 285. counts was found to correlate with accelerated DNA damage Bratengeier K, Guckenberger M, Meyer J, Mueller G, Pfreundner L, Schwab F and repair, and with low expression Flentje M 2007 A comparison between 2- Fig. 3: Clonogenic abilities of glioblastoma cell lines of topoisomerase I, a target of Step IMRT and conventional IMRT plan- as functions of radiation dose and CPT exposure. Un- CPT. ning Radiother.Oncol. 84 298-306. treated and CPT-treated cells (empty and filled sym-

SELECTED PUBLICATIONS Otto A Sauer, Determination of the qual- bols, respectively) were irradiated with single IR dos- ity index (Q) for photon beams at arbi- es ranging between 1 and 8 Gy. After irradiation, cells Clinical trials and quality as- trary field sizes. Med. Phys. 36 (9 / 2009) were plated in CGM and incubated under standard surance 4168-4172. conditions. Two weeks later, colonies containing at least 50 cells were scored as survivors. Note that CPT The department is responsible Djuzenova C.S, Güttler T., Berger S., Katzer A., Flentje M. (2008) Differen- enhanced the radiotoxicity in U87 and SNB19 cell for the conception and realisa- tial response of human glioblastoma cell lines (marked red). tion of radiation therapy in na- lines to combined camptothecin and ionizing radiation treatment. Cancer Biol Ther. 97 7:364-373. 3.18 Department of Oto-Rhino-Laryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery

Professor Dr. med. Dr. h.c. Rudolf Hagen Mission Inner ear biology (Head of the Department) and Structure (R. Mlynski, K. Rak, N. v. Wasielewski in cooperation with the institute of neurobiology, Josef-Schneider-Str. 11 The clinic of Otorhinolaryngology, plastic M. Sendtner) 97080 Würzburg and aesthetic surgery (28 physicians, 5 sci- Tel.: 0931/201-21701 entists, 8 research fellows) has 92 regular In vitro and in vivo investigations of neuro- Fax: 0931/201-21248 beds including 6 intensive care units. Be- trophic substances (FGFs, NT-3, CNTF, LIF) E-mail: [email protected] sides the complete basic care in the field of on survival and growth patterns of hair cells www.hno.uni-wuerzburg.de ORL there exist the following clinical speci- and spiral ganglion neurite extension in alities: device based and surgical supply of the mammalian cochlea; effects of recom- Professor Dr. med. Norbert Kleinsasser all kind of hearing disabilities by special di- binant adenoviruses on cochlear cells to CONTACT DETAILS CONTACT Tel.: 0931/201-21322 agnostics, conventional middle ear surgery, transducer cochlear tissues for future gene new active middle ear implants, implantable therapy, inner ear and hearing development hearing aids as well as cochlear implanta- in CNTF and LIF knockout mice, creation of tion (international reference centre), inter- transgenetic mice with a cell specific gene- disciplinary skull base surgery (tumours, knock-out in cochlear and spiral ganglion traumas), diagnostics and therapy of head cells; investigations of function of vasodi- and neck tumours with main focus on or- lator stimulated phosphoproteins (VASP) in gan and function preserving and microsur- terminal hair cell innervation. gical techniques and plastic-reconstructive surgery, national reference centre for surgical treatment of pediatric sarcomas, pho- Impact of stem cells in auditory pathway niatrics (including phonosurgery), pedaudi- (A. Radeloff, K. Rak, R. Mlynski) ology, allergology, sleep medicine (devices based and surgical treatment), neurootolo- Detection of adult stem cell populations gy, plastic and aesthetic interventions of the in inner ear and central auditory pathway. head and neck. Support of foreign ORL clin- In-vivo application of cultured stem cells ics in all continents by visitant professor- to damaged inner ear in animals (guinea ships and practical education of foreign ENT pigs). doctors. National and international surgical courses with 3D-Video-Live-Transmission of surgical interventions. Pedaudiological tests and newborn hearing screening (W. Shehata-Dieler, D. Ehrmann, R. Keim in Main Research cooperation with the center of pre-speech Interests development and developmental disorders, K. Wermke) Middle ear biology (R. Mlynski, M. Schmidt, A. Radeloff, R. Ha- Development of new objective test proce- gen) dures for frequency specific examination of newborns. Investigation of pre-speech Histological morphometry and surface cha- sounds in infants as a new tool for pedaudi- racteristics of middle ear implants; immu- ological testing. nology and immunhistology of cholesteato- mas for research of origin and maintenance of chronic otitis media, expression of bone Cochlear- and brain stem implants morphogenetic protein-2, MMP-9 and cy- (J. Müller, W. Shehata-Dieler, A. Radeloff, S. tokines in cells of cholesteatoma. Develop- Brill, S. Kaulitz in cooperation with the de- ment of coated electrode carriers for me- partment of neurosurgery, C. Matthies, and dicamentous treatment of middle and in- Univ. of Innsbruck, P. Nopp) ner ear. Evaluation of new stimulation strategies for further improvement of speech intelligibility Biophysics of middle ear following cochlear and brain stem implan- (J. Müller, S. Brill, F. Kraus, R. Hagen) tation. Advancement of intraoperative tele- metry and monitoring systems. LASER-vibrometrical measures of middle ear mechanics in petrous bones. Clinical and experimental investigations of middle Experimental audiology ear implants and transplants using EDP (M. Cebulla, R. Keim, W. Harnisch in co- supported documentation. Intraoperative operation with the department of psychia- monitoring of transmission function in ac- try, psychosomatics and psychotherapy, A. tive middle ear prostheses. Fallgatter)

98 Further development of diagnostic tools for Functional Electrostimulation of the la- objective frequency specific measurement rynx of the absolute threshold of hearing. Objec- (R. Hagen, W. Harnisch in cooperation with tification of binaural hearing in normal hear- the university departments Innsbruck and ing and hearing impaired persons. Jena and the ENT department Gera, C. Po- totschnig, O. Guntinas-Lichius, A. Müller)

Hearing research Development of a larygeal pacemaker for (M. Vollmer, T. Bremer in cooperation with treatment of uni- and bilateral recurrent the University of California, San Francisco, nerve paralysis. R. Beitel, and the Ludwig-Maximilians Uni- versity Munic, B. Grothe)

Electrophysiological basic research on cen- Teaching tral-neuronal processing of acoustic and electric stimulation of auditory pathway in Coworkers with postdoctoral lecture quali- an animal model. fication take part in the medical main lecture and in the clinical courses for medical students. Initiation and coaching of experi- Tumour biology and functional rehabili- mental and clinical medical dissertations. tation following tumour surgery Annual german and english speaking surgi- (R. Hagen, M. Schmidt, M. Scheich) cal courses for microsurgery of the ear, skull base surgery, phonosurgery, reconstructive Molecular biological investigations in head laryngeal surgery, endonasal surgery with and neck carcinomas (HNC), induced ex- live-3D-transmission and practical exer- pression of a deletional mutant of Pseu- cises for consultants. The foreign twin clin- domonas exotoxin A in cell lines of HNC, ics are served by course instructors (DAAD) development of a new control plasmid by in all the participating countries, 4 training subcloning (pGeneA-EGFP), investigations fellowships for practical education (actually in chemotaxis and angiogenesis of tumour doctors from China, Syria, Argentina, Alba- cells, effects of herbal anti-tumoural ex- nia). Full-time hospitations for consultants. tracts on paclitaxel sensitive and – resistant HNC cell lines, development of new surgical reconstructive techniques of larynx and trachea.

Ecological toxicology of the upper Ginzkey C, Kampfinger K, Friehs G, Köhler aerodigestive tract (UADT) C, Hagen R, Richter E, Kleinsasser N (N. Kleinsasser, C. Köhler, C. Ginskey, S. (2009) Nicotine induces DNA damages Hackenberg, G. Friehs) in human salivary glands. Toxicol Lett 184:1-4. Investigations on the toxicological effects of Schmidt M, Polednik C, Grünsfelder P, ecological toxins in tumour initiation testing Roller J, Hagen R (2009) The effects of human tissue cultures of the UADT, charac- PC-Spes on chemosensitive and che- terisation of genotoxical effects of tobacco moresistant head and neck cancer cells smoke and environmental toxins (nitrogen and primary keratinocytes. Oncol Rep 21:1297-1305. dioxide) on mini organ cultures of UADT. Tolsdorff B, Petersik A, Pflesser B, Pom- mert A, Tiede U, Leuwer R, Höhne KH Tissue engineering in laryngology (2009) Individual models for virtual bone (N. Kleinsasser, K. Frölich, A.Scherzed, M. drilling in mastoid surgery. Computer Aided Surgery 14:21-27. Burghartz, A. Technau in cooperation with the department of orthopaedics, U. Nöth) Radeloff A, Unkelbach MH, Mack MG,

SELECTED PUBLICATIONS Settevendemie C, Helbig S, Mueller J, Ha- Establishment of stable cartilaginous struc- gen R, Mlynski R (2009) A coated electrode carrier for cochlear implantation re- tures with different scaffold materials. In- duces insertion forces. The Laryngoscope vestigations on the functionality of stem cell 119:959-963. engineered tissue in an animal model. Brill S, Müller J, Hagen R, Möltner A, Brockmeier S, Stark T et al (2009) Site of cochlear stimulation and its effect on electrically evoked compound action potentials using the MED-EL standard electrode array. BioMedical Engineering On- 99 Line 8:40-49. 3.19 Department of Ophthalmology

Professor Dr. med. Dr. h.c. Franz Grehn Mission neously detect signals from distinct areas in (Head of the Department) and Structure the visual field. Recently, these techniques were adapted to study lateral retinal inter- Josef-Schneider-Str. 11 A staff of 29 physicians and 76 nurses, actions, to characterize genetically encod- 97080 Würzburg technicians and scientists cares for approx. ed maculopathies, to determine retinocorti- Tel.: 0931/201-20601 20.000 outpatients and more than 5.000 cal transmission speed, and to study basic Fax: 0931/201-20245 inpatients annually. In 2008, more than mechanisms in visual perception (e.g. long- E-mail: [email protected] 6.500 surgical procedures and 1.500 laser term potentiation). www.augenklinik.uni-wuerzburg.de treatments were performed. As one of the largest eye hospitals in Germany, we pro- Professor Dr. med. Gerd. Geerling vide the full range of medical and surgical Biometry and Optics CONTACT DETAILS CONTACT Tel.: 0931/201-20610 eye care and diagnostics. The hospital comprises a renowned glaucoma center with The proper selection of lens implants in cat- Professor Dr. med. Heimo Steffen distinct experience in pediatric glaucoma. aract surgery rests on an accurate determi- Tel.: 0931/201-20487 The retina service specializes in retinovitre- nation of intraocular distances. Internation- al diseases and ocular trauma. Specialized ally renowned for its research and develop- teams care for eyelid affections, conjuncti- ment, the biometry lab has played a crucial val, corneal and orbital diseases as well as role in the emergence of laser interference childhood eye diseases, neuroophthalmo- biometry techniques as the current gold logical disorders or strabismus. To supple- standard. Two instruments that are now ment our services, a cornea bank meeting widely used in clinical practice were devel- recent and future regulatory requirements is oped in a close ongoing collaboration with being established. An increasing number of Carl Zeiss Meditec AG. Another focus of the patients treated for eye disease suffers from lab is the development of algorithms to val- multiple systemic ailments and requires in- idate refractive implants. These algorithms patient care. At the same time it is our goal are being tested in an international network to improve and expand outpatient surgery and are provided to the scientific communi- facilities to provide the best possible care ty as an open access internet resource. for all patients.

Cell Biology Main Research Interests Ocular wound healing, intraocular pressure regulation and ocular surface regeneration Clinical Research are at the focus of the cell biology lab. Cen- tral to these issues are cell-cell and cell- Research activities focus on the fields of matrix interactions which drive cellular sig- cornea, glaucoma and retina. New strate- nal integration mechanisms to direct and gies are developed to treat ocular surface coordinate cell functions. Based on these disease, recent methods of cornea transplantation are studied, novel wound healing modulation techniques are assessed to prevent scarring following glaucoma surgery, new agents to treat age-related macular degeneration are evaluated and genetic glaucoma predisposition is studied. The glaucoma center leads the clinical assessment of innovative methods to measure intraocular pressure and develops new electronic data acquisition and management networking systems to improve national and international collaborations in patient care.

Basic Research Electrophysiology Fig. 1: Human trabecular meshwork cells deposit extracellular matrix proteins (fibro- Minimally invasive electrophysiological nectin, green) and process them to form methods allow for a differential examination extracellular network structures. An in- of distinct components of the visual path- creased matrix deposition appears to have way. The electrophysiology lab develops and a role in glaucoma pathophysiology. The validates new recording methods and spe- actin cytoskeleton (red) and the cell nucle- cializes in multifocal techniques to simulta- us (blue) are depicted as well.

100 Fig. 2: A tissue gap in the central retina (macular hole) due to membraneous traction leads to distorted vision and reduced visual acuity. At the stage depicted, retinal microsurgery allows for recovery in 90% of all patients. Optic coherence tomogram depicting retinal layers and intraretinal cysts.

mechanisms, specific kinase inhibitors were characterized as wound healing modulators in vitro and are currently being tested in advanced models. Similarily, the role of tissue elasticity emerges as an important determi- nant of trabecular meshwork cell functions with possible implications in glaucoma.

Teaching

Lectures, practical training and special interest seminars are offered to medical students. The residency program comprises daily morning rounds with case presenta- tions and a weekly CME-certified seminar Fritsche LG, Loenhardt T, Janssen A, series that is also open to guest visitors. Fisher SA, Rivera A, Keilhauer CN, We- Another series of four extensive seminars ber BH: Age-related macular degeneration is associated with an unstable per year is dedicated to update colleagues ARMS2 (LOC387715) mRNA. Nat Genet. in private practice on the most recent devel- 40(7):892-6, 2008. opments in the field. In addition, the Univer- sity Eye Hospital hosts regional and interna- Geerling G, Garrett J, Paterson K, Sieg P, Collin J, Carpenter G, Hakim S, Lauer I, tional ophthalmology conferences. Proctor G: Innervation and secretory function of transplanted human submandibular salivary glands.�Transplantation. 85:135- 140, 2008.

Haigis W: IOL calculation after refractive surgery for myopia: the Haigis-L formula. J Cataract Refract Surg. 34(10): 1658- 1663, 2008.

Pasutto F, Matsumoto T, Mardin CY, Sticht

SELECTED PUBLICATIONS SELECTED PUBLICATIONS H, Brandstätter JH, Michels-Rautenstrauss K, Weisschuh N, Gramer E, Ramdas WD, van Koolwijk LM, Klaver CC, Vingerling JR, Weber BH, Kruse FE, Rautenstrauss B, Barde YA, Reis A: Heterozygous NTF4 mutations impairing neurotrophin-4 signaling in patients with primary open-angle glaucoma. Am J Hum Genet. 85(4):447-56, 2009.

Schlunck G, Han H, Wecker T, Kampik D, Fig 3: Clear implant several days after full- Meyer-ter-Vehn T, Grehn F: Substrate rigid- thickness corneal transplantation. Two su- ity modulates cell matrix interactions and tures secure the implant. protein expression in human trabecular meshwork cells. Invest Ophthalmol Vis Sci. 101 49(19): 262-9, 2008. 3.20 Department of Neurosurgery

Professor Dr. med. Ralf-Ingo Ernestus The whole range of neurosurgery is per- Translational neurotrauma research (Head of the Department) formed at latest technique and supported (A.-L. Sirén) by modern technological devices such as Josef-Schneider-Str. 11 neuronavigation, neuro-endoscopy, intraop- Main focus of research is on the mecha- 97080 Würzburg erative ultrasound and micro-dopplersonog- nisms of neuroprotection and regeneration Tel.: 0931/201-24800 raphy as well as continuous neuro-anesthe- after brain injury and on translation of this Fax: 0931/201-24635 siological and neuro-physiological monitor- knowledge into new therapeutic approach- E-mail: [email protected] ing. Special interdisciplinary treatment pro- es for human brain disease using cell cul- ww2.uk-wuerzburg.de/deutsch/einrichtungen/ tocols have been established for patients ture, transgenic animals and experimental kliniken/nch/content.html with vascular malformations (in close coop- models of brain trauma. On-going work fo- eration with the Department of Neuroradi- cuses on regeneration using growth factor

CONTACT DETAILS CONTACT Professor Dr. med. Klaus Roosen ology), furthermore for patients with brain and stem cell based therapies for brain in- (Head until 31. 9. 2009) tumours together with radiotherapists and jury and on the changes in synaptic struc- neuro-oncologists as well as for skull base tural plasticity and their impact on function- Professor Dr. Anna-Leena Sirén lesions, namely vestibular schwannomas al deterioration after brain injury. A proof- Tel.: 0931/201-24579 and meningiomas with ENT surgeons. Spine of-concept clinical study is aiming at better surgery for complex neoplastic and neuro- prediction of outcome using dynamic math- Professor Dr. med. Cordula Matthies vascular lesions as well as for degenerative ematical modeling of the complex patho- Tel.: 0931/201-24805/-24808 disease is performed at high incidence and physiological cascades after traumatic brain for certain indications together with ortho- injury. pedic and trauma surgery. Regular quality control conferences guarantee an ongoing high standard in routine and in most sophis- Functional Microsurgery & Neurostimu- ticated operations. lation (C. Matthies) The Division of Experimental Neurosurgery Duties performs studies on neurotrauma, neuro- Functional microsurgery is the refined mi- and Structure degeneration and –regeneration, neurovas- crosurgical technique guided by online in- cular pathophysiology and neuro-oncology formation from continuous neurophysio- The Department of Neurosurgery employs and holds established collaborations with logical monitoring for achieving microsurgi- 22 medical doctors, 3 scientists, 96 nurs- other basic science and clinical depart- cal cure of pathologies at the skull base, es and 7 technicians. The clinical wards are ments. brainstem, medulla and specific function- comprised of a total of 87 beds with single, al brain areas along with functional integ- double and triple patient rooms and an in- rity of neural structures. Prospective clini- tensive care unit of 17 beds providing treat- Main Research cal studies are being run on improving cur- ment for patients with cranial and spinal Focus rent techniques of monitoring and adapting trauma, vascular malformations and spon- them to the microsurgical process. A pro- taneous haemorrhage, with brain or spinal Brain injury: Neurovascular neuro-inten- spective study on motor evoked potentials cord surgery as well as early neurological sive medicine of the cranial nerves has shown an increase rehabilitation within a subunit for interme- (J.-Y. Lee, E. Kunze, T. Westermaier) in monitoring safety and improved progno- diate care. The operating unit consists of sis of functional outcome in tumor surgery. 4 operating theatres and one additional Main focus of research is on development A further study on continuous monitoring OR for out-patients and emergencies. Over of novel therapies for and a better under- on the ICU after surgery has detected func- the passed 2 years (2008-2009) 1900 to standing of mechanisms of early brain in- tional changes in this early period and has 2000 patients were treated surgically and jury after subarachnoid hemorrhage as well prompted new intensive medication proto- 4900 to 5300 patients in the out-patient as on monitoring and maintenance of cere- cols, among those the application of rheo- department, resulting in an increase in ac- bral oxygenation and brain metabolism in logicly active substances. tivity of the department by 5 to 8%. The out- acute brain disease (bleeding/ stroke/ cere- patient clinic offers consultation for all neu- brovascular disease/ traumatic brain injury/ Neurostimulation therapy has been estab- rosurgical diagnoses in specialized clinics increased intracranial pressure). Besides lished for retrocochlear deafness and a cen- such as brain tumors, degenerative spine invasive monitoring, transcranial Doppler tre for “new diagnostic and treatment mo- and disc disease, pain syndromes, periph- sonography and perfusion imaging are used dalities” (NUB) has been set up for the ap- eral nerve lesions, pituitary tumors and dys- for control of vascular dynamics in the clini- plication of auditory brainstem implants in function, neurovascular disease, skull base cal setting during surgery and neurosurgical cooperation with the Department of ENT. tumors (jointly with Department of ENT) and intensive care as well as in the experimen- The current study shows – different to pre- movement disorders (jointly with Depart- tal setting using animal models. These ap- vious international reports – that also in pa- ment of Neurology). proaches are combined with electrophysio- tients with large tumors or with previous im- logical techniques in order to develop novel plant trials – very satisfactory results can be Infants and children with inborn malforma- brain tissue saving therapeutic strategies, obtained. The technique applied here by the tions of the nervous system and of the skull especially to counteract vasospasms. Fur- interdisciplinary team and the modern stim- and spine as well as children with neoplasia ther studies deal with the comparison of in- ulation processors provide useful auditory and trauma are taken care of by the Division terventional and surgical aneurysm treat- perception in the majority of patients. of Pediatric Neurosurgery. ment and with dural arteriovenous fistulas.

102 development of infants with craniosynostosis and positional deformations.

Teaching

Weekly lectures and associated bedside teaching are offered to medical students of all clinical years. Third and fourth years students undergo a joint introduction to neuro-intensive medicine, neurological-neurosurgical history taking and examination in a cooperative teaching programme by the De- partments of Neurology and Neurosurgery. Throughout the year medical students of the last clinical year may perform their period of choice or an elective period and are fully integrated into the clinical programme and supervised by neurosurgeons and consultants. Doctoral and diploma students from medicine and related sciences as well as for post-doctoral fellows are working in proj- Fig. 1: Hippocampus neurons (green) establish synaptic contacts with neural progenitor ects at the Section of Experimental Neuro- cells derived from embryonal stem cells (red). surgery, the Laboratory of Tumorbiology and the Neurophysiology Laboratory.

A cooperation with the Departments of nign and malignant tumors are further focus Neurology, Neuroradiology and Psychiatry of current interests. has been started for high frequency stimulation therapy in movement disorders (trem- Tumor biology and mutation analysis in be- or, dystonia and Parkinson’ disease). Ste- nign pathologies such as schwannomas reotaxy guided electrode implantation is and meningiomas, are investigated in es- performed for intra-operative micro-record- tablished national and international coop- ing and micro-stimulation tests in the thala- erations. Cell de-differentiation, adhesion mus, pallidum or subthalamic nucleus. The molecules, tumor invasion, promotors of established indications for deep brain stim- apoptosis are targets of investigation in be- Ammoun S, Ristic N, Matthies C, Hilton ulation are extended after careful investi- nign tumor cell cultures and shall be com- DA, Hanemann CO: Targeting ERK1/2 ac- gation for patients with previous ischemic pared for different clinical courses despite tivation and proliferation in human prima- brain lesions and life threatening dyston- identical histology. A basis for these labora- ry schwannoma cells with MEK1/2 inhibi- ic storms. A further developing topic is the tory investigations are large regular outpa- tor AZD6244. Neurobiol of Dis, Epub Oct 2009. combination of neuroprotective and regen- tient clinics for patients with skull base tu- erative factors. mors, sporadic and genetically based ves- Byts N, Samoylenko A, Fasshauer T, Ivani- tibular schwannomas and meningiomas sevic M, Henninghausen L, Ehrenreich H, (neurofibromatosis types 1 and 2). Sirén A-L: Essential role of Stat5 in the neurotrophic but not in the neuroprotec- Neuro-oncology tive effect of erythropoietin. Cell Death Dif- (G. Vince, C. Matthies) fer 15: 783-792, 2008. Craniofacial malformations A large patient population is being treated (T. Schweitzer, J. Krauß) Lee J-Y, Huang D-L, Keep R, Sagher O: Ef- neurosurgically for glioblastomas and low fect of electrical stimulation of the cervical cord on blood flow after subarachnoid he- grade astrocytomas and by the interdisci- An interdisciplinary team of pediatric neuro- morrhage. J Neurosurg 109: 1148-1154, plinary team of neuro-oncologists and ra- surgeons, neuropediatricians, neuroradiol- 2008. diotherapists and followed long-term in lon- ogists, maxillo-facial surgeons and special- gitudinal studies. They provide the base for a ists from seven further disciplines treats chil- SELECTED PUBLICATIONS Stojic J, Hagemann C, Haas S, Herbold C, Kühnel S, Gerngras S, Roggendorf W, unique collection of tumor cell lines. In-vitro dren with craniofacial malformations, espe- Roosen K, Vince GH: Expression of matrix tumor cell lines and in-vivo animal models cially craniosynostosis and cares long-term metalloproteinases MMP-1, MMP-11 and are used for investigations on invasiveness, for over 800 children all over the country. MMP-19 is correlated with the WHO-grad- progression and aggressiveness of brain tu- Investigations focus on underlying causes ing of human malignant gliomas. Neurosci mors. The identification of the importance of the disease, refinement of phenotypic Res 60(1):40-9. 2008. of metallo-proteinases and their proteolytic classification, molecular genetic diagnos- Westermaier T, Jauss A, Eriskat J, Kunze activity has significantly influenced the un- tics, secondary diseases and improvement E, Roosen K: Time course of cerebral per- derstanding of tumor progression. Different of surgical techniques. Longitudinal studies fusion and tissue oxygenation in the first grades of tumors and the edge between be- investigate problems of morphometrics and 6 h after experimental subarachnoid hemorrhage in rats. J Cereb Bood Flow Metab 29: 771-779, 2009. 103 3.21 Department of Neurology

Professor Dr. med. Klaus Viktor Toyka Mission cephalomyelitis (EAE) und neuritis (EAN), (Head of the Department) and Structure transgenic mouse models); studies on immune regulation, effector mechanisms of Josef-Schneider-Str. 11 The Department of Neurology and its as- immune-mediated tissue damage and new 97080 Würzburg sociated hospital department cover the en- immunotherapy; analysis of endogenous Tel.: 0931/201-23751 tire spectrum of neurological disorders. The mechanisms of immune tolerance in the Fax: 0931/201-23697 clinical service includes 89 beds with an 8 periphery and the CNS compartment; role E-mail: [email protected] bed Stroke Unit and a 10 bed Neurological of regulatory and dendritic cells; contribu- www.klinik.neurologie.uni-wuerzburg.de Intensive Care Unit with over 2800 in-pation of cytotoxic T-cells in neuroinflamma- tients per year. The outpatient department tion and of specific potassium channels in Professor Dr. med. Karlheinz Reiners cares for over 9000 out-patients per year T-cell activation and neuronal damage; mo- CONTACT DETAILS CONTACT Tel.: 0931/201-23758 including the hospital consultation service. lecular mechanisms of breakdown of the The special expertise includes neuroimmu- blood-brain-barrier; development of novel Professor Dr. rer. nat. Rudolf Martini nological diseases (multiple sclerosis, auto- MR-contrast agents for more sensitive de- Tel.: 0931/201-23268 immune nerve and muscle disorders), detection of demyelinating inflammatory le- generative neuromuscular disorders includ- sions in the CNS. Pathogenesis of antibody- Professor Dr. med. Guido Stoll ing an integrated nerve/muscle pathology mediated PNS and CNS disorders. Interna- Tel.: 0931/201-23769 service, cerebrovascular disorders, move- tional treatment trials. ment disorders, epilepsy, neurogenic pain Professor Dr. med. Heinz Wiendl and neurointensive care. The Department Tel.: 0931/201-23756 has integrated a Division of Clinical Neuro- Stroke and Neuroimaging physiology and a Clinical Research Group (G. Stoll, M. Bendszus, C. Kleinschnitz, W. for Multiple Sclerosis and Neuroimmunol- Müllges) ogy and numerous experimental and clinical laboratories allowing translational re- Molecular mechanisms of thrombus forma- search from molecular basics to the bed- tion in experimental cerebral ischemia (e.g. side. The Department holds 36 full time ac- von Willebrand-Faktor, STIM-1) and devel- ademic members, 88 on the nursing staff, opment of novel and safer treatment op- 24 technicians and 11 in administration tions; mechanisms of brain edema forma- and special services. In addition 11 aca- tion and neuroprotection; role of immune demics are supported by extramural grants. cells in stroke; imaging of lesion evolution Two endowed professorships for „Neuroim- by 17 TESLA-high-field MRI (in cooperation aging“ (Bayer-) Schering AG) and „Multiple with Dept of Physics V); novel MR contrast Sclerosis and Blood-Brain-Barrier“ (Teva agents for in-vivo visualization of inflamma- und Sanofi-Aventis) and one lecturership tion; cognitive decline and MRI abnormali- (Merck-Serono) have been transferred into ties as a consequence of microangiopathy, project grants. The Department contributes chronic heart failure and after heart sur- to the Sonderforschungsbereiche (Coop- gery. International treatment trials. erative Project Center Grants) #581 und #688. An intensive cooperation is established with the Research Institute for Clini- Neuromorphology and Pain Research cal Neurobiology (Head: Prof. Dr. Michael (C. Sommer) Sendtner, see separate entry) which had been outsourced from the Neurology De- Role of pro- and anti-inflammatory cyto- partment and its integrated Clinical Re- kines in neuropathic pain, utilizing different search Group for Motor Neuron Disorders lesion models and evaluation of underlying in 2000; and the Institute of Physiology II molecular signalling pathways; assessment (Head: Prof. Dr. Manfred Heckmann). of cytokine profiles in patients with chronic neuropathic pain; establishment of new diagnostic procedures for small-fiber neurop- Major Research athies. International pain treatment trials. Interests Standardization and diagnostic validation of peripheral nerve pathology. (Intramural co- Multiple Sclerosis and Neuroimmunolo- operation with K.V. Toyka) gy (Clinical Research Group, previously BMFT, now University of Würzburg) (H. Wiendl, G. Stoll, K.V. Toyka, A. Weishaupt, Experimental Developmental Neurobi- C. Sommer) ology (R. Martini) Pathogenesis of multiple sclerosis, poly- neuritis, myasthenia gravis and myositis in In the focus is the investigation of patho- humans and experimental rat and mouse genic mechanisms underlying genetically- models (experimental autoimmune en- mediated demyelination in the central and

104 degenerative brain diseases; pathophysiology and treatment of disorders of motor Teaching control; deep brain stimulation in cooperation with the Department of Neurosurgery. In the lectures, seminars and curricular (Intramural cooperation with K. Reiners, G. courses of general neurology the basics in Stoll, K.V. Toyka) clinical neurology are taught accompanied by bed-side teaching in small groups of students. The Department of Neurology more- Clinical Neurophysiology und Neuro- over provides special seminars in differ- muscular Disease Center; Motor Neu- ential diagnosis of neurological disorders, ron Disorders neuromuscular diseases and nerve/muscle (K. Reiners, M. Beck, C. Wessig) pathology and participates in numerous interdisciplinary seminars (Anatomy, Physiol- Neurophysiological examinations in pa- ogy, Oncology Center, Pain-Curriculum, Psy- tients with neuromuscular and CNS disor- chology, Neurobiology, and all classes of the Fig. 1: Identification of macrophage-like ders (> 25,000 examinations per year); Würzburg International Graduate School of cells (arrowheads, red colour) using an- development of tools for the assessment of Life Sciences). Teaching languages are Ger- tibodies to CD11b in the optic nerve of a disease severity and progression in MS and man and English. CNS myelin mutant mouse. The majority ALS, and correlation with molecular diag- of these pathogenic cells are resident cells nostic probes (Institute of Clinical Neurob and only few cells are of hematogeneous iology);coordination of the Interdisciplinary origin, as revealed by bone marrow trans- Neuromuscular Center together with Prof. fer experiments using mice transgenically Dr. T. Grimm, Department of Human Genet- expressing green fluorescent protein (GFP) ics; morphological assessment of nerve and as bone marrow donors. The arrow points muscle disorders by magnetic resonance to a rare immigrated green cell, which imaging and correlation with neurophysio- is additionally labelled by the macro- logical parameters. International treatment phage marker CD11b. The intrinsic origin trials in ALS. (Intramural cooperation with of pathogenic macrophage-like cells be- M. Sendtner; K.V. Toyka) hind a preserved blood brain barrier may have consequences for possible treatment strategies of the corresponding myelin dis- Autoantibodies and Disease Models in orders in humans. The bue colour identi- Neuroimmunological Disorders fies cell nuclei. (from: Mol Cell Neurosci (K. Toyka, C. Sommer) 38:489-494; 2008). Studies on the functional role of humoral serum factors in immune-mediated neurop- athies by in-vivo- and in-vitro-electrophys- Berra-Erro A, Braun A, Kraft R, Klein- peripheral nervous system using mouse iology (Patch-Clamp) , and on the patho- schnitz C, Schumann MK, Stegner D, mutants with spontaneous and genetically physiology of the anti-amphiphysin- and Wultsch T, Eilers J, Meuth SG, Stoll G, engineered defects in myelinating glial cells anti-GAD-associated stiff-person-syndrome Nieswandt B STIM2 regulates capacitive and other neural cells. Particular emphasis (reflex and slice studies); establishment of Ca2+ entry in neurons and plays a key is on the role of disease-modifying mecha- in-vivo models and cell culture systems; role in hypoxic neuronal cell death. Sci- ence Signaling 2009; 93: 2(93) ra67 nisms, like the impact of the immune sys- STED-microscopy (in cooperation with Ru- tem and emerging treatment strategies in dolf Virchow Research Center). Pathogenic Gentner, R., Wankerl, K., Reinsberger, C., the mouse models. Morphological meth- role of thymus abnormalities in myasthenia Zeller, D. and Classen, J. Depression of ods, such as confocal and electron micros- gravis (in cooperation with the Institute of human corticospinal excitability induced by magnetic theta-burst stimulation: evidence copy, combined with the assessment of mo- Pathology). of rapid polarity-reversing metaplasticity. lecular alterations are used for the analysis Cerebral Cortex 2008; 18: 2046-53 of glial damage, impaired axonal transport and synaptic alterations. (Intramural coop- Specialized Laboratory Medicine Chen Y, Geis C, Sommer C. Activation of eration with H. Wiendl, K.V. Toyka, C. Som- (K. Toyka, A. Weishaupt) TRPV1 Contributes to Morphine Tolerance: Involvement of the MAPK Signaling Path- mer) way. J Neurosci 2008; 28: 5836-5845 Laboratory support of all groups and proj-

ects in neuromorphology, neurogenetics SELECTED PUBLICATIONS Fischer S, Weishaupt A, Troppmair J, Mar- Motor Control and Movement Disor- and neuroimmunology. Research focus: The tini R. Increase of MCP-1 (CCL2) in myelin mutant Schwann cells is mediated by ders role of serum autoantibodies in the diagno- MEK-ERK signaling pathway. Glia 2008; (J. Classen) sis and prognostic assessment of neurolog- 56:836-843. ical diseases (anti-MAG-, anti-GM1, anti- Human cortical physiology; development aquaporin-4 antibodies, anti-acetylcholine- Huang YH, Zozulya AL, Weidenfeller C, and evaluation of human models of cortical receptor-antibodies). Serum and CSF bio- Metz I, Buck D, Toyka KV, Brück W, Wiendl H.. Specific central nervous system plasticity; functional significance of neuro- markers in dementia and other degenera- recruitment of HLA-G(+) regulatory T cells nal plasticity in inflammatory, ischemic and tive CNS disorders. in multiple sclerosis. Ann Neurol. 2009; 66:171-183. 105 3.22 Institute for Clinical Neurobiology

Mission animal models for spinal muscular atrophy Professor Dr. med. Michael Sendtner and Structure correlates with clinical observations in pa- (Head of the Institute) tients with spinal muscular atrophy. On the The Institute of Clinical Neurobiology basis of these experiments, new therapeu- Versbacher Str. 5 emerged in 2000 from a clinical research tic strategies for this disease can now be 97078 Würzburg group of the Deutsche Forschungsgemein- developed. Tel.: 0931/201-44000 schaft (“clinical research group for Neuro- Fax: 0931/201-44009 regeneration”), which had been established The Institute for Clinical Neurobiology is also E-mail: [email protected] and funded from 1994-2000 at the Depart- involved in the patient care of the special www-i.klinik.uni-wuerzburg.de/deutsch/ein- ment of Neurology at the University of Würz- care centre for motoneuron diseases (Dept. richtungen/kliniken/InstitutfrKlinischeNeurobi- burg. Since 2000, it is an independent in- of Neurology, Director Prof. K. V. Toyka), in

CONTACT DETAILS CONTACT ologie/content.html stitute at the University Hospital since 2000 order to ensure the transfer of basic science and is since then supported with substantial into clinical applications. funding by the Herrmann und Lilly Schilling- Stiftung. The Institute for clinical neurobiol- Central technologies, beside the generation ogy is mostly working in basic science, but of mouse models are modern microscopic it is also involved in sustaining the special techniques, including confocal microscopy, health care centre for motoneuron diseas- 2-photone microscopy and life imaging, in es at the Department of Neurology (Direc- order to study defects in structure and func- tor: Prof. K.V. Toyka), in order to allow and tion in neurons from models of neurodegen- ensure the transfer of scientific knowledge erative diseases. into clinical applications. It will receive new laboratories in 2010 after its move to the former MSZ. Teaching

Major Research The Institute for Clinical Neurobiology is in- Interests volved in the training of students in Neurolo- gy as well as the training of biology students Central research focus are studies on the (Bachelor and MSc Courses) with focus on mechanisms of neuronal cell death, the es- neurobiology. Another focus is the training tablishment and analysis of animal models of students in the MD/PhD program and for motoneuron diseases, as well as the de- participation in training programs for the velopment of therapeutic strategies for the class Neuroscience of the Graduate School treatment of amyotrophic laterals sclerosis Life Science at the University of Wuerzburg. and spinal muscular atrophy, the most com- Further courses are offered for students of mon forms of motoneuron disease in chil- the course molecular medicine within the dren and adults. training program for MD students.

Further lines of research focus on the mechanisms how neural stem cells differentiate into neurons and functional neural circuits. Investigation of the signal transduction pathways by which neurotrophic factors influence differentiation, survival and axonal growth of neurons are of central interest. The generation and analysis of gene knockout mice allows investigating which signal molecules are involved in mediating such essential cellular effects of neurotrophic factors.

Another research focus is the analysis of the pathophysiology of spinal muscular atrophy, the most common form of motoneuron disease in children. This disease is characterized by axonal defects and defects of neu- rotransmission at neuromuscular synapses. These defects are due to reduced β-actin mRNA transport in axons of motoneurons, resulting in functional deficits in the presynaptic parts of neuromuscular endplates. This finding in isolated motoneurons and in

106 Fig. 1: Alterations in axonal branching in the gastrocnemic muscle from a mouse model of spinal muscular atrophy (Smn+/-). The number of terminal sprouts is increased, a sign that compensatory mechanisms take place in the disease process.

Poesen, K., Lambrechts, DE., Van Damme, P., Dhondt, J., Bender, F., Frank, N., Bogaert, E., Claes, B., Heylen, L., Ver- heyen, A., Raes, K., Tjwa, M., Eriksson, U., Shibuya, M., Nuydens, R., Van Den Bosch, L., Meert, T., D‘Hooge, R., Sendt- ner, M., Robberecht, W. and P. Carmeliet. Novel Role for VEGF-Receptor-1 and its Ligand VEGF-B in Motor Neuron Degen- eration. J. Neurosci. 28, 10451-10459, 2008.

Fischer, M., Raabe, T., Heisenberg, M. and M. Sendtner. Drosophila RSK negatively regulates Bouton Number at the Neuromuscular Junction. Dev. Neurobiol. 69, 212-220, 2009.

Fischer, M., Marques Pereira, P., Holt- mann, B., Simon, C.M., Hanauer, A.,

SELECTED PUBLICATIONS SELECTED PUBLICATIONS Heisenberg, M. and Sendtner M. P90 Ri- bosomal s6 kinase 2 negatively regulates axon growth in motoneurons. Mol. Cell. Neurosci. 42, 134-41, 2009.

Trimbuch, T., Beed, P., Vogt, J., Schuch- mann, S., Maier, N., Kintscher, M., Breust- edt, J., Schuelke, M., Streu, N., Kiesel- mann, O., Brunk, I., Laube, G., Strauss, U., Battefeld, A., Wende, H., Birchmeier, C., Wiese, S., Sendtner, M., Kawabe, H., Kishimoto-Suga, M., Brose, N., Baumgart, J., Geist, B., Aoki, J., Savaskan, N.E., Bräuer. A.U., Chun, J., Ninnemann, O., Schmitz, D. and R. Nitsch. Synaptic PRG- 1 modulates excitatory transmission via lipid phosphate-mediated signaling. Cell 138,1222-35, 2009.

Drepper, C., Herrmann, T., Wessig, C., Beck, M. and Sendtner M. C-terminal FUS/TLS mutations in familial and sporadic ALS in Germany. Neurobiol Aging. Dec 107 15, Epub ahead of print, 2009. 3.23 Department of Psychiatry, Psychosomatics and Psychotherapy with Division of Forensic Psychiatry

Mission range from psychopysiological and modern Professor Dr. med. Jürgen Deckert and Structure imaging approaches such as near infrared (Head of the Department) spectroscopy and functional magnetic reso- The clinic of Psychiatry, Psychosomatics nance tomography (in cooperation with the Füchsleinstrasse 15 and Psychotherapy (PPP) at the UKWürz- Department of Neuroradiology and the re- 97080 Würzburg burg (UKW) offers comprehensive out-pa- search center Magnet-Resonanz-Bayern Tel.: 0931/201-77010 tient, day-care and in-patient diagnostic e.V. as well as the Institute of Psychology I) Fax: 0931/201-77020 and therapeutic services for all mental (psy- over modern methods of genomics and pro- E-mail: [email protected] chiatric and psychosomatic) disorders. The teomics such as high throughput genotyping www-i.klinik.uni-wuerzburg.de/deutsch/ein- therapeutic focus of the clinic is on affec- (Core Facility Genetics in cooperation with richtungen/kliniken/nervenklinik/content.html tive disorders and psychoses of the schizo- the Institute of Clinical Biochemistry and

CONTACT DETAILS CONTACT phrenia spectrum, but also on dementias the IZKF, BrainNet-Reference Center in co- Professor Dr. med. Andreas Fallgatter and substance abuse disorders, as well operation with the Department of Neuropa- Tel.: 0931/201-77110 as eating disorders, anxiety disorders and thology) and their combination in the con- adult attention deficit/hyperactivity disorder. text of imaging genomics up to cell culture Professor Dr. med. Helmut Heinsen Specialized out-patient services as part of and animal models, in particular knockout Tel.: 0931/201-76551 the outpatient department as well as 36 and transgenic mouse models (in coopera- day-care therapy slots for psychiatric and tion with the Institute of Clinical Neurobiol- Professor Dr. med. Klaus-Peter Lesch psychosomatic disorders complement the ogy, the ZEMM and the Biocenter). Tel.: 0931/201-77610 144 in-patient therapy slots with two intensive care units and units specialized on For clinical studies according to GCP guide- Professor Dr. med. Andreas Reif affective disorders (bipolar depression and lines a specialized clinical studies group Tel.: 0931/201-77210 treatment-resistant depression), substance was established (J. Deckert, A. Fallgatter), abuse therapy and psychotherapy. Special- which cooperates closely with the ZKS. Professor Dr. med. Martin Krupinski ized diagnostic and therapeutic options are Studies on suicide (A. Schmidtke, B. Pfuhl- (Head of the Division of Forensic Psychiatry) provided by the laboratory of therapeutic mann) have already resulted in defined pro- Tel.: 0931/201-77500 drug monitoring and the laboratory of psy- posals for suicide prevention. The signature chophysiology. The integrated department of the department is the close interaction of forensic psychiatry provides expert opin- between translational research laborato- ions on legal aspects of mental disorders. ries of the PPP, such as the laboratories on Clinical Neurochemistry, Psychiatric Neuro- biology, and Psychobiology (J. Deckert, K.- Major research P. Lesch, A. Reif, P. Riederer, A. Schmitt), interests Morphological Brain Research (H. Heinsen) and Psychophysiology and Functional Imag- The research activities of the clinic are char- ing (A. Fallgatter, M.J. Herrmann), with the acterized by their interdisciplinarity with re- clinical research groups of the clinic on one search groups of psychiatrists, psycholo- hand and core facilities of the UKW and ex- gists, chemists and biologists as well as ternal research facilities on the other hand. close cooperations at the level of the UKW Research topics include clinical neurosci- in the context of the KFO 125, the SFB 581, ence aspects such as the therapy of mental the GKs 1156 and 1253, the GSLS and disorders, translational aspects such as the the IZSF, at the national level in the con- pathogenesis of mental disorders including text of cooperations with institutes of the the functional characterization of the iden- Max-Planck Society, the Helmholtz Soci- tified pathomechanisms by means of mod- ety and participation in BMBF programs for ern imaging techniques and animal mod- Brain Research, Depression, Panic Disorder els as well as basic neuroscience aspects and ADHD, the SHIP study and the recently such as emotional and cognitive process- founded TRR SFB 58. At the international es, gene-environment-interactions, neuro- level, the PPP participates in cooperations nal plasticity and adult neurogenesis. with the NIH and EMBL and takes part in DAAD programs and EU programs for Brain Research and Depression, but also interna- The main research topics thus are: tional research collaborations such as IM- pACT, IMAGE2, the ADHD Molecular Genet- • Markers for early diagnosis and innova- ics Network, PANIC, ANGST, ConLiGen, and tive therapeutic approaches in affective the Psychiatric GWAS Consortium. Funding disorders, psychoses of the schizophre- agencies include the DFG, the BMBF, EU nia spectrum, dementias, substance and the NIH. abuse disorders, anxiety disorders and adult ADHD (J. Deckert, A. Fallgatter, Methodological approaches on the basis K.-P. Lesch, P. Riederer, A. Schmidtke, of differentiated clinical and neuropsycho- G. Stöber, B. Pfuhlmann, C. Jacob, A. logical diagnostic procedures cover a broad Reif).

108 • Identification of morphological and neurochemical pathological processes in psychoses of the schizophre- nia spectrum and neurodegenerative disorders (P. Riederer, H. Heinsen, E. Grünblatt, M. Lauer).

• Identification of genetic factors in affective disorders, psychoses of the schizophre- nia spectrum, anxiety disorders and ADHD (J. Deckert, K.-P. Lesch, G. Stöber, A. Reif).

• Imaging of emotional and cognitive processes in adults, ado- Fig .1: ß-Galactosidase (green) and Tph2 (red) double im- lescents and children munostaining in rostral raphe of Tph2 inducible knockout. (A. Fallgatter, M. Her- Tph2 tamoxifen-inducible KOs (TPH2-iKO) and Pet1-creER rmann). mice (control) were crossbred with the ROSA26 cre reporter strain; detection of green cells shows effective cre recom- • Gene-environment-in- bination of Tph2 floxed in the typical pattern of serotoner- teractions, neuronal gic cells of the raphe nuclei (a, b). Thus, double labelled plasticity and adult cells demonstrate effective cre recombination for ß-galac- neurogenesis in hu- tosidase but not for Tph2 floxed in cells which still express mans and in rodent Tph2-protein. Very low amount of double labelled cells was models (K.-P. Lesch, detected in inducible Tph2 knockout mice (b, d) demon- J. Deckert, A. Reif, A. strating the effective functioning of cre recombination in Baehne CG, Ehlis AC, Plichta MM, Con- Schmitt). combination with Tph2 deletion (from C. Kriegebaum et al., zelmann A, Pauli P, Jacob C, Gutknecht unpublished). L, Lesch KP, Fallgatter AJ. Tph2 gene variants modulate response control processes in adult ADHD patients and healthy individuals. Mol Psychiatry. 2009 Nov;14(11):1032-9. Teaching Childs E, Hohoff C, Deckert J, Xu K, Bad- ner J, de Wit H. Association between An integrated lecture and course on psy- ADORA2A and DRD2 polymorphisms and caffeine-induced anxiety. Neuropsycho- chiatry and psychosomatics are organized pharmacol. 2008 Nov;33(12):2791-800. and held by the PPP in cooperation with the KJPPP and other clinics and institutes. Spe- Grünblatt E, Monoranu CM, Apfelbacher cial curricular seminars are provided for in- M, Keller D, Michel TM, Alafuzoff I, Ferrer terns and students interested in special as- I, Al-Saraj S, Keyvani K, Schmitt A, Falkai P, Schittenhelm J, McLean C, Halliday GM, pects of psychiatry and psychosomatics. In Harper C, Deckert J, Roggendorf W, Rie- addition to the curricular lecture and course derer P. Tryptophan is a marker of human

for medical students the PPP also provides SELECTED PUBLICATIONS postmortem brain tissue quality. J Neuro- curricular lectures and courses for students chem. 2009 Sep;110(5):1400-8. of biomedicine, psychology and biology. Ex- Murphy DL, Lesch KP. Targeting the murine tracurricular seminars are offered to grad- serotonin transporter: insights into human uate students of medicine, experimental neurobiology. Nat Rev Neurosci. 2008 medicine, biology, and psychology. Feb;9(2):85-96. Reif A, Jacob CP, Rujescu D, Herterich S, Lang S, Gutknecht L, Baehne CG, Stro- bel A, Freitag CM, Giegling I, Romanos M, Hartmann A, Rösler M, Renner TJ, Fall- gatter AJ, Retz W, Ehlis AC, Lesch KP. In- fluence of functional variant of neuronal Fig. 2: Activation of amygdala by emotion- nitric oxide synthase on impulsive behav- al faces (from Hahn et al. unpublished). iors in humans. Arch Gen Psychiatry. 2009 Jan;66(1):41-50. 109 3.24 Department for Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy

tivity disorder (ADHD), obsessive-compul- ent training for the treatment of ADHD in Professor Dr. med. Dipl.-Psych. Andreas sive disorder, Tourette syndrome, conduct children is investigated depending on the Warnke disorder, autism spectrum disorders, specif- treatment of their mothers also affected by (Head of the Department) ic developmental disorders, and of co-exist- ADHD (BMBF; see page 200). ing psychiatric disorders in non-psychiatric Füchsleinstr 15 diseases and mental retardation. 97080 Würzburg Biomarkers Tel.: 0931/201-78000 (M. Gerlach, M. Romanos, R. Taurines) Fax: 0931/201-78040 Major Research E-mail: [email protected] Interests Different paradigms (real-time PCR, pro- www.klinik.uni-wuerzburg.de/kjp teomics, olfactory test) are evaluated in the

CONTACT DETAILS CONTACT Attention deficit-/hyperactivity disorder effort to achieve a substantial contribution Professor Dr. rer. nat. Dipl.-Chem. Manfred (ADHD) to an early and reliable diagnosis of ADHD, Gerlach (M. Gerlach, T. Jans, T. Renner, M. Roma- autism spectrum disorders and schizophre- Tel.: 0931/201-78010/78090 nus, A. Warnke) nia. Alterations in mRNA expression of mi- E-mail: [email protected] tochondrial genes could be identified as Pathogenesis, endophenotypes and co- potential biomarkers for early onset schizo- morbid features are investigated using for- phrenia. In a proteomic approach, patients mal and molecular genetics, neuropsycho- with autism spectrum disorders showed dif- logical and neurophysiologic methods as ferences in the serum proteome compared well as animal models and gene expression to controls; a characteristic that might be studies. There are many cooperations with used as a peripheral biomarker. These stud- local and national departments and inter- ies were done in cooperation with the Uni- national research networks on ADHD (DFG: versity of Ulm (Prof. Dr. C. Mehler-Wex), the KFO 125; see page 191). Multicentre clini- University of Bochum (Prof. Dr. K. Marcus), cal studies are carried out on the effica- the University of Leipzig (Prof. Dr. J. Claßen) cy and safety of extended release meth- and the University of Swansea, United King- ylphenidate in ADHD children and adoles- dom (Prof. Dr. J. Thome). cents. In cooperation with the Department Mission of Toxicology (Prof. Dr. H. Stopper) the oc- and Structure currence of possible adverse reactions (e.g. Developmental psychopharmacology chromosome aberrations) is investigated (M. Gerlach, K. Klampfl, A. Warnke) The department for child and adolescent during pharmacological treatment (The In- psychiatry, psychosomatics and psycho- terdisciplinary Centre for Clinical Trials IZKF To improve the security of the patients and therapy is providing state-of-the-art patient of Wuerzburg University). Within the frame- to establish quality standards the clinic is care for children and adolescents aged up work of the BMBF-network on psychothera- part of the international multicentre com- to 18 years offering assessment and treat- py research in ADHD the efficacy of a par- petence network on TDM. Data internet ment for all psychiatric and psychosomatic disorders. The clinic includes inpatient units (the responsible body for the locked ward is the “Bezirk Unterfranken”), a day clinic and a special school (responsible body: “Dia- konisches Werk”), a parent’s pavilion (responsible body: “Verein Menschenskinder e.V.”), a clinical research group (sponsored by the German Research Association, DFG) and a neurobiological laboratory. The clinical laboratory for therapeutic drug monitoring and a lecture hall are joint facilities of this department and the department for adult psychiatry. Therapeutic units (occupational therapy, exercise therapy, music therapy, orthopedagogy including animal assisted therapy) are connected with our three inpatient units. The staffs comprise 18 physicians, 10 psychologists 22 members of the medical and technical service, 5 special therapists, 8 members of the administrative department and 50 members of the nursing and educational service. Main focus of patient care are the assessment and treatment of eating-, affective-, anxiety dis- Fig. 1: Formal genetics of ADHD. Genealogical tree. Family members affected by atten- orders, psychosis, attention deficit hyperac- tion deficit / hyperactivity disorder ADHD are red-coloured.

110 recruitment is standardised. Blood levels, conditions of medication, effectiveness and Teaching undesirable side-effects are documented at the course of the treatment (www.tdm-kjp. The obligatory lectures for students of hu- com). man medicine comprising the subject matter on psychosomatics are conjointly held by the clinic for child and adolescent psychi- Eating disorders atry (CAPP), the clinics for adult psychiatry (APP), neurology, general medicine and the Treatment of anorexia nervosa in chil- department for medical psychology. Oblig- dren and adolescents (BMBF: ANDI): atory lectures and examinations also refer The multicentre study compares a day clin- to study courses on psychology, education ic and an inpatient treatment to investigate and special education (diplomas, state ex- if patients partly remaining in their family aminations). Further lessons and trainings have a more favourable outcome. refer e.g. to forensic child and adolescent Katamnese study on anorexia nervosa psychiatry, developmental psychiatry and (BMBF): In this study those patients of the psychodiagnostics, neurophysiological as- ANDI sample are reexamened 1,5 years af- sessment, postgraduate and research col- ter the first treatment period. Study on the loquia, open lectures on clinical issues and long-term course of very early onset anorex- colloquia on neuropsychiatry conducted to- ia nervosa: Patients who were treated in the gether with the Departments of Adult Psy- years 2002-2006 and were younger than chiatry and the Department of Neurology. 13 years old are re-examined. The quality of our lecture on child and adolescent psychiatry has been awarded (“Leh- rpreis” of the faculty of medicine). In 2009 Dyslexia the 2nd International Congress on ADHD“ (A. Warnke) (Vienna) with over 1800 participants from over 70 countries was organised by the de- Research (DFG) on aetiology focuses on partment. correlates of the disorder on the genetic level and on the behavioural level (reading, Walitza S, Kämpf K, Artamonov N, Roma- nos M, Gnana Oli R, Wirth S, Warnke A, spelling) accounting for associations with Gerlach M, Stopper H (2009). No elevat- psychological and neurophysiologic en- ed genomic damage in children and ado- dophenotypes. The DCDC2-gene which is lescents with attention deficit/hyperactiv- important for the foetal brain development ity disorder after methylphenidate therapy. Toxicology Letters 184, 38-43. was identified to be associated with dyslexia. National and international cooperations Klampfl K, Taurines R, Preuss A, Burger R, have been established. Rothenhöfer S, Wewetzer Ch, Pfuhlmann B, Fegert J, Gerlach M, Mehler-Wex C (2010) Serum concentrations, therapeutic response and side effects in children Obsessive-compulsive disorder and adolescents with impulsive-aggres- (T. Renner, A. Warnke) sive symptoms during risperidone therapy. Pharmacopsychiatry 43: 58-65 In a multicentre project (DFG) family studies Reif A, Jacob CP, Rujescu D, Herterich S, are conducted on OCD. Patients and their Lang S, Gutknecht L, Baehne CG, Stro- parents are assessed by standardized diag- bel A, Freitag CM, Giegling I, Romanos M,

nostic methods before inclusion into molec- SELECTED PUBLICATIONS Hartmann A, Rösler M, Renner TJ, Fallgat- ular genetic association studies. The results ter AJ, Retz W, Ehlis AC, Lesch KP (2009) indicate associations of genes involved in Influence of functional variant of neuronal nitric oxide synthase on impulsive behav- the serotonergic and dopaminergic neuro- iors in humans. Arch Gen Psychiatry 66: transmission with early onset OCD. Further, 41-50. the present study design includes also the first prospective follow-up study of early on- Schimmelmann BG, Friedel S, Nguyen TT, Sauer S, Vogel CI, Konrad K, Wilhelm C, set OCD in Germany. The genetic research Sinzig J, Renner TJ, Romanos M, Palma- is strengthened by cooperation with inter- son H, Dempfle A, Walitza S, Freitag C, national research networks on OCD and the Meyer J, Linder M, Schäfer H, Warnke A, Centre of Child and Adolescent Psychiatry of Lesch KP, Herpertz-Dahlman B, Hinney A, the University of Zürich, Switzerland (Prof. Hebebrand J (2009). Exploring the genetic link between RLS and ADHD. J Psychiatr Dr. S. Walitza). Res. 43(10), 941-945.

Schmitt J, Romanos M, Schmitt NM, Meu- rer M, Kirch W (2009), Atopic eczema and attention-deficit/hyperactivity disorder in a population-based sample of children and adolescents. JAMA 301(7), 724-726. 111 3.25 Chair of Experimental Biomedicine - Vascular Medicine

Professor Dr. rer. nat. Bernhard Nieswandt Mission vital organs. Our main scientific interest lies (Chair) and Structure on the function of platelet surface receptors and their intracellular signaling path- Josef-Schneider-Str. 2 The Chair of Experimental Biomedicine / ways in hemostasis as well as thrombotic 97080 Würzburg Vascular Medicine was established in 2008 and inflammatory events. By use of geneti- Tel.: 0931/31-80405 and is part of the Rudolf Virchow Center cally modified mouse lines that display de- Fax: 0931/201-61652 (RVZ), DFG Research Center for Experi- fined defects in platelet receptors or sig- E-mail: [email protected] mental Biomedicine (see page 150), and is naling pathways we aim to investigate the www.virchow.uni-wuerzburg.de/labpages/ co-funded by the University Hospital Würz- molecular mechanisms that regulate plate- nieswandt/ burg. It emerged from the Research group let adhesion, activation and aggregation. “Vascular Biology” that was jointly appoint- These experiments serve as a basis for the

CONTACT DETAILS CONTACT ed at the RVZ (from 2002) and the Insti- development of novel anti-thrombotic ther- tute of Clinical Biochemistry (2004 – 2008; apeutical strategies which are subsequently see page 86). The chair focuses on basic tested using in vivo models of ischemic and research in the field of cardiovascular dis- inflammatory diseases. Furthermore, signal eases and is actively engaged in the edu- transduction processes in T-cells and mac- cation of Bachelor and Master students of rophages in the context of autoimmune- Biomedicine. Most of the research projects inflammatory diseases are studied in vitro are integrated into Collaborative Research and in vivo. Centers (SFB 688, page 140 and SFB 487 page 132) at the University of Würzburg. Mechanisms of Ca2+-Signaling

Major Research Changes in the intracellular Ca2+ concen- Interests tration regulate fundamental processes in virtually all cell types. In platelets, the Our scientifc work focuses on the mecha- mechanisms of agonist-induced Ca2+ en- nisms of platelet and immune cell activa- try have remained elusive. Recently, STIM1 tion in physiological and pathological pro- has been identified as the Ca2+ sensor in cesses. the endoplasmic reticulum (ER) which ac- Damage of the endothelial layer of blood tivates store-operated calcium (SOC) chan- vessels results in rapid adhesion and activa- nels (Orai1) in T-cells, however, its general tion of platelets at the site of injury, followed physiological relevance remained unclear. By by coagulant activity and subsequently the use of different knock-out mice generated formation of fibrin-rich thrombi that seal in our laboratory we could show that STIM1 the wound. These processes are crucial for represents the Ca2+ sensor also in patelets wound healing (hemostasis), however, in which subsequently induces Ca2+ entry by diseased vessels they can lead to complete activating Orai1. Importantly, STIM1-, as occlusion and thus to ischemic infarction of well as Orai1-deficient mice were protect-

Fig. 1: STIM1 and Orai1 are essential for store-operated Ca2+ entry (SOCE) in platelets. A. Structure of STIM1. SAM, sterile α-motif; TM, transmembrane domain; CC, coiled-coil domain. B. Platelet receptors induce activation of PLCβ and PLCγ leading to Ca2+ store

release through inositol-1,4,5-trisphosphate receptors (IP3-R) in the endoplasmic reticulum (ER) membrane. The decrease in ER Ca2+ concentration is detected by STIM1 which translocates to the plasma membrane and activates the SOC channel Orai1 that induces Ca2+ influx into the cell. C. Measurement of store release and SOCE in platelets. The store content was estimated by addition of the SERCA inhibitor thapsigargin and SOCE was measured by subsequent addition of extracellular Ca2+.

112

Teaching

We are engaged in the education of students in the Bachelor and Master Program in Biomedicine, where we offer lectures, seminars and practical lab courses. All doctoral students are members of the section “Biomedicine” of the “Graduate School of Life Sciences“ at the University of Würzburg. The chair regularly participates in the organization of symposia and conferences for medical and natural scientists.

Fig. 2. CLEC-2 is an essential platelet-activating receptor in hemostasis and thrombosis. A. Scheme of CLEC-2 activation in platelets by the snake venom toxin rhodocytin and INU1. B. Immunoprecipitation of CLEC-2 and GPVI from surface-biotinylated platelets from control and INU1-treated mice. C. Representative images of thrombus formation in

FeCl3 injured arterioles of control and CLEC-2-deficient mice. The asterisk indicates vessel occlusion. ed from arterial thrombosis and ischemic ment of mice with INU1 led to the loss of brain infarction whereas hemostasis was CLEC-2 from the platelet surface for several only slightly affected. Furthermore, it could days and thus resulted in a knock-out-like be demonstrated that STIM1 is essential for phenotype. CLEC-2-deficient platelets dis- Berna-Erro, A., Braun, A., Kraft, R., Klein- Fcγ receptor activation and phagocytosis in played unaltered adhesion under flow in vi- schnitz, C., Schuhmann, M.K., Stegner, macrophages and that STIM1 deficiency tro and in vivo, however, subsequent plate- D., Wultsch, T., Eilers, J., Meuth, S.G., resulted in protection from IgG-mediated let aggregation was markedly reduced. In Stoll, G., Nieswandt, B. (2009) STIM2 regulates capacitive Ca2+ entry in neu- auto-inflammatory diseases. vivo, CLEC-2 deficiency resulted in protec- rons and plays a key role in hypoxic neu- By analyzing recently generated STIM2-de- tion from arterial thrombosis and prolonged ronal cell death. Science Signaling 2(93), ficient mice we were able to demonstrate bleeding. Thus, CLEC-2 was identified as a ra67. for the first time that STIM2, but not STIM1, new platelet-activating receptor in the grow- 2+ May, F., Hagedorn, I., Pleines, I., Bend- is essential for Ca entry in neurons and ing thrombus. er, M., Vögtle, T., Eble, J., Elvers, M., that STIM2 deficiency protected neurons Nieswandt B. (2009) CLEC-2 is an es- from cell death under hypoxic conditions. Cytoskeletal rearrangements not only play a sential platelet-activating receptor in he- key role for receptor-mediated platelet ac- mostasis and thrombosis. Blood 114(16), tivation, but also for the formation of new 3464-3472. Platelet membrane receptors and cyto- platelets from their precursor cells, the Braun, A., Gessner, J.E., Varga-Szabo, skeletal dynamics in platelet function megakaryocytes (MK). By using different D., Syed, S.N., Konrad, S., Stegner, D., and formation genetically modified mouse lines with MK- Vögtle, T., Schmidt, R.E., Nieswandt, B. and platelet-specific deficiencies for regu- (2009) STIM1 is essential for Fcgamma

SELECTED PUBLICATIONS SELECTED PUBLICATIONS receptor activation and autoimmune in- The process of platelet activation, aggrega- latory proteins of the actin cytoskeleton we flammation. Blood 113(5), 1097-1104. tion and thrombus formation is complex and study the impact of cytoskeletal rearrange- involves the activation of various membrane ments for differentiation, maturation and Varga-Szabo, D., Braun, A., Kleinschnitz, receptors and their downstream signaling platelet formation from MKs, as well as for C., Bender, M., Pleines, I., Pham, M., pathways. Due to their easy accessibility, platelet function. Renné, T., Stoll, G., Nieswandt, B. (2008) The calcium sensor STIM1 is an essen- platelet receptors represent attractive tar- tial mediator of arterial thrombosis and gets for the development of new antithrom- ischemic brain infarction. J. Exp. Med. botic therapy strategies. We have generated 205(7):1583-1591. an antibody against CLEC-2, an activating Moser, M., Nieswandt, B., Ussar, S., receptor recently identified to be expressed Pozgajova, M., Fässler, R. (2008) Kind- in platelets. We could show that that treat- lin-3 is essential for integrin activation and platelet aggregation. Nature Medicine 113 2008 Mar;14(3), 325-330. 3.26 Chair of Tissue Engineering and Regenerative Medicine

Mission Tissue Engineering and Regenerative Medi- Professor Dr. rer. biol. hum. Heike Walles and Structure cine a Fraunhofer Projektgruppe »Regener- (Chair) ative Technologies in Oncology« was found- The Chair Tissue Engineering und Regener- ed at the Röntgenring 11. In proof of con- Röntgenring 11 ative Medicine has been established 2009 cept experiments Prof. Walles has shown, 97070 Würzburg at the University of Würzburg. Since August that it is possible to engineer human vascu- Tel.: 0931/31-88828 it is headed by Prof. Heike Walles. larised solid tumour tissue on the vascular- Fax: 0931/31-81068 ised scaffold BioVaSc® (figure). In coopera- E-mail: [email protected] The discrepancy between necessary trans- tion with different faculties of the University www.uni-wuerzburg.de/ueber/fakultaeten/ plants and donor organs increases steadi- Würzburg vascularised human tumour mod- medizin/lehrstuehle/Lehrstuhl_ ly. Additionally, there are problems like re- els will be used to develop new methods for

CONTACT DETAILS CONTACT Tissue_Engineering_und_Regenerative_ jection reactions and lifelong immune sup- Diagnosis and individual therapies. Medizin pressions. By means of tissue engineering, damaged, affected or even missing tissues and organs can be replaced by biological Major Research compatible and functional implants gener- Interests ated from primary cells. All concepts in Re- generative Medicine have the proliferation Bioreactor technology necessity of capable human cells in com- (T. Schwarz, H. Walles) mon. After isolation, the relevant primary cells will be increased by cell-culture tech- As a prerequisite of the in vitro generation niques until sufficient cells are available for of functional 3D human tissue models the the culture on 3D scaffolds (matrix) or even construction of near-natural cellular and or- for the cell therapeutically application. gan-like functional units will be established, based on (I) computer simulation of struc- New drugs and substances have to be test- tural arrangements and interactions in hu- ed before market authorization regarding man tissues and (II) the development of their quality, safety and efficacy. For lack computer-controlled tissue specific biore- of equivalent alternative methods, animal actor. experiments are an important standard instrument in drug research. Due to species- specific differences, however, animal exper- Vascularised human tissue and disease iments are not in every case suitable for models the authorization of new substances or the (A. Heymer, H. Walles) adaptation of new therapies to humans. Therefore, Prof. Walles group has been in- In 2010, the EU project VascuBone (FP7- creasingly engaged in the development of Gesundheitsprogramm) coordinated by Prof. alternative human tissue models (test sys- Walles will start. The goal of VascuBone is tems) that reflect the complex characteris- to develop a “tool box” for bone regener- tics of the body and permit the investiga- ation, which on one hand fulfils basic re- tion according to the ADMET criteria (ab- quirements and on the other hand is freely sorption, distribution, metabolism, excre- combinable with what is needed in the re- tion and toxicity). These test systems are spective patient’s situation. The tool box will based on in vitro cultivated human primary include a variation of biocompatible bioma- cells. In order to ensure the functionality of terials and cell types, FDA approved growth these cells in vitro, culture conditions must factors, biomaterial modification technolo- be created that are similar to the natural gies, simulation and analytical tools. This microenvironment of the cell in the body. tool box will be used to develop translation- This requires, in addition to the sufficient al approaches for regenerative therapies of supply of the cells, co-culture with other cell different types of bone defects, e.g. avas- types as well as the provision of a suitable cular necrosis of the hip (FHN), therapy of biomaterials as carrier structures. large defects in jaw and long bone.

The core competences of the chair are based on the following technologies: biomaterials, Biomaterial 3D co-culture of primary cells, and bioreac- (A. Appelt, H. Walles) tor technology. By applying these technologies human tissue models will be developed Every implantation of alloplastic materials to study in vitro mechanisms of diseases causes a reaction based on the material- and infections as a prerequisite for the de- tissue-interaction resulting in limited or an- velopment of regenerative therapies. nihilated implant efficiency. Spider silk could have an essential effect on the function of In addition to the establishment of the Chair the medicinal implants. In an IZKF founded

114 Fig. 1: In this figure the biological vascularised scaffold BioVaSc® is shown. The BioVaSc® is used as matrix for the generation of autologous transplants, human tissue and tumour models. project in vitro und in vivo studies will be Project group »Regenerative Technolo- performed to enhance the biocompatibility gies in Oncology« of alloplastic implants by surface modifica- (H. Walles) tion using recombinant spider silk. Human vascularised tumour models will be Mertsching H (since Sept. 09 Walles), established to develop new methods for in- Schanz J, Steger V, Schandar M, Schenk Transplants dividualised diagnosis and therapies. M, Hansmann J, Dally I, Friedel G, Walles (A. Heymer, H. Walles) T (2009) Generation and transplantation of an autologous vascularized bioartificial human tissue. Transplantation. 27, 203- Tears of the avascular zone of the meniscus 210. do not heal, have to be removed surgically Teaching and inevitably lead to premature osteoar- Heymer A, Bradica G, Eulert J, Nöth U. (2009) Multiphasic collagen fibre-PLA thritis of the knee joint. To date, implants The Degree program Technologie der Funk- composites seeded with human mesen- as well as tissue engineering constructs for tionswerkstoffe (Technology of functional chymal stem cells for osteochondral defect meniscus regeneration failed, due to their materials) (TEC-FUN) is an interdisciplinary repair: an in vitro study. J. Tissue Eng. Re- limited integration capacities. Therefore, engineering study course. It includes edu- gen. Med. 3, 389-397. we will generate vascularised neo-menis- cation in the chemical synthesis of materi- Mertsching H (since Sept. 09 Walles), cus tissue by using a multi-stage approach. als, physical characterisation of these ma- Walles T (2009) Europe‘s advanced thera- Vascularised fibrocartilage constructs will terials and the development of biomaterials py medicinal products: chances and chal- be generated by seeding collagen matrices for clinical applications as medicinal prod- lenges. Expert Rev. Med. Devices. 6, 109- and the BioVaSc with mesenchymal and uct and in the field regenerative medicine. 110. SELECTED PUBLICATIONS SELECTED PUBLICATIONS endothelial progenitor cells. This project The program of study is organised by the Mertsching H (since Sept. 09 Walles), will be performed in cooperation with the faculty of Chemistry and Pharmacy, Phys- Hansmann J (2009) Bioreactor Technol- König-Ludwig-Haus and the Muskuloskelet- ics, Medicine (Prof. Dr. Walles, Prof. Dr. Ja- ogy in Cardiovascular Tissue Engineer- tales Centrum Würzburg (MCW) founded by kob), the technical college Würzburg-Sch- ing. Adv. Biochem. Eng. Biotechnol. 112, the IZKF. weinfurt, the Fraunhofer Institute for “Sil- 29-37. icatforschung”, the “Zentrum angewandte Heymer A, Haddad D, Weber M, Gbureck Energieforschung (ZAE)”, and the “Südde- U, Jakob PM, Eulert J, Nöth U (2008) utschen Kunststoffzentrum” (SKZ). Iron oxide labelling of human mesenchymal stem cells in collagen hydrogels for articular cartilage repair. Biomaterials. 115 29,1473-1483. 4 Dental Hospital

116 4.1 Introduction

There are four separate departments or clin- ing chairman (at present: Professor Dr. Dipl- ics, which are comprised under the name of Ing. Ernst-Jürgen Richter). university hospital for dentistry and oral and maxillofacial surgery: At this Hospital there are scarcely 600 students of dental medicine, approximately • Department of Conservative Dentistry half of them working in the clinical section. and Periodontology As far as formation and research is con- (Head: Professor Dr. Bernd Klaiber) cerned, as well as medical specialist care • Department of Oral and Maxillofacial of sick people we have 224 positions at our Surgery disposal. (Head: Professor Dr. Dr. Alexander Kübler) • Department of Prosthodontics By means of Extra-budgetary Funds and (Head: Professor Dr. Dipl.-Ing. Ernst- half-time employment however, the num- Jürgen Richter) ber of employees is around 300, seventy of • Department of Orthodontics which are scientists. (Head: Professor Dr. Angelika Stellzig- Eisenhauer) Apart from the instruction of students, research and care for sick persons our hospi- Part of our hospital is furthermore the De- tal is occupied with the post-graduate ed- partment for Functional Materials in Med- ucation of dentists, as well as with further icine and Dentistry (acting Head: Profes- training for medical and dental specialists. sor Dr. Bernd Klaiber) and the Division of In 2008 about 26600 persons got outpa- Periodontology (Head: Professor Dr. Ulrich tient treatment and about 1250 were treat- Schlagenhauf) ed as in-patients.

All the different heads of the departments Professor Dr. Dipl-Ing. Ernst-Jürgen Rich- form the Board of Directors of the “Univer- ter sity Dental Hospital”, headed by the act- (acting Chairman)

117 4.2 Department of Orthodontics

General (Oral, Maxillary and Plastic Facial Surgery), Professor Dr. med. dent. Angelika Stellzig- Information T. Schweitzer (Neurosurgery) Eisenhauer (Head of the Department) In the Department of Orthodontics under In a clinical research project involving the the directorship of Professor Stellzig-Eisen- Department of Neurosurgery, the Depart- Pleicherwall 2 hauer, nine research assistants work in pa- ment of Oral, Maxillary and Plastic Facial 97070 Würzburg tient care, research and student teaching. Surgery and the Department of Orthodon- Tel.: 0931/201-73320 tics, a valid, non-invasive method is to be Fax: 00931/201-73300 Patient care in the Department of Ortho- developed in order to record and analyze E-mail: [email protected] dontics covers the whole range of orthodon- the form and development of children’s www.kfo.uni-wuerzburg.de tic anomalies. These include in childhood skulls three-dimensionally. The results are

CONTACT DETAILS CONTACT and adolescence (1) the prevention of mis- expected to help resolve unanswered ques- Professor Dr. rer. nat. Kathleen Wermke alignment of teeth and jaws, (2) the treat- tions about the treatment of children with Tel.: 0931/201-73310 ment of malpositions of the jaws by wear cranial deformities (with/without surgery or and control of endogenous growth and (3) with/without helmet therapy). the correction of misaligned teeth. A special focus of the Department of Orthodon- The contribution of the Department of Or- tics is the treatment of adult patients using thodontics is: Longitudinal 3D data acquisi- specific fixed treatment techniques based tion from the neurocranium and viscerocra- on the particular periodontal and prosthetic nium of healthy children and children with situation. cranial deformities.

In addition, patient care in the Department To date there are no standardized longi- of Orthodontics is characterized by interdis- tudinally recorded 3D standard values for ciplinary cooperation with specialties asso- babies’ cranial shape. The objective is to ciated with dentistry. In particular, there is build up a database of three-dimensional, a close clinical collaboration with the Oral, morphometric, longitudinally recorded data Maxillary and Plastic Facial Surgery in the from baby and infant skulls with and without treatment of patients with complex cranio- premature sagittal suture synostosis. facial deformities (cleft lip and palate, syndromes), pronounced malocclusions (dys- gnathia) and condylar neck fractures. Recording prespeech or early speech development in children with and with- Reorientation of the teeth is performed in out cranial deformities collaboration with Dental Prosthetics and (K. Wermke in cooperation with the Pediat- Restorative Dentistry/Periodontology. This ric Clinic and the Department of Education- therapeutic measure is indicated as prep- al Psychology ) aration prior to restorative rehabilitation of the entire stomatognathic system. Development of a 3D soft tissue analy- In the Department of Orthodontics, around sis in orthodontics 1500 patients from all age groups are treat- (J. Kochel, P. Meyer-Marcotty, A. Stellzig- ed annually, with check-ups every 3 to 6 Eisenhauer) weeks. Approximately 600 patients a year attend the department for an orthodontic In a pilot study by the Department of Or- consultation. thodontics in collaboration with the Institute

Major Research Interests

Three-dimensional stereophotogrammetric diagnostics of the skull and progress analysis in children with positional plagiocephaly or sagittal suture synostosis taking into account psychomotor development.

Establishing and 3D evaluation of a non- invasive dynamic treatment method by means of individually adjusted head or- thosis. (P. Meyer-Marcotty (Orthodontics), H. Böhm Fig. 1: Visualization of 3d-Data.

118 of Optics, Information and Photonics of Erlan- gen-Nürnberg Univer- sity, three-dimensional soft tissue imaging was successfully integrated into orthodontic diagnostics and treatment (see 2008 Research Report).

The aim of further research projects is: to expand conventional two-dimensional orthodontic imaging of the facial soft tissues to include 3D analysis Fig. 2: Lingual fixed appliance for the upper jaw.

Primary Failure of Eruption (PFE) – clinical and molecular genetic analysis The “Course on Orthodontic Treatment I and (A. Stellzig-Eisenhauer in cooperation with II” explores theoretical knowledge in depth the Institute of Human Genetics) in small groups and accompanying seminars. In addition, students draw up diagnos- The molecular basis of a disturbance in the tic records on patients and learn to use and eruption mechanism of primary, non-anky- check therapeutic equipment. losed teeth is so far unknown. Three heterozygous mutations in the PTHR1 gene in diseased patients were first described in an interdisciplinary clinical and molecular genetic study. In a proposed future study in collaboration with the Physiology Institute and the Department of Oral, Maxillary and Plastic Facial Surgery, it is planned to analyze the underlying pathogenesis of failure of eruption.

Teaching

The orthodontic courses aim to convey Decker E, Stellzig-Eisenhauer A, Fiebig knowledge about the nature, extent and BS, Rau C, Kress W, Saar K, Rüschendorf F, Hubner N, Grimm T, Weber BH. PTHR1 pathogenesis of positional defects of the loss-of-function mutations in familial, non- teeth and jaws and to present possible pre- syndromic primary failure of tooth erup- ventive methods and orthodontic treatment tion. Am J Hum Genet 83:781-6,2008. options. Meyer-Marcotty P, Gerdes ABM, Reuther T, Stellzig-Eisenhauer A, Alpers GW. Star- The lecture “Introduction to Orthodontics” ing face-to-face: patients with cleft lip and is intended to provide an overview of the palate are looked at differently. J Dent Res nature, extent and pathogenesis of various 2009; accepted. jaw anomalies. Meyer-Marcotty P, Gerdes ABM, Stellzig- Eisenhauer A, Alpers GW. Biased to asym- The principal lecture “Orthodontics I and II” metry – face perception of adults with cleft focuses on preparing students to perform lip and palate - an eye tracking study. Cleft treatment on patients. Palate Craniofac J 2009; accepted. Kochel J, Meyer-Marcotty P, Kochel M, The “Course on Orthodontic Technology” SELECTED PUBLICATIONS Stellzig-Eisenhauer A. 3D-soft tissue anal- aims to provide knowledge about the type, ysis – Part 1: sagittal parameters. J Orofac indications, mode of action and fabrication Orthop 71:40-52 ,2010. of orthodontic appliances.

119 4.3 Department of Functional Materials in Medicine and Dentistry

Professor Dr. med. dent. Bernd Klaiber Mission biotics or growth factors can be printed di- (acting Head) and Structure rectly into the structure, thus enabling the controlled release of pharmacologically ef- Pleicherwall 2 Biologists, chemists, physicists and mate- fective doses at the application site without 97070 Würzburg rial scientists in cooperation with clinicians systemic side effects. Besides the applica- Tel.: 0931/201-72420 are engaged in the Department of Func- tion of protein based growth factors, the use 2+ 2+ Fax: 0931/201-73500 tional Materials in Medicine and Dentistry in of bioactive metal ions like Sr or Cu is E-mail: [email protected] tailoring functional materials for the use in being investigated, which would have the www.fmz.uni-wuerzburg.de medical products and application in the hu- advantage of better availability and man- man body. Research is focused on analyzing ageability. the requirements of material properties de-

CONTACT DETAILS CONTACT pending on the location in the body. Mate- rial properties are adjusted by modification Biological testing of materials of the bulk and surface of materials to influence the interface to the biological envi- One crucial precondition for a good tissue ronment. The workings were funded in the attachment to the implant material is an op- past years by the „Deutsche Forschungs- timal contact between the biological system gemeinschaft“ with two projects as individ- and the material surface. Improvements of ual grants. this contact can be achieved either by the modification of the metallic implant surfaces or by the application of calcium or mag- Major Research nesium phosphate cements, which are sim- Interests ilar to biological minerals and thus can be converted in the body and replaced by nat- Surface modification of functional ma- ural material. The differentiation of osteo- terials clasts on the surfaces and the degradation of those is being analyzed by means of cell The biocompatibility of a functional material vitality and proliferation rate as well as tis- emanates from the surface and is influenced sue specific protein expression and distribu- by its composition, its topography, and its tion in the cell. Also the interaction of cells electric and electronic properties. Current of different origin (fibroblasts, osteoblasts work is focused on the surface modifica- etc.) with variably modified surfaces and cetion of refractory metal implants with low- ments is investigated. Antimicrobial implant crystalline calcium and magnesium phos- surfaces are being developed to avoid in- phate layers, produced by electrochemical fections, which still cause problems during deposition. One aim of these studies is the implant osseointegration and wound heal- development of novel multi-phase coatings ing. Here an important role is played by an- combining antimicrobial with biocompatible timicrobial metal ions like Ag+ as well as by properties, thus lowering the risk of inflam- calcium hydroxide compounds or antibiot- mation after surgery as well as supporting ic loaded cements. These materials, which the ingrowth of the implant. Another surface were developed by the department, showed modification is based on anodic oxidation significant bactericidity combined with good of the metal surface in fluoride-containing tolerance by eukaryotic culture cells. electrolytes leading to tube-like structures, which may be utilized as reservoirs for the inclusion of antibiotics.

Rapid-Prototyping of patient specific implants

The combination of reactive cement systems with 3D powder printing allows the fabrication of patient specific implants and porous scaffolds for tissue regeneration from bioactive and degradable bone replacement materials, mainly calcium and magnesium phosphates. The scaffolds made by this method consist of a micro porous structure, Fig. 1: Electron-microscopical image of a which contributes to the bioactivity. Further- titanium surface after anodisation in an more, the printing method at room temper- electrolyte based on ethylen glycol. The ature offers the possibility to introduce or- nanotubes consist of titanium dioxide and ganic modifications into the material. Anti- have a diameter of about 160 nm.

120 Fig. 2: Calcium phosphate based mandibular implant (blue) made by 3D powder printing.

Teaching

The teaching activity contains lessons about functional materials for clinical applications and their interaction mechanisms with the biological system, courses about quality management systems and risk analysis of medical devices, medical application of x-rays, as well as practical measuring techniques for material analysis. The lectures are designed for dental students, graduate students of Biomedicine and, together with the faculty of Physics and Astronomy C. Moseke, A. Ewald: Cell and protein ad- for students of „Nanostrukturtechnik“ and sorption studies using quartz crystal mi- with the faculty for Chemistry and Pharmacy crogravimetry with dissipation monitoring. for students of „Technologie der Funktions- Mat.-wiss. U. Werkstofftech. 2009; 40: werkstoffe“. 36-42. C. Moseke, W. Braun, A. Ewald: Elec- trochemically deposited (Ca(OH)2 coatings as a bactericidal and osteointegrative modification of Ti implants. Advanced En- gineering Materials, 2009; 11:B1-B6.

U. Gbureck, E. Vorndran, J.E. Barralet: Vancomycin release kinetics from porous calcium phosphate ceramics comparing static and dynamic immersion conditions, Acta Biomaterialia 2008; 4: 1480-1486.

E. Vorndran, M. Klarner, U. Klammert, L.M. Grover, S. Patel, J.E. Barralet, U.

SELECTED PUBLICATIONS Gbureck: 3D Powder Printing of ß-Trical- cium Phosphate Ceramics using different Strategies, Advanced Biomaterials 2008; 10: B67-B71.

J.E. Barralet, U. Gbureck, P. Habibovic, E. Vorndran, C. Gerard, C.J Doillon: Vascu- larization and wound healing response in bioceramic implants loaded with copper and/or VEGF, Tissue Engineering 2009; 15: 1601-1609. 121 4.4 Department of Oral and Maxillofacial Surgery

Mission • follow-up of patients suffering from os- Professor Dr. med. Dr. med. dent. Alexander and Structure teoradionecrosis Kübler (Head of the Department) The clinic has got 20 permanent staff positions and a further half post which is funded Differential diagnosis of oral mucosa le- Pleicherwall 2 externally. The clinic provides 40 permanent sions 97070 Würzburg beds and covers the whole spectrum of oral (U. Müller-Richter, T. Reuther) Tel.: 0931/201-72720 and maxillofacial plastic surgery. Beside the Fax: 0931/201-72700 in-patient care (about 1.200 patients each The investigations aim to establish new E-mail: [email protected] year), approximately 15.000 patients are markers which improve the estimation of www.mkg.uni-wuerzburg.de treated in the outpatient clinic. Further more the prognosis of different oral lesions. That

CONTACT DETAILS CONTACT the clinic provides a comprehensive consul- shall enable the assessment of the dignity tant support, particularly for the paediatric and help to establish screening methods. clinic (craniofacial dysplasia and cleft-lip-palate patients) and within the interdisciplinary emergency treatment and intensive care of Research team for antigens of oral traumatised patients. Together with the ad- squamous cell carcinoma jacent specialities, especially orthodontics, (U. Müller-Richter, A. Kübler) neurosurgery, paediatrics and ENT, the interdisciplinary treatment of patients with com- Focus of the research is the characterisa- plex malformations and trauma is ensured. tion of the cancer/testis antigen subgroup MAGE-A in oral squamous cell carcinoma. Within the in-patient treatment as well as Distinct antigens are investigated concern- the consultation hours for outpatients, we ing their clinical relevance for prognosis and treat patients with: therapy.

• tumors of the head and neck (treatment and functional and aesthetical recon- Clinical research team for imaging struction including microsurgical tissue methods transfer) (U. Müller-Richter, M. Kochel) • trauma of jaws and face • craniofacial dysplasia (orthognathic Different imaging methods (e.g. based on malformations, clefts of lip and palate, ionised radiation, ultrasound, magnetic craniosynostoses) resonance) are evaluated for their applica- • plastic-aesthetic reconstruction bility in well-defined interrogations. A fur- • dental implants including bone aug- ther topic is the fusing facility of the various mentation methods. New 3D-Methods like cone beam • oral surgery (e.g. cysts, abscesses, os- computed tomography and 3D-surface im- teomyelitis) aging are examined to predict the outcome • diseases of salivary glands of aesthetic and orthognathic surgery. • TMJ disorders • atypical facial pain and nerve lesions Clinical research team for bisphospho- nate-associated necrosis of the jaw Major Research (A. Kübler, T. Reuther, T. Bittner) Interests In collaboration with the pathologic insti- Clinical research team for neoplasia of tute the histological characterization of the head and neck affected bone as well as clinical prospec- (T. Reuther, U. Müller-Richter, I. Reuther, A. tive and retrospective studies concerning Kübler) risk factors and concomitant diseases are conducted. • clinical study concerning neo-adjuvant vs. adjuvant therapy of oral and oropha- ryngeal cancer Research team for tissue regeneration • in vitro study of oral mucosa exposed to of oral mucosa carcinogens (T. Reuther, U. Kriegebaum, C. Klingelhöffer, • satisfaction survey of patients with A. Kübler) transplants from the arm and shoulder region The main focus is the evaluation of various • follow-up of donor-site morbidity of mi- dermal equivalents, i.e. biopolymer matri- crovascular forearm flaps and scapular ces with cultivated fibroblasts on their sur- flaps face. The aim is the tissue engineering of

122 oral mucosa. The comparison of typical co- for counseling and disease progress under cultures (dermal equivalents plus keratino- different therapeutical strategies will be de- cytes) with dermal equivalents alone tends fined. to reveal insights about dermal-epithelial interaction. A further topic is the investigation of the vascularisation capability using this model. The mechanical forces affecting a Teaching transplant in the oral cavity are emulated and analyzed (mechanotransduction). The clinic ensures theoretical and practical educational engagements within both the medicine and the dentistry course. Research team for bone regeneration and bone substitution For medical students the clinic provides op- (U. Klammert, T. Reuther, C. Jahn, A. Kübler, portunities within multidisciplinary lessons U. Kriegebaum) and clinical traineeships. In the context of interdisciplinary oncological lectures typi- In collaboration with the Department for cal tumorous lesions of the oral cavity, jaw Functional Materials in Medicine and Den- and face are presented, including treatment tistry, novel bone replacement materials strategies and reconstructive options. with calcium phosphate chemistry fabri- cated by the rapid prototyping technique of Within dentistry the fields of oral structure 3D powder printing, are investigated in vitro biology, oral pathology, oral and maxillofa- and in vivo. These implants are examined cial surgery as well as dental radiology are to be used as individual Skull substitutes. taught. That includes the local dental an- Furthermore different agents (e.g. growing aesthetic techniques. These various fields factors) are tested to enhance their prop- are communicated theoretical as well as in erties. Another topic is the improvement of practical courses and clinical traineeships. the integration of autologous bone grafts by Further more the clinic is involved in the different modifications at the recipient site. advanced education for already approbated Of particular interest is the volume mainte- colleagues due to the organisation of certi- nance of the transplant. New methods of fied meetings and courses. cryoconservation of autologous bone grafts are utilized in the clinical routine.

Three dimensional stereophotogrammetric diagnosis and treatment evalua- Klammert U, Gbureck U, Vorndran E, Rö- diger J, Meyer-Marcotty P, Kübler AC. 3D tion of children with craniofacial anom- powder printed calcium phosphate im- alies plants for reconstruction of cranial and (H. Böhm, in cooperation with P. Meyer- maxillofacial defects. J Craniomaxillofac Marcotty (department of orthodontics) T. Surg [Epub ahead of print]. Schweitzer (department of neurosurgery) Klammert U, Reuther T, Blank M, Reske I, Barralet JE, Grover LM, Kübler AC, Gbu- This study examines children with prema- reck U. Phase composition, mechanical ture closure of the cranial sutures or posi- performance and in vitro biocompatibility tional plagiocephaly. of hydraulic setting calcium magnesium phosphate cement. Acta Biomater 2010, The aim of this project is: First, to estab- 6:1529-1535. lish a three dimensional stereophotogram- metry as a non invasive imaging technique Reuther T, Kochel M, Klammert U, Meyer- in diagnostics and follow up of infantile skull Marcotty P, Müller-Richter UDA, Kübler AC. Cryopreservation of autologous bone deformities; second, comparing different grafts: an experimental study on a sheep therapeutical strategies (surgical or conser- animal model. Cells Tissues Organs 2010,

vative approach in children with a sagittal SELECTED PUBLICATIONS 191:394-400. craniosynostosis, and molding therapy in positional plagiocephaly (with an individu- Müller-Richter UDA, Dowejko A, Driemel O, Reuther T, Reichert TE, Kübler AC al CAD/CAM manufactured orthesis) versus Impact of MAGE-A antigens on taxane re- positioning and physiotherapy alone) in response in oral squamous cell carcinoma gard to morphologic skull changes and neu- Oncology Letters 2009 [in press]. ropsychological development. Documenta- Müller-Richter UDA, Dowejko A, Peters tion and analysis of early language skills as S, Rauthe S, Reuther T, Gattenlöhner S, well as individual evolution of neuropsychol- Reichert TE, Driemel O, Kübler AC. MAGE- ogy parameters are monitored at different A antigens in patients with primary oral defined time-points. Predictive parameters squamous cell carcinoma Clinical Oral In- vestigations [EPub 2009]. 123 4.5 Department of Prosthodontics

Professor Dr. med. dent. Dipl.-Ing. Mission offering a broader spectrum of indications Ernst-Jürgen Richter and Structure at improved usability and aesthetics, grace (Head of the Department) to new materials. The Department of Prosthodontics (current- Pleicherwall 2 ly 46 employees) is one of five departments A cooperation with other faculties (Depart- 97070 Würzburg in the Dental University Clinic. Its main mis- ment of Experimental Physics V) and an in- Tel.: 0931/201-73020 sion is to provide theoretical and hands-on dustry-sponsored (Prokuro GmbH, Degu- Fax: 0931/201-73000 education to students in material scienc- Dent-Dentsply) workgroup are working on E-mail: [email protected] es as well as medial fields. The ambula- implementation of magnetic resonance www.klinik.uni-wuerzburg.de/deutsch/einrich- tory care comprises all fields with a main tomography into dental medicine (dMRT). tungen/kliniken/PoliklinikfrZahnrztlicheProt- focus on prosthetic-restorative dentistry. The long-term goal is to eliminate diagnos- CONTACT DETAILS CONTACT hetik/content.html Classic restorations like crowns, bridges or tic routines which make use of X-rays from removables are supported as are current dentistry. For example, information about Professor Dr. med. dent. Thomas Holste techniques, such as metal-free-, implant- anatomy of teeth and the alveolar proces- Tel.: 0931/201-73080 , perioprosthodontics and facial prosthe- sus as well as the amount and density of ses, in addition to which treatment of cra- alveolar bone can be used in surgical plan- Professor Dr. med. dent. Alfred Renk nio-mandibular dysfunctions and myofacial ning, while precise information on size and Tel.: 0931/201-73060 pain syndromes is offered. localization of caries is of importance for conserving therapy.

Major Research In regards to therapy of cranio-mandibu- Interests lar dysfunctions special sampling methods were developed which, for the first time, en- Clinical field studies and experimental re- able real-time visualization of the temporo- search in the field of dental implantology mandibular joint under different load situa- are prominent research topics, spanning tions (Figure 1). evaluation of temporary index-implants as stabilizers for surgical guides and biody- On the other hand, dMRT data can be used namic analysis of implant superstructure to fabricate fixed partial dentures, elimi- loading. For 12 years, research has also nating the need for displeasing and error- been focussed on the concept of „strate- prone impressions of prepared teeth. For gic“ and angulated implants in conjunction this purpose, a proprietary HF-receiver coil with removable dentures. was conceived and developed which allows high resolution images of prepared teeth. The „Wuerzburg Post“, which was devel- The proof of principle has been provided oped by the Department of Prosthodontics by a bridge which was modelled and milled and has been commercially available since (CAD/CAM) based on dMRT data, which 2006, is undergoing clinical testing as part could be permanently placed (Figure 2). of a long-term study. Since May of 2005 almost 150 of these cores have been placed in fractured teeth. At that point the survival rate amounted to over 90%, underlining Teaching the competitiveness of this system versus „classic“ post-and-cores. The premed curriculum comprises two classes (technical propaedeutics, 66 stu- On the basis of this concept‘s good results dents and Phantom I, 65 students). The a successor version is under development, six week Phantom II course (128 students)

Fig. 1: a: Clinical situation: there is a visible discoloration on the upper right incisor which suggest the presence of a carious lesion (arrow). b: dMRT image of the same tooth. The significant site of the lesion is visible, as is the dental pulp (pink). c: X-ray of said tooth: By contrast, the lesion is more difficult to make out.

124 Fig. 2: a: Segmented dMRT dataset of two prepared upper teeth as well as the adjacent canine. b: intra-oral image of the clinical situation. c: definitively placed restoration which was modelled and manufactured based on the dMRT dataset.

takes place annually during the summer off- term. A total of 257 students participated in the medical courses of 2009, aided by 8 instructional videos, 4 written instructional booklets and two scripts for material sciences. Material science classes span two semesters. All materials are also made available as digital downloads. As of summer 2010, an eLearning project will be institut- ed in cooperation with the VHB.

Two clinical courses are being offered as part of the medical curriculum for fourth and fifth year students, during which the trainees treat own patients under close supervision of professors and assistant doctors. 56 students are trained per class. The lecture on prosthodontics covers general fields of prosthetic dentistry, wherease the Tymofiyeva O., Boldt J., Rottner K. et al.: lecture on special prosthodontics aims at High-resolution 3D magnetic resonance CMD and geriatric dentistry. Both lectures imaging and quantification of carious le- span two semesters. sions and dental pulp in vivo. MAGMA 2009, 22 (6): 365-374. On average, each student performs three Weng D., Poehling S., Pippig S. et al.: The restorations which are subject to individual effects of recombinant human growth/dif- grades. Accordingly, there were 672 resto- ferentiation factor-5 (rhGDF-5) on bone rations in both courses and 448 in the 10- regeneration around titanium dental im- day biannual state examinations which had plants in barrier membrane-protected defects: a pilot study in the mandible of bea- to be monitored and graded. In each course gle dogs. Int J Oral Maxillofac Implants there are two written tests, summing up to 2009, 24 (1): 31-7. roughly 300 corrections and gradings! Tymofiyeva O, Rottner K, Jakob PM, Rich- ter EJ, Proff P.: Three-dimensional localization of impacted teeth using magnetic resonance imaging. Clin Oral Investig. 2009 Apr 28. [Epub ahead of print]. SELECTED PUBLICATIONS Boldt J., Richter E.-J., Schilling K.-U. et al.: Failure analysis of a new post-and- core restoration system using the finite element method. Biomed Tech (Berl) 2008, 53 (5): 251-4.

Proff P., Bayerlein T., Rottner K. et al.: Ef- fect of bone conditioning on primary stability of FRIALIT-2 implants. Clin Oral Im- plants Res 2008, 19 (1): 42-7. 125 4.6 Department of Conservative Dentistry and Periodontology

Professor Dr. med. dent. Bernd Klaiber Mission Due to the micro-mechanical anchorage of (Head of the Department) and Structure the restoring materials to the conditioned enamel and dentine, the preparation of Pleicherwall 2 The Department of Operative Dentistry and macro-mechanical cavities - with further 97070 Würzburg Periodontology (16 dentists - 4 of them in loss of healthy tooth-substance - can be Tel.: 0931/201-72420 the section of periodontology, 12,5 den- set aside. Further emphasis is based on Fax: 0931/201-72400 tal assistants 2.5 of them in the section the Aesthetic Dentistry: adjustments of E-mail: [email protected] of periodontology, 2 dental technicians) is contour-, colour- and position-anomalies www.klinik.uni-wuerzburg.de/deutsch/ endued with 10 dental chairs - 3 of them with non-invasive or minimal-invasive tech- einrichtungen/kliniken/PoliklinikfrZahner in the section of periodontology, 2 working niques are made possible through the use haltungundParodontologie/content.html centres for the dental technicians and facil- of adhesive materials and modern resin-

CONTACT DETAILS CONTACT ities for taking radiographs. For the practical based composites. In the majority of cases Professor Dr. med. dent. Wolfgang part of the students´ education 24 dental there is no more need to prepare the teeth Wiedemann chairs are available, 40 working centres for for veneers or crowns. The conservation of Tel.: 0931/201-72660 laboratory dentistry as well as 40 working healthy tooth substance and the renuncia- centres providing phantom-puppets. tion of lab-made restorations are obvious advantages in respect of biologic and finan- The area of responsibility of the Depart- cial interests. ment of Operative Dentistry and Periodon- tology contains prevention, diagnostics and therapy of diseases to enamel and dentine Major (caries, abrasion, erosion and trauma) as Research Interests well as to the pulp (pulpitis, trauma) and to the periodontal ligament (periodontitis) Research at the Department of Operative and their sequelae. Each year approximate- Dentistry and Periodontology is focused on ly 4.000 patients are treated ambulatory. In the evaluation of restorative materials, ap- co-operation with the Department of Paedi- pliances and devices required for conserva- atrics, the Department of Anaesthesiology tive restorative therapy. In this context, the and the Department for Oral and Maxillofa- interactions between restorative materials cial Surgery patients can be treated in gen- and dental hard tissues and among differ- eral anaesthesia. ent restorative materials are studied.

In patient-care special emphasis is based A universal testing machine allows the de- on minimal-invasive preparation and its ad- termination of mechanical properties (com- equate supply with adhesive techniques: pressive strength, flexural strength, ten-

Fig.1: Uniform interproximal spaces following traumatic loss of one lower incisor and subsequent orthodontic treatment (above). By non-invasive procedures the spaces could be closed and a natural appearance has been restored (below).

126 sile bond strength, shear bond strength, extru- sion shear bond strength). Defor- mation of teeth under load and during photo-activated polymerization of resin-based composite restorations can be studied using displacement transducers. Addi- tional experimental setups allow the evaluation of the kinetics and the to- Fig. 2: Spectral absorbance of photo-initiators compared to the tal amount of poly- spectral irradiance of different light curing units. merization shrink- age of restorative resin-based composites, as well as the spectral irradiance Another clinical study investigates a further of dental light curing units. developed composite, which will be mainly used in the anterior region. The duration of The marginal seal of restorations is evalu- this study will be four years. ated using dye penetration techniques and computer-based image analysis. The margin fidelity of restorations in vivo and in vitro is monitored morphologically by the replica technique and a scanning electron microscope, which is used together with other departments of the dental school.

An atomic force microscope is used in cooperation with the Department and Chair of Functional Materials in Medicine and Den- tistry for studying the interface between dental hard tissues and restorative materials.

The purpose of the current clinical studies is to compare newly developed restorative materials and appliances with those consid- Kremeier K, Pontius O, Klaiber B, Hüls- ered to be the gold standard in the past. In mann M (2007) Nonsurgical endodontic some cases, undergraduate students can management of a double tooth: a case report. Int Endod J 40(11): 908-915. be involved in these studies. This lets them come to know the different tasks of a uni- Feierabend S, Klaiber B (2008) Atypische versity hospital. Odontalgie und protrahierte psychische Reaktion auf diese Erkrankung nach Currently, endodontic treatments, per- inkonsequenter zahnärztlicher Behand- lung. Quintessenz 59(3):289-297. formed during the students‘ courses 10 years ago, are clinically and radiographical- Eichelsbacher F, Denner W, Klaiber B, ly examined. An investigation of this kind is Schlagenhauf U (2009) Periodontal sta- nationwide unique so far. Moreover, a new- tus of teeth with crown-root fractures: results two years after adhesive fragment rely developed rubber dam system (appliance attachement. J Clin Periodontol 36(10): for moisture control during operative proce- 905-911. dures) was compared to the conventional one. The general acceptance among both Klaiber B (2009) Inlays und Teilkronen clinicians and patients was good, which is aus Gold – wann noch und dann Wie?

SELECTED PUBLICATIONS Quintessenz 60(10):1163-1174. in contrast to most of the published data up to now. Feierabend S, Gerhardt-Szep S (2010) Evidence based Dentistry – Tipps für die Praxis. Fall 1: Avulsion bleibender Zähne. 127 Dtsch Zahnärztl Z 65(1): 94-98. 4.6.1 Division of Periodontology

Professor Dr. med. dent. Ulrich Schlagenhauf Mission other institutes and clinics in Würzburg and (Head) and Structure other national or international institutions.

Pleicherwall 2 Besides Prof. Schlagenhauf the staff of the 97070 Würzburg division comprises further four dentists and Adjunctive use of systemic antibiotics Tel.: 0931/201-72630 3 dental assistents. The Division of Peri- in the therapy of chronic and aggressive Fax: 0931/201-72680 odontology forms part of the Department periodontal disease E-mail: [email protected] of Conservative Dentistry and Periodontol- (U. Schlagenhauf, Y. Jockel, M. Bechtold) www.uk-wuerzburg.de/parodontologie ogy and is a clinical center for referrals of patients suffering from severe periodontal In preceding clinical trials realized in col- disease beyond the scope of an average laboration with the Institute of Hygiene and

CONTACT DETAILS CONTACT practicing dentist. Especially the therapy of Microbiology the adjunctive use of system- refractory aggressive periodontitis and gin- ic antibiotics subsequent to the mechan- givoperiodontal manifestations of systemic ical removal of microbial biofilms for ex- diseases is at the focus of the special composed root surfaces resulted in a marked petence provided by the division to referring enhancement of periodontal healing even dentists and the public in the region of Un- in severly compromised teeth. The extend- terfranken and beyond. In collaboration with ed periodontal healing made it possible the Institute of Microbiology and Hygiene of to maintain severly compromised teeth in the University of Wuerzburg antiinfectious function long-term, which, previously had strategies for the therapy of aggressive peri- to be removed already at the beginning of odontitis and perimplantitis have been de- the initial phase of periodontal therapy. In vised. Furthermore a therapy concept for order to further verify the scientific validity the treatment of oral manifestations of juve- of this tooth-saving therapy concept, the nile hypophosphatasia has been developed Division. of Periodontology participates in in close contact with the Pediatric Clinic of a multicenter clinical trial supported by the the University of Wuerzburg. Also surgical Deutsche Forschungsgemeinschaft (DFG) interventions for the minimally invasive cor- and is contributing more than 100 own rection or regeneration of periodontal lesion study patients.. belongs to the clinical standard procedures provided by the division. Periodontal diseases and cardiovascular health Major Research (Y. Jockel, J. Baulmann, G. Ertl, U. Schla- Interests genhauf)

The main research projects of the Division. Recent investigations performed in collabo- of Periodontology are listed below. Some of ration with the Clinic for Internal Medicine I them are joint efforts in collaboration with revealed, that patientes suffering from peri-

Fig. 1: Advanced chronic periodontitis in a patient suffering from angiomatosis Rendu- Osler.

128 ed and practically instructed in a pig jaw model. Junior staff members of the Division of Periodontology are given the opportunity to acquire a formal postgraduate specialization in periodontology by following a formal 3 year postgraduate training program according to the guidelines of the German Society of Periodontology.

Fig. 2: Pronounced plaque-induced gingi- val inflammation in a patient with insuffi- cently controlled diabetes type I.

odontal disease frequently display a significantly elevated vascular augmentation when compared to age-matched periodon- tally healthy controls. Whether successful periodontal therapy has a significant impact on the status of cardivovascular health is subject to an ongoing clinical trial which also is realized in collaboration with the Clinic for Internal Medicine I and supported by the DFG.

Socket preservation after tooth extraction (S. Fickl, U. Schlagenhauf)

Subsequent to the extraction of a tooth the neighbouring alveolar bone tends to be re- sorbed to an extent, which frequently en- dangers a functionally and esthetically in- Eichelsbacher, F., Denner, W., Klaiber, B. & Schlagenhauf, U. (2009). Periodontal conspicuous rehabilitation of the defect by status of teeth with crown-root fractures: a fixed bridge or a dental implant without results two years after adhesive fragment additional surgical augmentative interven- reattachment. J Clin Periodontol, 36, 905- tions. Preliminary clinical studies proved 911. that a preferably tight seal of the alveolar Fickl, S. Zuhr, O. Wachtel, H. Kebschull, bone defect by the placement of a mucosal M. & Hürzeler, M. B. (2009). Hard tissue connective tissue graft significantly reduced alterations after socket preservation with the exent of aveolar bone resorption. The additional buccal overbuilding: a study identification of further co-factors is subject in the beagle dog. J Clin Periodontol 36, 898-904. of current investigations. Fickl, S., Schneider, D., Zuhr, O., Hinze, M., Ender, A., Jung, R.E. & Hürzeler, M. B. (2009). Dimensional changes of the ridge contour after socket preservation and buc- Teaching cal overbuilding: an animal study. J Clin Periodontol. 36, 442-448. Dental undergraduate training compris- SELECTED PUBLICATIONS es the clinically most relevant aspects of Valenza, G., Veihelmann, S., Peplies, J., periodontal diagnosis and therapy. Sub- Tichy, D., Roldan-Pareja Mdel, C., Schla- genhauf, U. & Vogel, U. (2009). Microbial sequent to the intensive teaching of the changes in periodontitis successfully treat- basic principles of periodontology firstly in ed by mechanical plaque removal and sys- dummy heads and subsequently in real pa- temic amoxicillin and metronidazole. Int J tients nonsurgical minimally invasive peri- Med Microbiol, 299, 427-438. odontal therapy procedures are instructed Valenza, G., Burgemeister, S., Girschick, and trained under the close supervision of H., Schoen, C., Veihelmann, S., Moter, A., experienced clinicians. The basic facts of Haban, V., Vogel, U. & Schlagenhauf, U. periodontal surgergy are also demonstrat- (2006). Analysis of the periodontal microbiota in childhood-type hypophosphatasia. 129 Int J Med Microbiol, 296, 493-500. 5 Additional Scientific Units

In this chapter information on scientific in- bereiche), four Transregios, six Graduate Furthermore, the MD/Ph.D. program, the In- stitutions, cooperations and centers will Colleges, and other joint activities which ternational Graduate School and Research be given which are initiated or partly or- are performed together with institutions of Centers, Research Units and Research Alli- ganized by the Medical Faculty. The chap- other faculties, especially of the Biological ances are described which are dealing with ter comprises information on six Collabora- Faculty. particular scientific problems. tive Research Centers (Sonderforschungs-

130 5.1 Collaborative Research Centers 5.1.1 Collaborative Research Center 479, Variability of Pathogens and Host Reactions in Infectious Diseases

Professor Dr. rer. nat. Thomas Hünig General It will be the specific aspects of microbi- (Speaker) Information al adaptation to the host environment, and of the study and instrumentalisation of Institute of Virology and Immunbiology With the year 2009, the SFB 479 complet- the host’s immune response to pathogens Versbacher Str. 7 ed its life cycle of four three year funding which will provide the basis for future re- 97078 Würzburg periods. During those 12 years, microbiol- search networks. Tel.: 0931/201-49951 ogists, infection biologists and immunolo- Fax: 0931/201-49243 gists have intensively interacted to create a E-mail: [email protected] truly interdisciplinary network and research www.sfb479.uni-wuerzburg.de programme. Boundaries between faculties Teaching played no role, and the recruitment of new

CONTACT DETAILS CONTACT Professor Dr. med. Matthias Frosch professors in the faculties of biology and The Ph.D. students of the SFB 479 were (Vice-Speaker) medicine was used to further strengthen associated with the various training pro- Tel.: 0931/201-46160 our infection biology focus. Participation of grammes of the class “Infection and Im- the juniour research groups of the Center munity” within the Graduate School for Professor Dr. rer. nat. Roy Gross for Research on Infectious Diseases was an Life Sciences. These are the Graduate Col- (Vice-Speaker) important tool to promote young research- lege “Immunomodulation” (GRK 520) (now Tel.: 0931/888-4403 ers within the SFB, and with the inclusion of continued as Graduate Training Programme the Medical Clinic II, a firm bridge from ba- “Immunomodulation”), the graduate pro- sic to clinical research was established. gramme of the Center for Research on In- fectious Diseases, and the International Research Training Group (IRTG 1522) “HIV Major Research and Related Diseases in Southern Africa”, Interests thereby providing a structured scientific education. Over the 12 years of DFG funding, the researchers of the SFB 479 have been interested in the adaptation of pathogens to Symposia their hosts both during evolution and in the course of an infection, in the interaction of The biannual symposia held by the SFB microorganisms with their target cells, and throughout its twelve year life cycle culmi- in the interplay between the host’s immune nated in a final international symposium system and the invaders. Accordingly, the in July 2009 with the heading “Living with SFB was structured into three project areas: Pathogens: Never Lose Control”. This meet- the variability of pathogens (A), pathomech- ing provided an optimal opportunity to sum- anisms in the interaction between microbe marize the SFB’s achievements, and to dis- and host cells (B), and immune response cuss new roads to be taken with our inter- to and immunomodulation by microbial in- national guests. fections (C).

Fig. 1: GFP expression in a brain of a 2 week-old mouse infected with recombinant measles virus MV-eGFP-CAMH. The overview (coronal section) of the left hemisphere (A), enlarge- ment (B), and GFP/marker colocalizations with neurofilament in neurons (red) (C) and absence of colocalization with GFAP in astrocytes (red) (D) demonstrates the exclusive infection of neurons. (TP C11 Jürgen Schneider-Schaulies).

131 5.1.2 Collaborative Research Center 487, Regulatory Membrane Proteins: From Molecular Recognition to Drug Targets

Professor Dr. med. Hermann Koepsell (Speaker) General Furthermore, membrane associated proteins Information play a critical role in the regulation of cell me- Institute of Anatomy and Cell Biology tabolism, specific cell functions and mitosis Koellikerstr. 6 The SFB 487 „regulatory membrane pro- because they initiate activation cascades. 97070 Würzburg teins“ has been founded in 2000 and is in Tel.: 0931/31-82711 its fourth period of funding. The SFB 487 Important aims of the SFB 487 are to deter- Fax: 0931/31-82087 consists of 18 research groups from the fac- mine structures of physiologicaly and bio- E-mail: [email protected] ulties of medicine and biology. The research medicaly relevant membrane proteins and www.sfb487.uni-wuerzburg.de/ is focussed on molecular mechanisms of to identify their functional epitopes. This function and regulation of membrane pro- includes binding sites for hormones, neu- Professor Dr. rer. nat. Roland Benz teins trying to extend our knowledge con- rotransmitters, substrates and interacting CONTACT DETAILS CONTACT (Vice-Speaker) cerning function of receptors, channels, proteins. The structural results will be sup- Tel.: 0931/31-48903 transporters and membrane associated plemented with functional investigations to regulatory proteins. Therefore a broad spec- understand the physiology role of individu- Professor Dr. rer. nat. Rainer Hedrich trum of methods is applied ranging from al proteins. Functional data of membrane (Vice-Speaker) measurements on isolated proteins to in- proteins in vivo are acquired from cultivated Tel.: 0931/31-86100 vestigations in living animals. Biochemical cells, intact organs or living animals (see for methods are used to identify interaction do- example Fig.1). After the establishment of Professor Dr. med. Martin J. Lohse mains of proteins and ligand binding sites, functional mechanisms of individual mem- (Vice-Speaker) and to determine tertiary structures of the brane proteins the acquired knowledge will Tel.: 0931/201-48401 proteins. Protein interactions and protein be used for the development of novel ther- motion in cells are analysed using meth- apeutic drugs. Professor Dr. rer. nat. Thomas Müller ods of cell biology, biochemistry, and ge- (Vice-Speaker) netics. Finally the physiological function of Tel.: 0931/31-89207 membrane proteins is investigated in intact Research area A: Proteins with several organs and living animals after knock out transmembrane domains or over-expression of certain genes. Thus, the SFB 487 is a methodological platform A1 Lohse/Hoffmann (Pharmacology): Acti- that allows access to a variety of methods vation, desensitization and internalization of for the investigation of membrane proteins. G-protein coupled receptors The ultimate goal of all efforts is the identification of novel pharmaceutical targets in A4 Koepsell/Gorboulev (Anatomy and Cell membrane proteins. This may lead to novel Biology I): Structure-function-relationships therapies of diseases caused by membrane of substrate recognition and transport protein mal-function or mal-regulation. mechanism of polyspecific transporters of the SLC22 family

Major Research A5 Benz (Biotechnology): Mechanism and Interests pharmacology of toxin transport across model membranes The common research topics of the SFB 487 are proteins at cell surfaces that regulate cell A9 Hedrich (Molecular Plant Physiology functions. Cells are surrounded by a phos- and Biophysics): Regulation and Targeting pholipide bilayer membrane, which sepa- of Arabidopsis Tandem-Pore-K+ (TPK) chan- rates them from the environment. In these nels bilayer membrane a multitude of proteins (integral membrane proteins) are embed- A10 Bünemann (Pharmacology): Kinetics ded. Other proteins are associated with the and structural aspects of G-protein coupled outer or inner leaflet of the plasma mem- signal transduction brane (membrane associated proteins). In- tegral membrane proteins are parts of signal A12 Nagel (Molecular Plant Physiology and transduction pathways (receptors), involved Biophysics): Characterization and mutagen- in solute shuttling across the plasma mem- esis of channelrhodopsins brane (channels, pores, transporters), or are involved in cell-cell communication (cell contact proteins). Membrane associated pro- Research area B: Proteins with a single teins stabilise the plasma membrane and transmembrane domain mediate contacts of cells with extracellular (i.e. collagen fibers) or intracellular proteins B2 Müller (Molecular Plant Physiology and (i.e. actin filaments). Membrane associated Biophysics): Affinity, specificity and promis- proteins regulate the amount (endocytosis, cuity of cytokine and BMP receptors exocytosis) and the activity of integral membrane proteins in the plasma membrane. B3 Schartl/Meierjohann (Physiological

132 7 - 9, 2007

Fig. 1: Generation of neuronal activity by light. A fluorescence labelled cation channel was expressed in neurons of rat brain (left). A member of SFB 487 detected that this channel (channelrhodopsin) opens after illumination. Short applications of light impulses lead to short depolarization signals in neurons (right).

Chemistry I): Protein interactions at the on- C6 Nieswandt (Rudolf-Virchow-Zentrum, cogenic growth factor receptor Xmrk DFG Research Center for Experimental Bio- medicine): Mechanisms of agonist-induced B5 Waschke/Drenckhahn (Anatomy and Ca2+-entry in platelets in vitro und in vivo Cell Biology II): Modulation of the Cadherin- Binding C7 Schindelin (Rudolf-Virchow-Zentrum, DFG Research Center for Experimental Bio- B7 Wajant (Molecular Internal Medicine): medicine): Structural and functional ba- Mechanisms of TNF-receptor-activation sis of gephyrin-induced clustering of neurotransmitter receptors B8 Kuhn (Institute for Physiology) Cardiac function and dysfunction of the guanylyl cyclase-A receptor for ANP: lessons from ge- Zentrale Verwaltung netic mouse models Z1 Service Koepsell/Müller (Anatomy and B9 Hermanns (Rudolf-Virchow-Zentrum, Cell Biology/Molecular Plant Physiology and DFG Research Center for Experimental Bio- Biophysics): Analysis of protein-protein in- medicine): „Structural requirements for cy- teractions employing surface plasmon res- tokine receptor-mediated activation of the onance JAK/STAT and MAPK signaling pathways“ Z2 Administration Koepsell (Anatomy and Cell Biology) Research area C: Membrane-associated regulatory proteins Symposia C1 Koepsell (Anatomy and Cell Biology I): Functions of Na+-D-glucose cotransporters Internal SFB-Symposia: and their regulation by the regulator pro- October 6 - 7, 2000, Bad Brückenau tein RS1 September 28 - 29, 2001, Pommers- felden C3 Rapp (Institute for Radiation Biology and October 11 – 12, 2002, Bad Brückenau Cell Research): Mechanisms of isoform- October 2 - 3, 2003, Bad Brückenau specific regulation of membrane-integrat- October 15 - 16, 2004, Staffelstein ing protein kinases of the RAF family October 6 - 7, 2006, Bad Brückenau October 5 - 6, 2007, Bad Brückenau C4 Sendtner (Klinische Neurobiologie): July 24 – 25, 2009, Pommersfelden Protein interactions at receptors for neurotrophic factors International Symposia: C5 Raabe (Institute for Radiation Biology and Cell Research): Regulation of cell ad- “Molecular Physiology of the Synapse”, hesion and the cytoskeleton by „p21-acti- June 14 -16, 2001 vated kinases“ (PAK) during neuronal cell “Mechanisms of protein activation”, June differentiation 10 – 12, 2004 “Membrane proteins and diseases”, June

133 5.1.3 Collaborative Research Center 567, Mechanisms of Interspecific Interactions of Organisms

Professor Dr. rer. nat. Markus Riederer General pathology and analytical chemistry in order (Speaker) Information to address the following central questions:

Julius-von-Sachs-Institute for Biosciences The Coordinated Research Centre (Sonder- • What are the mechanisms underlying Julius-von-Sachs-Platz 3 forschungsbereich) 567 “Mechanisms of interspecies recognition in different in- 97082 Würzburg Interspecific Interactions of Organisms” at teraction systems? Tel.: 0931/318-6200 the Julius-Maximilians-Universität Würzburg • What kind of information flow is required Fax: 0931/318-6235 was established in January 2001 with the for the establishment and maintenance E-mail: [email protected] objective to provide a substantial multidis- of interactions? www.sfb567.uni-wuerzburg.de ciplinary contribution to the investigation of • What is the nature of substantial and interactions between organisms belonging energetic resources to be exchanged

CONTACT DETAILS CONTACT Professor Dr. rer. nat. Rainer Hedrich to different species – symbioses in a broad- between interaction partners? How is (Vice-Speaker) er sense. This is achieved by investigating this exchange initiated and regulated? Tel.: 0931/318-6100 interaction systems from a wide spectrum What are the genetic and physiological of species and over several levels of orga- predispositions required to permit inter- nization. action? • How is the flow of information and re- This integrative approach combining molec- sources generated within the interac- ular and organismic biology is supposed to tion partners and how is it finally trans- strengthen and intensify the technical and mitted? conceptual exchange between these two • What is the role of the phenotypic plas- mainstream fields of modern biology rep- ticity of the partners with respect to es- resented by various disciplines within three tablishment and maintenance of inter- faculties (biology, medicine, chemistry and action? pharmacy). • What are the molecular, morphological and behavioural adaptations that can The interdisciplinary structure of the Coor- be explained as an evolutionary conse- dinated Research Centre greatly facilitates quence of interaction? the incorporation of multidisciplinary aspects into teaching. This helps to familiarize Only the comparative assessment and in- undergraduate and postgraduate students tegration of results based on a wide range with current methods and techniques used of levels of complexity can elucidate com- in biology and adjacent fields in order to mon principles, characteristics and benefits improve their qualifications to meet the re- of symbioses. quirements of the professional world. The Sonderforschungsbereich 567 is subdivided into three project areas: „Recognition Major Research and Reaction“, „Signals in the Interaction Interests Partners“ and “Continuity and Evolution”.

In 13 projects scientists are engaged in approaches based on physiology, molecular Recognition and Reaction biology, ecology, evolutionary biology and biophysics. A broad systematic spectrum of This project area focuses on signals that interaction systems is analyzed by applying lead to the unilateral or mutual recogni- techniques from infectious biology, phyto- tion of interaction partners and investigates

Fig. 1: Molecular Mechanisms controlling the interaction between Arabidopsis thaliana and Agrobacterium tumefaciens (TP B5).

134 Fig. 2: Interactions between the marine sponge Aplysina aerophoba and its symbiotic microbial consortia (TP C3). mechanisms involved in the development of project whose principal investigator is mem- compatibility or incompatibility between or- ber of the Medical Faculty is included, which ganisms of different species. This includes is working on the “Interactions of the gyno- the analysis of plant surface characteristics genetic Amazon molly Poecilia formosa and affecting the recognition of hosts and non- its hosts”. hosts by obligate biotrophic fungi. Other approaches investigate pathogen defense reactions in plant and animal systems on the molecular and cellular scales.

Signals in the Interaction Partners

The central objects of investigation in this project area are those signals and resulting adaptations, which are formed within organisms as a response to biotic interaction. Trans-membrane ion and metabolite flows and their functional role in the molecular response of a plant upon interaction with microorganisms are investigated. Here, the molecular basis and role of Ca²+ signals, expression and regulation of mass transport with respect to an infection with Agrobacterium or Pseudomonas are analyzed. In response to interactions between microbes and plants the formation of secondary plant metabolites, specific molecular patterns and the structural and functional characteristics of involved proteins are investigated.

Continuity and Evolution

This project area is concerned with the regulation and maintenance of interspecific interactions, investigating a broad spectrum of tight and obligate symbiotic systems. Regulatory aspects of even intracellular symbioses (bacteria/ants, microbes/sponges) and mutual interactions of more than two partners (plant/bee/herbivore) are analyzed. Moreover, a gynogenetic fish species serves as a model system to explore the evolutionary advantages and/or disad- vantages of sexual reproduction. Within the project area „Continuity and Evolution“ one

135 5.1.4 Collaborative Research Center 581, Molecular Models for Diseases of the Nervous System

Professor Dr. med. Michael Sendtner nisms of degenerative diseases. These two research to the understanding of the com- (Speaker) project parts are supplemented by two cen- plex course of disease processes. As this tral projects on morphology/electron mi- can only be achieved in an interdisciplinary Institute for Clinical Neurobiology croscopy and modern light microscopic approach, the SFB 581 links groups work- Versbacher Str. 5 techniques (confocal microscopy). ing with different methods on model sys- 97078 Würzburg tems for neurodegenerative and neuroim- Tel.: 0931/201-44000 munological disease processes. Fax: 0931/201-49788 Major Research E-mail: [email protected] Interests This collaborative research centre contrib- www-i.klinik.uni-wuerzburg.de/deutsch/forsc- utes significantly to training programs for hunglehre/forschung/sonderforschungsbe- The SFB 581 has set the goal to investigate students in the fields of Biology, Biomed- CONTACT DETAILS CONTACT reiche/SFB581/content.html the complex course of primary and second- icine as well as Experimental Medicine. ary pathophysiological processes in diseas- Since the SFB was established, students Steering committee: es of the nervous system. Diseases of the that are trained in these fields are enabled nervous system follow a complex course of to participate actively in the projects. For Professor Dr. Esther Asan primary and secondary pathophysiological this purpose the Deutsche Forschungsge- Institut für Anatomie und Zellbiologie processes leading from a causative cellular meinschaft and the University are provid- dysfunction to the disease phenotype. De- ing a considerable budget for student and Professor Dr. Klaus.V. Toyka spite the fast progress in the last two de- graduate assistants. Members of the SFB Neurologische Klinik cades in uncovering gene defects, which 581 are actively involved in courses within was particularly made possible due to the the training programs for these students. Professor Dr. Manfred Heckmann genome projects for human, mouse, dro- The SFB 581 is also involved in the training Physiologisches Institut sophila and other species, it is often not of graduate students which is being coordi- possible to understand the pathophysiolog- nated in the class “Neuroscience” of the In- Professor Dr. Rudolf Martini ical steps from the primary cause of these ternational Graduate School (GSLS) by the Neurologische Klinik diseases, for example a gene defect, to the University of Würzburg. Thus the SFB plays a specific disease phenotype and from there- major role not only in promoting research in Professor Dr. Utz Fischer on to development of new therapeutic strat- neurobiological research groups at the Uni- Institut für Biochemie egies. This situation calls for a cell biologi- versity of Würzburg, but also in promoting cally oriented neurobiology, which, in a net- young researchers in training programs in Professor Dr. Klaus-Peter Lesch work with clinical researchers, investigates the field of neurobiology. Klinik für Psychiatrie the cell biological cascade of disease development using suitable disease models. Frau Urveen Oberoi-Lehrieder (Office) Thus the main emphasis in the SFB 581 is Projects supported within the collabora- Tel.: 0931/201-49787 put on mouse and drosophila models, with tive research center 581: which not only the direct effect of signal transduction mechanisms on cellular struc- Projects Section A: tures and functions in the nervous system can be investigated, but also pathophysi- A3 Martini (Neurologie): Immunpatholo- ological processes with which the interac- gische Mechanismen bei Tiermodellen für General tions of different cell types can be investi- erbliche Neuropathien Information gated in neuroimmunological and neurodegenerative diseases. A5 Hünig (Virologie und Immunbiologie): The “Collaborative Research Centre” SFB Auslösung und Therapie einer Ovalbumin- 581 „Molecular models of diseases of the The goal of the SFB is to connect the molec- spezifischen experimentellen autoimmunen nervous system“ has been established in ular cell biologically oriented fundamental Enzephalomyelitis the year 2000 at the University of Würz- burg. In 2009, it was reviewed and now will be funded for a final round of support until June 2012. It comprises groups from the faculties of medicine (clinical and theoretical institutes), biology and chemistry. The central goal is to investigate how gene mutations ultimatively lead to the specific phenotypes in these diseases, to identify contributions of reactive cells and neural activity in diseases of the nervous system and thus to contribute to a better understanding of the underlying disease mechanisms. For that purpose two main focuses were set: the projects of part A focus on mechanisms Fig. 1: Degeneration of spinal motoneurons in a mouse model for spinal muscular atro- of inflammatory diseases, whereas the proj- phy (Smn+/- right side). The area where motoneurons degenerate is labelled with white ects in part B deal with molecular mecha- arrows.

136 A7 Toyka/Sommer (Neurol- Core projects: ogie): Immunpathogenese des Stiff-Person-Syndroms V1 Sendtner (Klinische Neurobiologie): Sprecher, Sekretariat und Verwaltung des A8 Wiendl (Neurologie): SFB Pathogene Mechanismen neuroinflammatorischer Er- Z3 Asan (Anatomie und Zellbiologie): krankungen: Rolle koinhibi- Zentrales Serviceprojekt für Morphologie, torischer Signale für die pa- insbesondere Elektronenmikroskopie renchymale Immunregula- tion Z4 Sendtner (Klinische Neurobiologie): Konfokale Mikroskopie A9 Lutz (Virologie und Im- munbiologie): Präsentation cerebraler Glycolipide durch Scientific meetings organized by the dendritische Zellen an NKT- collaborative research centre 581: Zellen und persistierende ZNS-Virus-Infektionen bei July 3-4, 2009: International symposium, der Auslösung der EAE CRC 581 in Würzburg

A10 Meuth (Neurologie): December 1st, 2009: International sympo- Pathophysiologische Rel- sium “Latrophilin-2” evanz von Zwei-Poren-Kal- ziumkanälen (K2P) für In- flammation und Neurode- generation in T-Zell-ver- mittelten Autoimmun-erkrankungen des zentralen Nervensystems

Projects Section B: Fig. 2: Differentiation of neural stem cells in cell culture. Immature stem cells are labelled with an antibody against B1 Sendtner (Klinische Nestin (panel a), 24 hrs after plating on Laminin, differ- Neurobiologie): Pathogen- entiated neurons that grow long neurites can be identified ese der Spinalen Muskel- by labelling with antibodies against Neurofilament-N (low- atrophie (SMA): Charakte- er panel). risierung von Zellkulturen und Tiermodellen zur Anal- yse der axonalen Pathologie bei der SMA RSK in neurologischen Erkrankungsproz- essen Chari,A., Golas,M.M., Klingenhager,M., B4 Sendtner (Klinische Neurobiologie): Die Neuenkirchen,N., Sander,B., Rolle neurotropher Faktoren bei der Patho- B18 Fischer (Biochemie): Defekte im RNA- Englbrecht,C., Sickmann,A., Stark,H., and genese von Motoneuronerkrankungen: Un- Metabolismus als Ursache von neuronaler Fischer,U. (2008). An assembly chaper- tersuchungen an Gen-Knockout-Mäusen Degeneration: Molekulare Analyse der spi- one collaborates with the SMN complex to nalen Muskelatrophie und der Retinitis Pig- generate spliceosomal SnRNPs. Cell 135, 497-509. B5 Rapp (Medizinische Strahlenkunde mentosa und Zellforschung): Molekulare Mechanis- Jablonka,S., Beck,M., Lechner,B.D., men des Überlebens, der Migration und B24 Jablonka (Klinische Neurobiologie): Mayer,C., and Sendtner,M. (2007). Defec- der Axonregeneration von Nervenzellen bei Untersuchung von Krankheitsmechanis- tive Ca2+ channel clustering in axon ter- minals disturbs excitability in motoneurons Mausmutanten mit Fehlsteuerung der Raf- men an Motoneuronen eines Mausmodells in spinal muscular atrophy. J. Cell Biol. Wirkung für spinale Muskelatrophie mit Ateminsuffi- 179, 139-149. zienz (SMARD) B9 Lesch (Psychiatrie): Multiple moleku- Kroner,A., Schwab,N., Ip,C.W., Ortler,S., lare Defekte des zentralen Serotoninsys- B26 Eilers (Physiologische Chemie): Rolle Gobel,K., Nave,K.A., Maurer,M., Martini,R., and Wiendl,H. (2009). Acceler- tems und ihre Rolle in der Pathophysiologie von Myc und Miz1 in der Neurogenese im ated course of experimental autoimmune neuropsychiatrischer Erkrankungen Zentralnervensystem encephalomyelitis in PD-1-deficient central nervous system myelin mutants. Am. J. B14 Raabe (Medizinische Strahlenkunde B27 Heckmann (Physiologie): Molekulare SELECTED PUBLICATIONS Pathol. 174, 2290-2299. und Zellforschung): Drosophila als Mod- Mechanismen der Plastizität präsynaptisch- Schmid,A., Hallermann,S., Kittel,R.J., ellsystem zur Untersuchung der Rolle von er aktiver Zonen Khorramshahi,O., Frolich,A.M., Quentin,C., RhoGTPasen regulierten Kinasen aus der Rasse,T.M., Mertel,S., Heckmann,M., and PAK-Familie sowie der Kinasen CK2 und Sigrist,S.J. (2008). Activity-dependent site-specific changes of glutamate receptor composition in vivo. Nat. Neurosci. 11, 137 659-666. 5.1.5 Collaborative Research Center 630, Recognition, Preparation and Functional Analysis of Agents against Infectious Diseases

Goals and activities. Based on the three-dimensional Structure structure of the target proteins, quantum mechanical calculations and docking allow Researchers of four faculties of the Univer- the design of optimized structures for the sity of Würzburg together with the Medi- subsequent chemical synthesis. The next cal Mission Clinic founded the SFB 630 in stage is the examination of the pharmaco- 2003 driven by their common vision to iden- kinetic and toxicologic effects in vitro and tify and to develop novel agents against in- in vivo. fectious diseases. The extraordinarily high level of interdisciplinary exchange of the Professor Dr. rer. nat. Dr. h.c. Gerhard Bring- presently 15 individual projects belonging to Project Area A: Preparation, character- mann (Speaker) CONTACT DETAILS CONTACT Organic Chemistry, Pharmacy, Microbiology, ization and optimization of agents Theoretical Chemistry, Bioinformatics, Phys- Institut for Organic Chemistry ics, and Medicine accounts for the success A1 U. Holzgrabe (Institute for Pharmacy Am Hubland of the concept. The SFB is divided in three and Food chemistry) 97074 Würzburg Project Areas: Project Area A is responsible Small molecules for the treatment of in- Tel.: 0931/31-85323 for the preparation and characterization of fectious diseases Fax: 0931/31-84762 the compounds, which are then analyzed for E-mail: [email protected] their interaction with several clinically rele- A2 G. Bringmann (Institute for Organic www.sfb-630.uni-wuerzburg.de vant pathogens and pathogenicity factors at Chemistry) the cellular and molecular level in Project A new class of active agents against in- Professor Dr. Ulrike Holzgrabe Area B. The determination of the mode of fectious diseases (Vice-Speaker) action of the agents and also predictions for Tel.: 0931/31-85461 their further structural optimization are im- A4 T. Schirmeister (Institute for Pharmacy plemented in Project Area C. and Food Chemistry) Professor Dr. Dr. Heidrun Moll Proteases as targets for agents against (Vice-Speaker) infectious diseases Tel.: 0931/31-82627 Major Research Interests A5 U. Hentschel (Julius-von-Sachs Institute Angela Dreher (Office) for Biological Sciences) Tel.: 0931/31-85361 In spite of the efforts of modern medi- Novel secondary metabolites from cine, infectious diseases are still the major sponge-associated microbiota cause of deaths worldwide. The rapid development of resistances against common antimicrobials and the expeditious distribu- Project Area B: Interaction with cellular tion of novel pathogens by technical means and molecular systems due to enhanced geographical mobility and tourism impede the fight against the patho- B1 J. Hacker (Institute for Molecular In- gens. In addition, economical factors pre- fection Biology / Robert-Koch-Institute, vent the development of novel therapeutics Berlin) especially for tropical diseases. Therefore, Prolylisomerases and serine proteas- the search for novel agents against infec- es as targets for rational drug develop- tious diseases with novel modes of action ment integrated in a state-aided research environment is of pivotal importance. The re- B2 J. Morschhäuser (Institute for Molecular searchers of the SFB make use of natural Infection biology) sources like plants and marine microorgan- Inhibition of virulence and resistance isms to isolate active compounds as lead mechanisms of Candida albicans structures for synthetic analogs and derivatives. Furthermore, the versatile potential B3 H. Moll (Institute for Molecular Infection of combinatory chemistry is used to gener- Biology) ate novel chemical entities. The antimicro- Analysis of the action of naphthyliso- bial activity of these compounds is routine- quinoline alkaloids and cysteine prote- ly analyzed against several clinically impor- ase inhibitors against Leishmania para- tant bacteria, fungi, and parasites. Up to sites now, out of more than 1500 screened compounds, 109 showed activities in the same B5 K. Ohlsen (Institute for Molecular Infec- range as conventional antimicrobial agents tion Biology) or are even superior to them. A network of Drug-induced gene expression in staph- modern technologies like proteomics, tran- ylococci scriptomics, metabolomics and spectroscopic and bioinformatic analysis is utilized B7 C. Kisker (Rudolf-Virchow Center) to reveal the effective mechanism of their Structure-based drug design on essen-

138 Fig. 1: After crossing the blood-brain barrier, the parasite Trypanosoma brucei causes the typical symptoms of sleeping sickness, which is fatal without treatment. Novel anti- trypanosomal agents developed in the SFB 830 are examined in cell cultures for their activity.

tial enzymes from Mycobacterium tu- Central Project berculosis and other pathogens Z1 T. Ölschläger (Institute for Molecular In- fection Biology) Project Area C: Characterization of the A. Stich (Medical Mission Clinic) molecular mechanism of antiinfectives Laboratory for the central evaluation of and predictions for their accelerated potential antiinfective agents optimization

C1 T. Hertel (Institute for Physical and The- Quality Management oretical Chemistry) QM H. Bruhn CARS microscopy, Raman and IR spectroscopy for the localization and characterization of drugs and their interac- Symposia since 2008 tions 2nd International Symposium Novel Agents against Infectious Diseases – C2 P. Jakob (Physical Institute) An Interdisciplinary Approach NMR spectroscopy and imaging for in 7. – 10.10.2009 vivo and in vitro characterization of infections and agents against infectious Joint PhD-student meetings of the SFB disease 630, SFB 544 and SFB 766 New Trends in Infectious Disease Research C3 B. Engels (Institute for Organic Chemis- 10. – 12.11.2004, Würzburg try) 23. – 25.11.2006, Heidelberg Theoretical studies to characterize in- 28. – 29.06.2007, Benediktushöhe Retz- hibition mechanisms and ligand-target bach complexes 20. – 22.11.2008, Kloster Bronnbach 19. – 21.11.2009, Heidelberg C6 T. Dandekar (Institute for Bioinformat- ics) M. Unger (Institute for Pharmacy and Food chemistry) Metabolic and bioinformatical analysis of drug effects on cellular networks exemplified in Candida albicans

C7 C. Sotriffer (Institute for Pharmacy and Food Chemistry) Computational structure-based drug design for the identification and characterization of new inhibitors of antimicrobial targets

139 5.1.6 Collaborative Research Center 688, Mechanisms and Imaging of Cell-Cell Interactions in the Cardiovascular System

Professor Dr. med. Ulich Walter General The adhesion and activation of platelets (Speaker) Information and other cells to the vascular wall, and the local activation of the plasmatic coagulation Institute for Clinical Biochemistry and Cardio- and cerebrovascular diseases ac- is a complex process leading to pathologi- Pathobiochemistry count for most deaths worldwide. The SFB cal thrombus formation. During the last two Oberdürrbacher Str. 6 688 centre grant founded in 2006 and re- years again important new insights have 97080 Würzburg cently extended until 2013 creates a re- been obtained: Tel.: 09931/201-45000 search network involving Würzburg scien- Fax: 0931/201-64500 tists and clinicians from four faculties and By generating transgenic mice the cen- E-mail: [email protected] eleven institutes/clinics of the University. Its tral role of the calcium sensor STIM-1 for www.sfb688.de aim is the understanding of central patho- platelet activation and intravascular throm-

CONTACT DETAILS CONTACT physiological processes in vascular disor- bus formation could first be shown. Impor- Professor Dr. med. Georg Ertl ders such as thrombus formation and of tantly, STIM-1 deficient mice were protect- (1. Vice-Speaker) secondary processes leading to damage ed from cerebral ischemia without bleed- Tel.: 0931/201-39001 and failure of heart, vascular system and ing complications pointing to a new thera- brain. New signalling molecules for cell-cell peutic target in cardio- and cerebrovascu- Professor Dr. rer. nat. Bernhard Nieswandt interactions are aimed to be identified to lar diseases. Moreover, it could be shown (2. Vice-Speaker) create innovative concepts for prevention that polyphosphates released from human Tel.: 0931/31-80405 and treatment of cardio- and cerebrovas- platelets display proinflammatory and pro- cular diseases. coagulant properties. Functional proteome and phosphoproteome analysis of human Of special importance is the development platelets revealed a novel molecular inter- of new magnetic resonance (MR) imaging action between activating (von Willebrand techniques that allow in-vivo monitoring of factor/GPIb) and inhibitory signaling path- disease progression in experimental models ways (soluble guanylyl cylcase) that might and patients with vascular disorders. regulate the fine balance between thrombus formation and bleeding.

Major Research The heart hormones ANP and BNP exert an Interests endocrine function by regulating blood pressure and volume. The corresponding guany- This integrated approach unites comple- lyl cylclase receptor-A (GC-A-R) is expressed mentary areas of research including mo- by the microvascular endothelium. Studies lecular biology, physiology, biophysics, pro- in transgenic mice with an endothelial spe- teomics and bioinformatics, with clinical cific knock-out of their GC-A-R showed that medicine. Molecular and pharmacological the modulation of endothelial permeability murine disease models are generated in the by ANP is decisive for systemic volume ho- SFB that allow clinically orientated groups meostasis. Novel insights have also been to gain new insights into the development obtained into the regulation of the endo- of thrombosis, myocardial infarction and thelial barrier function via cAMP-mediated stroke. Additional emphasis lies on second- Rac1 activation and VE-cadherin as well as ary complications such as oedema and scar on the effects of glucocorticosteroids and formation that strongly influence heart and estrogens at the blood brain barrier. brain function. The use of new MR contrast agents and high field MR imaging (up to The heart is often affected by vascular dys- 17.6 Tesla) in animal models for myocardial function. Recently, the expression of the infarction and stroke shall allow the better microRNA miR-21 could be identified as a surveillance of heart and vascular function novel and predominant mechanism leading in the living organism and provides a further to myocardial fibrosis, hypertrophy and in- link to clinical medicine. sufficiency. Accordingly, antagonizing miR- 21 led to a better functional outcome in a mouse model of heart failure. In another Project Area A (Fundamentals and approach it could be shown that the activa- mechanisms of vascular cell-cell inter- tion of NF-κB in immune cells led to dete- actions) rioration of heart function after myocardial infarction. This project area investigates the initiation of pathological cell-cell interactions espe- The long-term objective of this combined cially of platelets, monocytes, leukocytes research efforts are better therapeutic op- and endothelial cells within the vascular tions for patients with atherosclerosis, myo- system. These cells play a central role for cardial infarction and stroke, among others primary haemostasis, but also for vascular a more effective and safer prevention of thromboses leading to organ dysfunction. thromboembolic events.

140 Project Area B (Molecular and functional imaging of the cardiovascular system and its cell-cell interactions)

This project area encompasses imaging projects with the long-term goal of visualizing the dynamics of lesion development in murine models of vascular diseases in vivo. For this purpose, new MR techniques for the imaging of the vascular system, assessment of cellular infiltration and expression of critical signalling molecules are developed and applied to the disease models generated in Area A. During the last 2 years perfusion and diffusion weighted MR imaging was established in the mouse brain and used to follow study stroke development under antithrombotic treatments. In addition, a novel contrast agent allowed more sensitive detection of blood-brain barrier disturbances. To assess early stages of atherosclerosis in-vivo a technique was developed allowing measurement of pulse wave velocities in the mouse aorta. Thereby it will be possible to compare functional parameters and inflammation within the vessel wall as revealed by iron particle enhanced MRI. Furthermore, mathematical models were developed that allow quantification of cellular and vascular structures by field inho- mogeneities and of their influence on MR Dittrich M, Birschmann I, Mietner S, Sick- signals. mann A, Walter U, Dandekar T (2008) Platelet protein interactions: map, signaling components, and phosphorylation groundstate. Arterioscler Thromb Vasc Biol 28:1326-31.

Kuhn M, Völker K, Schwarz K, Carbajo-Lo- zoya J, Flögel U, Jacoby C, Stypmann J, van Eickels M, Gambaryan S, Hartmann M, Werner M, Wieland T, Schrader J, Baba HA (2009) The natriuretic peptide/guanylyl cyclase - A system functions as a stress- responsive regulator of angiogenesis in mice. J Clin Invest 119:2019-30.

Pham M, Kleinschnitz C, Helluy X, Bartsch AJ, Austinat M, Behr VC, Renné T, Nieswandt B, Stoll G, Bendszus M (2009) Enhanced cortical reperfusion protects co-

SELECTED PUBLICATIONS agulation factor XII-deficient mice from ischemic stroke as revealed by high-field MRI. Neuroimage [Epub ahead of print]

Thum T, Gross C, Fiedler J, Fischer T, Kissler S, Bussen M, Galuppo P, Just S, Rottbauer W, Frantz S, Castoldi M, Sout- schek J, Koteliansky V, Rosenwald A, Bas- son MA, Licht JD, Pena JT, Rouhanifard SH, Muckenthaler MU, Tuschl T, Martin GR, Bauersachs J, Engelhardt S (2008) MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 456:980-4.

Varga-Szabo D, Braun A, Kleinschnitz C, Bender M, Pleines I, Pham M, Renné T, Stoll G, Nieswandt B (2008) The calcium sensor STIM1 is an essential mediator of arterial thrombosis and ischemic brain infarction. J Exp Med 205:1583-91. 141 5.1.7 Transregio-Collaborative Research Center 17, Ras-Dependent Pathways in Human Cancer

General tumor cells. Cancer is most often defined as Information a disease of aberrant cell signaling. While the individual molecules that constitute sig- The Transregio 17 is formed by researchers nal transduction pathways, their biochemi- at the universities of Marburg and Würzburg cal functions and the way they are mutat- and is co-ordinated by Martin Eilers and ed in human cancers are increasingly well Andreas Neubauer. The Transregio started understood, we know very little about how in 2004 and has continued its work for a deregulated signal transduction translates second period after a very positive evalu- into those cellular and clinical phenomena ation in February 2008. In total there are that ultimately dictate the course of the dis- about 20 project leaders and within each ease in the patient. This is particularly true

CONTACT DETAILS CONTACT project there are diploma and PhD students for the Ras pathway, which has emerged as working on their theses. All PhD students a key signal transduction pathway that con- are members of an integrated Graduate tributes to the genesis of a wide variety of Professor Dr. rer. nat. Martin Eilers College, organized by the members of the human tumors. (Speaker Würzburg) Transregio. The projects are subdivided into three areas distributed over the two par- The striking observation underlying much of Chair of Physiological Chemistry II ticipating universities, however, there is a the work in this Transregio is that the out- Theodor-Boveri-Institut für Biowissen- very close interaction between all areas and come of deregulated signaling through the schaften, Biozentrum projects. A special focus of the Transregio is Ras pathway is not stereotype, but is dictat- Am Hubland the integration of clinical and translational ed by the genetic status of the cell. Humans 97074 Würzburg research and the establishment of key tech- harbor protective mechanisms that prevent Tel.: 0931/31-84111 nologies through central facilities and spe- tumor induction by a single mutation of a Fax: 0931/31-84113 cific projects. proto-oncogene such as Ras. As a result, E-mail: [email protected] multiple mutations have to accumulate in a zburg.de single cell before it develops into a tumor. www.imt.uni-marburg.de/tr17/index.php Major Therefore, it is necessary to understand in Research Interests molecular detail how the genetic status of a Professor Dr. med. Andreas Neubauer cell affects the outcome of deregulated sig- (Speaker Marburg) The Transregio aims at understanding how naling through the Ras pathway. This does key cellular properties of tumor cells, such not solely apply to cellular phenotypes, but Department of Haematology, Oncology and as deregulated proliferation, apoptosis, che- also to the clinical phenomena that we ul- Immunology moresistance and metastasis emerge from timately need to understand, like invasion, Philippsuniversität Marburg the interaction between deregulated signal- metastasis and the response to therapy. Baldingerstraße ing pathways and the genetic status of the 35043 Marburg

Fig. 1: Oncogenic transformation by Ras alters the response of acute myelocytic leukemia cells to a cytostatic drug. Control and Ras-transformed cells were treated with cytarabine for 24 hours. Ras-transformed cells stained with May-Grunwald/Giemsa show morphological features of differentiation upon treatment of with cytarabine (Meyer et al., PLOS One 2009).

142 istry I (Stefan Gaubatz, Svenja Meierjohann, Manfred Schartl), Phys- iological Chemistry II (Martin Eilers, Peter Gal- lant) and Internal Medi- cine II (Ralf Bargou).

Symposia

Meeting of the Gradu- ate College of the Tran- sregio Location: Würzburg Res- idenz Date: 06.10.2010 - 08.10.2010 Organizer: Graduate Students

3rd Transregio Meeting Location: Schloss Hirschberg, Beilngries Date: 02.04.2009 - 04.04.2009 Organizer: Martin Ei- lers, Würzburg; Andreas Neubauer, Marburg

Fig. 2: Complexes of the Myc-proteins. The immunofluorescence pictures show the distribution of the Myc-oncoproteins and one of their partner proteins, Miz1 in a growing cell (left) and in a cell expressing the Arf tumor suppressor protein and undergoing apoptosis under the influence of Arf (right). The changes in the localization arise from an Arf-induced modification of Miz1 (Herkert et al., Journal of Cell Biology, 2010).

To approach these questions, the research program concentrates on the elucidation of signal transduction through the Ras pathway (project area A), the analysis of cellular responses to Ras and their genetic control (project area B), and investigation of Ras-dependent signaling in human tumors (project area C). Key technologies supplied by members of the Transregio are the development of animal models for understanding Ras dependent pathways in human cancers, gene expression profiling, high-throughput RNAi screening using high- content microscopy, tissue-based pathology and mass-spectrometry assisted protein analysis.

The research teams from the Medical Facul- ty of Würzburg include Physiological Chem-

143 5.1.8 Transregio-Collaborative Research Center 34, Pathophysiology of Staphylococci in the Post-genomic Era

PD Dr. rer. nat. Knut Ohlsen General pathogen constitutes an essential step to- (Speaker Würzburg) Information wards the development of new antibacterial approaches to combat S. aureus infections. Institute for Molecular Infection Biology The aim of this SFB/Transregional collabora- In the SFB/TR34 projects, the great poten- Josef-Schneider-Str. 2 tive research center (TR34) is to take advan- tial of functional genomics will be used to 97080 Würzburg tage of the great opportunities offered by the accomplish such a new quality in the com- Tel.: 0931/31-82155 post-genome era to achieve a new quality prehension of S. aureus physiology and in- Fax: 0931/31-82578 of understanding of the life processes of the fection biology, leading finally to a better un- [email protected] important human pathogen Staphylococcus derstanding of the entire infection process. www.uni-greifswald.de/forschen/sonderforsc- aureus. To reach this ambitious aim the ex- The projects of the groups in Würzburg deal hungsbereiche/staphylokokken.html pertise of groups in Tübingen and Würzburg especially with different aspects of host-

CONTACT DETAILS CONTACT in cell physiology/biochemistry and infection pathogen interactions. Project part A2 stud- Professor Dr. rer. nat. Michael Hecker biology of Staphylococcus aureus in gener- ies eukaryotic-type serine/threonine protein (Coordinating Speaker) al is combined with the established exper- kinases (ESTPKs) and protein phosphatas- tise in proteomics of Gram-positive bacte- es that are probably involved in the regula- Institute for Microbiology and Molecular ria in Greifswald. The research projects are tion of several physiological pathways. The Biology grouped in three parts: in part A (5 proj- outcome of this work will open a new field Friedrich-Ludwig-Jahn-Straße 15 ects), the general physiology of S. aureus in signal transduction. Comparative protein 17487 Greifswald is considered, dealing with such essential expression/mRNA profiling of the wild-type chapters as the regulation of metabolism, and the corresponding mutants will provide and the stress and starvation responses data on the physiological role of both pro- with a tight connection to its pathophysiol- teins. Furthermore, mutant constructions ogy, a theme that has frequently been un- followed by a structural analysis of the ki- derestimated in the past. The regulation of nase will explore the structure and function cell-surface-bound and extracellular viru- of these proteins. Moreover, phosphopro- lence factors constitutes the focus of part teome analysis will be performed to unravel B (5 projects). Project area C (5 projects) the function of the kinases and correspond- deals with the behavior of the pathogen in ing phosphatases in S. aureus to identify the host and will provide new information on putative substrates of kinase and phospha- the host-pathogen interaction. tase activity (Fig. 1).

In the A5 project, modern techniques of Project leader Würzburg: bioinformatics are applied for modelling of PD Dr. K. Ohlsen (A2) metabolic and cellular networks and en- Prof. Dr. T. Dandekar (A5) zyme cascades to describe the physiology PD Dr. W. Ziebuhr (B4) of different staphylococcal strains under Prof. Dr. Dr. h.c. mult. J. Hacker (C2, C3) different growth conditions. Different func- Prof. Dr. A. Szalay (C3) tional genomics and system response data Prof. Dr. Dr. B. Sinha (C6) are integrated to model central metabolism (e.g. central carbon metabolism) and the stress and adaptation network during dif- Major Research ferent stages of the growth cycle in vitro. Interests These models will then be expanded to the metabolism of S. aureus in general. A new Staphylococcus aureus is a human patho- and emerging field that is becoming the in- gen of increasing importance, mainly as a creasing focus in model bacteria such as E. result of the spread of antibiotic resistanc- coli and B. subtilis is the role of small regu- es. The pathogenicity of this species is very latory RNAs in cell physiology. These RNAs complex and involves the strongly regulat- are significantly involved in stress adapta- ed synthesis of cell surface-associated and tion of bacteria, and it can be expected that extracellular proteins forming a highly vari- these crucial molecules also play a role in able set of virulence factors. Due to the the control of virulence. This novel problem great variety of these proteins, S. aureus is being addressed in project part B4. Spe- causes a broad spectrum of infectious dis- cifically, a sRNA was found that is encoded eases ranging from superficial abscesses of upstream of the ica-operon in S. epidermi- the skin to endocarditis, osteomyelitis, toxic dis which is probably involved in the regu- shock syndrome, and sepsis. Methicillin-relation of the ica-expression. This small RNA sistant S. aureus (MRSA) strains are cur- could thus influence pathogenicity via pro- rently predominant and dangerous nosoco- duction of PIA (polysaccharide intercellular mial pathogens, since infections caused by adhesin), synthesized by enzymes encod- these strains have become difficult to treat. ed by the ica-operon, and therefore con- It is generally accepted that a more holistic stitutes a good starting point for the analy- understanding of the cell physiology of this sis of the role of regulatory RNAs. In addi-

144 Fig. 1: Phophoproteome analysis of Staphylococcus aureus wild-type strain 8325 and isogenic ser/thr kinase ∆pknB. Phospoproteins were visualized with proQ dye (red spots).

tion, a bioinformatic approach that aims at Symposia the prediction of additional small RNAs will be followed. Subsequently, such new small Internationales Symposium “Pathophysiol- regulatory RNAs can be analyzed for their ogy of Staphylococci”, Kloster Banz 28. – role in cell physiology, stress adaptation, 31. October 2008 and virulence.

The analysis of the interplay between the S. aureus and its host environment is the focus of project C2. Transcriptional profiling using microarray technologies as well as proteomics approaches are utilized to determine the global responses of host cells and pathogens in the host-pathogen interaction. The project part C3 relies on innovative imaging procedures that should allow the real time visualization of the expression of selected genes at different locations in the host and to study the dynamics of staphylococcal infections by using non-invasive techniques. By means of bioluminescence monitoring and confocal laser microscopy, the interaction between the bacterium and the host is being studied on cellular and subcellular level. The high resolution of this technique allows a very detailed description of molecular interactions and the local recruitment of factors of the host and the bacterium, respectively. Using these techniques, the kinetics of S. aureus infection can be directly followed in the host providing new insights into the processes of host-pathogen interaction. The understanding of these mechanisms serves as the basis for the development of new concepts to combat infections caused by staphylococci. The C3 project deals with the fate of the S. aureus–containing phagosomal compartment after invasion of host cells. The fate of this compartment and delineate virulence factors involved in phagosomal modulation/ escape is studied. In addition, the fate of S. aureus residing in this compartment and its adaptive response to this environment is investigated using a combination of functional genomics and cellular microbiology.

145 5.1.9 Transregio-Collaborative Research Center 52, Transcriptional Programming of Individual T-Cell Subsets

Professor Dr. rer. nat. Dr. sc. nat. Edgar of lymphocytes by assembly of DNA seg- Serfling (Speaker) Structure ments that are separated in the germ line genome as well as by somatic mutations. Institute of Pathology Project group A: Transcriptional Program- These manifold genetic changes occur dur- Josef-Schneider-Str. 2 ing of Regulatory T-Cells ing the complex process of differentiation of 97080 Würzburg haematopoietic stem cells to lymphocytes, Tel.: 0931/201-474-31 Project group B: Transcriptional Program- which primarily takes place in the bone mar- Fax: 0931/201-471-31 ing of Effector T-Cells by T-Cell row and, in the case of T-lymphocytes, in E-mail: [email protected] Receptor and Co-Receptor Signals the thymus. The differentiation of lympho- www.pathologie.uni-wuerzburg.de/forschung/ cytes is regulated by finely tuned transcrip- transregio_52/ Project Group C: Animal Models for the tional control mechanisms which, in the CONTACT DETAILS CONTACT Analysis of Defective Transcription in T- case of defects such as the deficiency in Cells certain transcription factors, can lead to the Professor Dr. Edgar Schmitt (Speaker Mainz) loss of further differentiation. Institute for Immunology Z projects: University of Mainz Obere Zahlbacher Str. 67 Research 55101 Mainz Major Research Interest Interest Professor Dr. Richard Kroczek (Speaker Berlin) Through complex interactions, the cells of Robert-Koch-Institute The Transregional Collaborative Research the immune system initiate and uphold an Nordufer 20 Center (Transregio, TR) TR52 – Wuerz- “adaptive” immune response until invad- 13353 Berlin burg/Mainz/Berlin - has been established in ing pathogens have been destroyed. How- 2008 by the DFG and started its scientific ever, the effector cells in the immune sys- activities on July 01, 2008. tem can also get out of control and thus become the cause for life threatening dis- The long term research aim of this newly eases themselves. This is the case in au- founded TR52 is to gain new scientific in- toimmune disorders and severe allergies. sights into the function of T-lymphocytes. In the case of autoimmune diseases, the This shall be achieved through the intensi- immune system erroneously attacks the fication and concentration of scientific re- body’s own tissue. When we lose the ca- search on the transcriptional control of gene pability to differentiate between harmless expression in this vital population of lym- antigens and hazardous pathogens, aller- phoid cells. Thereby, it is the aim to merge gies can occur, which represent “exces- the different fields of expertise of laborato- sive” reactions to otherwise harmless sub- ries in Würzburg, Mainz and Berlin, each of stances in the environment. The basis of whose work is devoted to different aspects both disease forms is a loss of balance in of T-cell biology. The expected findings are our immune system to be ready to defend intended to significantly broaden our insight us against infectious agents, while at the into the regulation of transcription, one of same time being tolerant towards harm- the fundamental steps in the control of the less environmental antigens and struc- immune system. They will contribute to ren- tures of our own bodies. In the case of dering the development of causal therapeu- T-lymphocytes, this tolerance is achieved tic approaches to frequent diseases of the mainly through positive and negative se- immune system, above all auto-immune lection of thymocytes. In the thymus, dou- disorders and allergies, in future. ble-positive thymocytes with „correct“ T- cell receptors are propagated, while those with dysfunctional or auto-aggressive re- Major Research ceptors are deleted through apoptosis. Activities At present, allergies such as asthma, rhi- T- and B-lymphocytes are at the heart nitis and allergic skin reactions are among of the adaptive immune system of verte- the most common disorders in western in- brates, which was formed with these dur- dustrialized nations and their importance is ing evolution approximately 400 million constantly increasing. They are based upon years ago. These cells are equipped with imbalances and hyper reactivity of periph- the unique capability to identify antigens as eral T-lymphocytes. An increased number foreign with the help of their immune re- of Th2-cells, which secrete large amounts ceptors and thereby to initiate the immune of IL-4, IL-5 and IL-13 are a typical trait of response which protects the organism from these diseases. Although much has been infections. The functional genes for immune learned concerning the molecular mecha- receptors, i.e. T- and B-cell receptors, only nisms of Th1/Th2-cell differentiation, very emerge during the somatic development little is still known concerning the signals

146 as GATA-3, STAT6, Foxp3 and Runx factors (TPA3 [Friederike Berberich-Siebelt] and TPA8 [Stefan Gattenlöhner]). This shall be achieved in collaboration with further laboratories. These are the Proteomics facility at the Rudolf-Virchow-Center of Experimen- Von besseren Tiermodellen bis hin zu kausalen Therapien von Autoimmunkrankheiten tal Biomedicine guided by Albert Sickmann and the Institute of Immunology, Mainz Basic Research Verification Clinical (head: E. Schmitt). By using the TAP tech- Studies Preclinical Mouse Improvement nology and protein sequencing facilities in Models & Refinement A. Sickmann`s team, in TPA3 multi-protein complexes formed with selected TFs will be isolated and characterized.

The close scientific contacts between the Department of Molecular Pathology and the Institute of Virology and Immunobiology of Univ. Würzburg (Head: Thomas Hünig) are reflected in the participation of two immu- Mouse Humanized Mouse Human nological research laboratories directed by Thomas Hünig and Manfred Lutz. While the scientific work in Thomas Hünig`s team is Fig. 1: The vision of the Transregio TR52: The generation of scientific knowledge, mainly devoted to various aspects of CD28 struc- by establishing new animal models for human diseases, should lay the ground for new ture, expression and function, the project rational therapies. Autoimmune diseases like inflammatory gastro-intestinal diseases (eg proposed here (TPA5) deals with the stimu- Morbus Crohn) and asthma are major areas of interest. latory role which CD28 signals play in the generation, homeostasis and function of regulatory T cells. Manfred Lutz` major interest summarized in his project application (TPB7) is devoted to the role of program- that lead to the frequently fatal conse- Research Activities ming Th2 effector cells by differentially ma- quences of these atopic reactions via STAT6 in Würzburg tured dendritic cells. and, above all, GATA-3. This TR52 is based on long-standing ex- Numerous projects of TR52 will profit from These examples show that the transcrip- perimetal collaborations that started more the participation of Andreas Beilhack (Medi- tional control of differential gene expression than 10 years ago between research labo- cal Clinic and Policlinic II, Univ. Würzburg), determines cellular differentiation, which is ratories of Universities of Würzburg (Dept. of a young expert in bioluminescence imag- expressed in the differentiation of naïve T- Molecular Pathology) and Mainz (Institute ing, who leads the Central core project Z2, cells into effector T-cells and memory T- of Immunology). One result of these col- In vivo imaging. cells. However, the underlying molecular laborations are more than 10 manuscripts mechanisms and their effects on the devel- which were published in (or have been sub- opment and activity of the adaptive immune mitted to) excellent scientific journals. system are largely unknown. This is based in part on the complexity of the transcrip- The experimental work of Department of tion process as well as on the complexity Molecular Pathology (Head: E. Serfling) at of the adaptive immune system itself. As the Institute of Pathology of University Würz- is the case in protein biosynthesis, more burg is devoted to the transcriptional con- than fifty, more probably hundreds of pro- trol of lymphokine genes in T lymphocytes, teins are involved in the transcription of a in particular to that of IL-2, IL-4 and IL-5 single gene, which together form the gen- genes. This work led to a detailed analy- eral transcription machinery, the transcrip- sis of NFAT transcription factors whose in- tion complex, and the chromatin proteins. duction - by increasing elevated Ca++ lev- The activity of many of these (nuclear) pro- els and calcineurin-mediated signals – ap- teins is controlled by receptor-mediated sig- pears to be unique for the activation of lym- nals and is responsible for the differentia- phocytes. In the TR, the experimental work tion of haematopoietic precursor cells into shall be extended by (1.) studies on the ex- effector T-cells, which in turn control the im- pression and function of individual NFATc1 mune system. One of the significant goals isoforms (TPC5; E.S. & Andris Avots) and of this TR is to unravel the complexity of the characterisation of DNA sequence el- these processes. A further aim is to intro- ements and TFs controling NFATc1 expres- duce the findings achieved into the causal sion in vivo (B2; Andris Avots & E.S.) and treatment of human autoimmune and al- (2.) the analysis of interaction of NFATc fac- lergic disorders. tors with further transcription factors, such

147 5.1.10 Transregio-Collaborative Research Center 58, Fear, Anxiety, Anxiety Disorders

Mission development of fear in animal models. Professor Dr. med. Jürgen Deckert and Structure Studies of serotonin-transporter knock-out (Speaker Würzburg) mice as best-established animal model of The Transregio-SFB 58 was initiated in July fear with regard to the impact of pre- and Department of Psychiatry, Psychosomatics 2008 and comprises work groups of the postnatal stress on subsequent behav- and Psychotherapy Universities of Hamburg, Münster and Würz- iour and epigenetic programming (Lesch, Füchsleinstrasse 15 burg. The speakers are C. Büchel (Ham- Schmitt, Seidenbecher, Sachser) are com- 97080 Würzburg burg, deputy speaker), H.-C. Pape (Mün- plemented by studies of neuronal plasticity Tel.: 0931/201-77010 ster, speaker) and J. Deckert in Würzburg of amygdaloid networks and the role of syn- Fax: 0931/201-77020 (deputy speaker). Altogether, over 40 sci- chronized neuronal activity with a special fo- E-mail: [email protected] entists collaborate in 13 subprojects of the cus on the GABA-A and the endocannabi- http://sfbtrr58.uni-muenster.de/ CONTACT DETAILS CONTACT SFB-TRR 58 in an interdisciplinary way and noid system (Pape, Lutz). The mechanisms numerous graduates and Ph.D. students of safety learning as a process of relevance undergo research training in a structured for therapy is studied in drosophila mutants Professor Dr. Hans-Christian Pape Ph.D. program, at Würzburg in the context (Gerber). (Coordinating Speaker) of the GSLS and the GK1156. Institute for Physiology I In research area B – behavioural science Westfälische Wilhelms-Universität Münster Fear and anxiety, the two phylogenetic old- - healthy subjects are investigated on mul- Robert-Koch-Str. 27a est emotions, are in the focus of research. tiple levels with experimental psychophysi- 48149 Münster These emotions may emerge in pathologi- ological paradigms for fear and anxiety –rel- cal anxiety states in humans and as anxiety evant processes such as perception, condi- Professor Dr. Christian Büchel disorders are important precursors of de- tioning and extinction. In each experiment, (Speaker Hamburg) pressive disorders, both being the two most the genetic modulation (e.g. by variations common mental disorders. Together with in the NPS receptor gene or in the endo- colleagues from the other two universities, cannabinoid system) of the behavioural re- the scientists in Würzburg want to explore sponse is scrutinized. Startle studies on cue the development of anxiety in its physiologi- versus context fear conditioning in virtual re- cal as well as pathological form on a com- ality (Pauli, Mühlberger) are applied as well prehensive and integrative basis from the as functional magnetic resonance imaging gene over the single cell and complex cell studies to display neuronal correlates of networks to human behaviour and back. fear-relevant prediction errors (Büchel). An Obtaining a better understanding of the un- alternative approach is pursued by the last derlying complex molecular and psychologi- project of this area (Engel, Büchel) which cal mechanisms of the development and re- explores the impact of cerebral coherence mission of pathological anxiety will hopefully on emotional and cognitive modulation of lead to innovative and individualized treat- stimulus salience using magnetoencepha- ment strategies. lography.

Research area C – translational science - Research focuses on the investigation of pathomech- topics anisms relevant for anxiety disorders. Using again magnetencephalography, fast neuro- Aim of the Transregio-SFB is to explore the nal processes in multimodal fear condition- pathogenesis of physiological and patholog- ing and extinction and their modulation by ical anxiety from the gene level to humans transcranial magnetic stimulation are inves- suffering from panic disorder in a transla- tigated (Junghöfer, Pantev and Zwanzger). tional approach. To do so, molecular biol- In the second project, the emotional per- ogists and neurophysiologists, physicists ception of fear-relevant stimuli and their and psychologists, neurologists and psychi- modulation by dopamine or caffeine is in- atrists closely work together in an interdis- vestigated (Domschke, Deckert). The func- ciplinary manner (Figure 1). Results from tion of the prefrontal cortex and its modu- model organisms like knock-out mice and lation by transcranial magnetic stimulation. drosophila will be validated in humans by as a possible innovative therapy approach innovative experimental approaches (imag- is explored by fMRI and fNIRS in patients ing genomics, pharmacogenomics). Genet- suffering from panic disorder (Figure 2) in ic findings in humans will in turn be experi- the third project (Fallgatter, Ehlis). The role mentally verified in animal models (reverse of genetic variants is again under investiga- genetics). To achieve these aims, the TRR- tion in all three projects. SFB 58 consists of three closely connected areas of research: A large (n=1500) cohort with ex ante phe- notypically and genetically well defined con- Research area A - basic science - ex- trol subjects for the studies of areas B and plores the molecular mechanisms of the C is made available by the central proj-

148 Symposia

International Sympo- sium on Fear, Anxi- ety, Anxiety Disor- ders; Münster, 10.- 12.12.2009

Fig. 1: From mice to men and back: Combining basic, behavioural and translational science at three university sites (Ham- burg, Münster and Würzburg) as exemplified by the central project Z2 (Deckert, Reif and Pauli).

ect Z2 (Deckert, Reif, Pauli). In addition, this project deals with the complex genetics of fear-and anxiety-relevant behaviours and thus provides new candidate molecules for research area A.

At the University of Würzburg, the following institutions are involved: Medical Faculty, Department of Psychiatry, Psychosomatics and Psychotherapy (project leaders: J. Deckert, A.-C. Ehlis. A.J. Fallgat- ter, K.P. Lesch, A. Reif, A. Schmitt); Faculty of Philosophy, Institute of Psychol- ogy I (project leaders: A. Mühlberger, P. Pau- li); Faculty of Biology, Chair of Genetics and Neurobiology (project leader: B. Gerber).

Fig. 2: Effects of NIRS-guided facilitating rTMS treatment in patients with panic disorder: Protocol of project C4 (Fallgatter and Ehlis).

149 5.2 Research Centers 5.2.1 Rudolf Virchow Center / DFG Research Center for Experimental Biomedicine

Professor Dr. med. Martin Lohse General strengthen collaborations with researchers (Chairman) Information in Würzburg the RVZ Network program was added. In addition to research, the Rudolf Versbacher Str.9 In 2001, the University of Würzburg won ap- Virchow Center was also involved in con- 97078 Würzburg proval in the context of the first nationwide ceiving and establishing the new Bachelor Tel.: 0931/201-48400 competition of the German Research Foun- and Masters Program in Biomedicine, ini- Fax: 0931/201-48702 dation for Research Centers. The concept tiated in the winter term 2001/02 at the E-mail: [email protected] of the Rudolf Virchow Center was chosen University of Würzburg and is now coordi- www.rudolf-virchow-zentrum.de among 80 submitted concepts. After recon- nating the Program. A “Graduate School” struction of the temporary accommodation, for Biomedicine was developed that has be- Professor Dr. Dr. Stefan Engelhardt (until 2008) the Center was founded in 2002. In July come the nucleus for a large-scale reform

CONTACT DETAILS CONTACT (Cardiac Target Proteins) 2009, researchers of the Rudolf Virchow of graduate training at the University and Center and the Center for Infectious Dis- culminated in the foundation of the “Grad- Professor Dr. Antje Gohla (since 2009) ease Research moved together into a new uate School of Life Sciences“. This school (Biology of Cytoskeleton) building, the former surgical hospital. Al- won approval in the context of the national Tel.: 0931/201-48977 most 10.000 m2 of space with excellent fa- “Excellence Initiative” in the fall of 2006. cilities are now open for research, teaching Finally, the “Public Science Center“ offers Professor Dr. Gregory Harms and training, as well as events for the pub- several courses for pupils. (Molecular Microscopy) lic. The overall cost of the building was 78 Tel.: 0931/31-80357 million Euro, covered by the Federal Gov- ernment and Bavarian Government. Major Research Professor Dr. Manfred Heckmann (since 2008) Interests (Synapse Architecture) The center spans multiple faculties and was Tel.: 0931/31-82731 therefore established as a central institution At the time of reporting eleven research of the University. Group leaders, if they are groups and five projects within the RVZ Dr. Heike Hermanns professors, belong to the Medical Faculty or Network are established at the Rudolf Vir- (Cellular Signal Transduction) have a dual membership in another faculty. chow Center. Research groups work on “tar- Tel.: 0931/31-80362 The Rudolf Virchow Center is composed of get proteins“. The research pursued at the different elements in research and teaching Center can therefore be grouped into four Dr. Asparouh Iliev (Fig. 1). Its interdisciplinary research focus- Research Fields: (1) Protein Structure and (Membrane/Cytoskeleton Interactions) es on „target proteins“, that are analyzed at Function, (2) Proteins in Cellular Signaling, Tel.: 0931/201-48997 several levels from molecules to diseases. (3) Nucleic Acid Binding Proteins, and (4) Proteins in Cell-Cell Interactions and Mo- Professor Dr. Caroline Kisker Right from the beginning the Rudolf Vir- tility. The main projects reflect the focus (Structural Biology: DNA-Repair and Struc- chow Center´s intention was to create in- on cell surface proteins and their signaling ture-Based Drug-Design) novative structures within a University. An proteins, and on nucleic acid binding pro- Tel.: 0931/31-80381 Institute for Junior Research Groups was teins. established, providing junior scientists the Dr. Stephan Kissler possibility to work independently with the (Immune Tolerance) option of extension into temporary research Biology of Cytoskeleton Tel.: 0931/31-80367 professorships (tenure track) for excellent (A. Gohla) Professor Dr. Bernhard Nieswandt group leaders. To ensure the transfer into (Vascular Biology) industry one group is funded by industry Failure of cells to migrate, or migration of Tel.: 0931/31-80406 and the Bavarian Ministry of Economics. The Core Cen- Professor Dr. Hermann Schindelin ter comprises groups that (Structural Biology: Protein Folding, Function develop and utilize innova- and Degradation) tive and special research Tel.: 0931/31-80382 methods. Excellent established scientists have the Professor Dr. Michael Schön (until 2008) possibility to concentrate (Inflammation and Tumor Biology) on a five-year, high-risk project as Research Profes- Professor Dr. Albert Sickmann (until 2008) sors on the model of Ameri- (Functional Proteomics) can Howard Hughes professorships. The Bio-Imaging Professor Dr. Stephan Sigrist (until 2008) Center is a new entity and (Synapse Architecture) comprises at present three and is planned to hold four Dr. Alma Zernecke (since 2009) research groups funded by (Immunopathogenesis of Arteriosclerosis) the State of Bavaria and Tel.: 0931/31-80373 the University of Würzburg as basic funding. In order to Fig. 1: Structure of the Rudolf Virchow Center.

150 cells to aberrant locations, is intricately in- Structural Biology: DNA-Repair and volved in pathologies including vascular and Structure-Based Drug-Design inflammatory diseases as well as in tumor (C. Kisker) formation and metastasis. Effective cell adhesion and migration are based on the pre- It has been shown that 80 to 90% of all cise integration of localized, transient sig- human cancers are due to DNA damage. naling events with changes in the cytoskel- Among the various DNA repair mechanisms eton and appropriate cell-cell and cell-ma- available to the cell nucleotide excision re- trix interactions. The goal is to understand pair (NER) stands out because of its broad the physiological and pathological functions substrate specificity. The group aims to un- of the newly identified phosphatases Chro- derstand the fundamental mechanisms of nophin and AUM, which emerge as major the bacterial and mammalian NER machin- regulators of Rho-GTPase-dependent cyto- ery. Since damage can accumulate and may skeletal dynamics. not be repaired prior to replication and due to the role of DNA polymerases in certain diseases, the group also analyzes different Molecular Microscopy DNA polymerases and their role in genetic (G. Harms) maintenance. A second focus is structure- based drug design to identify new therapeu- The research group studies molecular inter- tics against infectious diseases. actions in cell signaling of membrane proteins and cytosolic messengers like platelet adhesion through the Src kinase family, and Fig. 2: Molecular mechanisms are linked Immune Tolerance growth and development through the Bone to cardiovascu¬lar diseases: Lipid depos- (S. Kissler) Morphogenetic Protein (BMP)/Smad path- its stained by Oil-red-O in an atheroscle- way. Therefore the group uses techniques rotic lesion in the aortic root of an apoli- While our Immune system is tightly regulat- like fluorescence resonance energy trans- poprotein E-deficient mouse transplanted ed and usually recognizes only harmful anti- fer (FRET) microscopy, single-molecule mi- with cx3cr1+/gfp bone marrow and fed on genes like pathogens, a significant number croscopy and dynamic confocal microscopy. a high fat diet (left panel); immunfluores- of people react to self-antigens and devel- These microscopes allow the detection of cence staining was performed for mono- op autoimmune diseases. The group seeks low, endogenous levels of proteins in and cytes/macrophages (using the marker to understand the genetic polymorphisms on living cells. Key objectives are the de- MOMA-2, red) in co-localization with gfp+ that predispose individuals to autoimmuni- velopment of biosensors and imaging tech- cells (green), cell nuclei were counter- ty and the regulatory pathways that fail dur- niques. stained with DAPI (blue, right panel). ing onset of disease. The main approach is the genetic manipulation of model organ- lecular complexes. This explains why many isms by RNA interference (RNAi). Therefore Synapse Architecture of the signaling cascades are common to lentiviral transgenesis is used to generate (M. Heckmann) a number of different cytokines, but leaves animals in which target genes are consti- the question of signaling specificity open. tutively silenced by RNAi. After pioneering The birth of synaptic connections between Using the family of interleukin-6-type cyto- nerve cells is an intriguing developmental kines as a model system the laboratory in- period that paves the way for the complex vestigates this question. functions executed by nervous systems. If A. Gohla Kurig, B., Shymanets, A., Bohnacker, the intricate network between neurons is T., Prajwal, Brock, C., Ahmadian, M.R., improperly formed during embryogenesis or Membrane/Cytoskeleton Interactions Schäfer, M., Gohla, A., Wymann, M.P., is subsequently injured, network malfunc- (A. Iliev) Jeanclos, E., Nürnberg, B. (2009) Ras is tions cause severe disability. How synapses an indispensable coregulator of the class IB are established during embryogenesis and Streptococcus pneumoniae is a common phosphoinositide 3-kinase p87/p110. Proc Natl Acad Sci USA, 106(48):20312-7. by which molecular means their highly spe- pathogen causing the most frequent form of cialized properties are maintained through- bacterial meningitis. A major virulence fac- G. Harms out a lifetime is studied in this group (see tor of S. pneumoniae is the pore-forming Gromova, K., Friedrich, M., Noskov, A., also 2.5, page 24). toxin pneumolysin. It induces rapid cell lysis Harms, G.S. (2007) Visualizing SMAD1/4 signaling response to Bone Morphogenetic or apoptosis in a concentration-dependent Protein-4 activation by FRET biosensors. manner. The serious outcome and progno- BBA Mol. Cell Res, 1773, 1759-1773. Cellular Signal Transduction sis of pneumococcal meningitis contrast (H. Hermanns) with the limited presence of cell death. The M. Heckmann aim of the project is to clarify the molecu- Meuth, S.G., Herrmann, A.M., Simon, O.J., Siffrin, V., Melzer, N., Bittner, S., Deregulated cytokine signaling is involved lar steps leading to the small GTPase acti- Meuth, P., Langer, H.F., Hallermann, S., in the pathogenesis of a large number of vation, to redistribution of the cytoskeleton SELECTED PUBLICATIONS Boldakowa, N., Herz, J., Munsch, T., diseases including chronic inflammation, and to changes in cell signaling of neuronal Landgraf, P., Aktas, O., Heckmann, M., autoimmunity and cancer. A large number target cells after pneumolysin challenge. Lessmann, V., Budde, T., Kieseier, B.C., Zipp, F., Wiendl, H. (2009) Cytotoxic of cytokines transduces signals via shared CD8+ T cell-neuron interactions: perfo- cell surface receptors that form multi-mo- rin-dependent electrical silencing precedes but is not causally linked to neuronal cell 151 death. J Neurosci, 29(49):15397-409. this strategy in the model for type 1 dia- to X-ray crystallography. Mis-folding and ag- H. Hermanns Radtke, S., Wüller, S., Yang, X.P., Lippok, betes, the group is now refining lentiviral gregation due to defects in the endoplasmic B.E., Mütze, B., Mais, C., Schmitz-Van de technology to make its application for the reticulum associated degradation (ERAD) Leur, H., Bode, J.G., Gaestel, M., Heinrich, study of immune tolerance more versatile pathway, for example, lead to a variety of P.C., Behrmann, I., Schaper, F. and Her- and specific. pathophysiological states, such as the neu- manns, H.M. (2010) Cross-regulation of rodegenerative disorders of Alzheimer’s and cytokine signalling: proinflammatory cytokines restrict IL-6 signalling through recep- Parkinson’s disease. tor internalisation and degradation. J. Cell. Signalling Processes of Receptors Sci. in press. (M. Lohse) Immunopathogenesis of Arteriosclero- A. Iliev Iliev, A.I., Djannatian, J.R., Opazo, F., Ger- Cyclic nucleotides – cyclic AMP (cAMP) and sis ber, J., Nau, R., Mitchell, T.J., Wouters, cyclic GMP (cGMP) – belong to the most (A. Zernecke) F.S. (2009) Rapid microtubule bundling ubiquitous intracellular messengers. Both and stabilization by the Streptococcus are produced in response to multiple stim- Atherosclerosis is imminently becoming the pneumoniae neurotoxin pneumolysin in a uli, act on several intracellular targets, and leading cause of death worldwide. Impor- cholesterol-dependent, non-lytic and Src- kinase dependent manner inhibits intracel- regulate a vast array of biological functions. tantly, immune responses are described to lular trafficking. Mol Microbiol, 71(2):461- However, in spite of the fundamental im- participate in all phases of atherosclerosis. 77. SELECTED PUBLICATIONS portance of these signaling systems, very The exact functions of immune cells in con- little is known about the temporal and spa- trolling the development of atherosclerosis, C. Kisker Wolski, S.C., Kuper, J., Hänzelmann, P., tial patterns of their production and action. however, remain elusive to date. By tar- Truglio, J.J., Croteau, D.L., Van Houten, B., To gain an insight into these dimensions, geting specific chemokines/ cytokines and Kisker, C. (2008) Crystal structure of the the group develops methods to create im- their receptors the group addresses the role FeS cluster-containing nucleotide excision ages of these second messengers in intact of different immune cell subpopulations in repair helicase XPD. PLoS Biol. 6(6):e149. cells, and to resolve these intracellular sig- atherosclerosis. The focus is to study cel- PMID: 18578568. nals in space and in time (see also 2.16, lular constituents and understanding the S. Kissler page 46). complex equilibrium and interplay between Thum, T., Gross, C., Fiedler, J., Fischer, T., immune-cell subpopulations. Kissler, S., Bussen, M., Galuppo, P., Just, S., Rottbauer, W., Frantz, S., Castoldi, M., Soutscheck, J., Koteliansky, V., Rosenwald, Vascular Biology A., Basson, M.A., Licht, J.D., Pena, J.T.R., (B. Nieswandt) Rouhanifard, S.H., Muckenthaler, M.U., Teaching Tuschl, T., Martin, G.R., Bauersachs, J., At sites of vascular injury, blood platelets and Engelhardt, S.(2008) MicroRNA-21 come into contact with the subendothelial All groups offer internships and lectures for contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. extracellular matrix, which triggers their ac- students of the Bachelor and Masters Pro- Nature, 456, 980-984. tivation and the formation of a hemostatic gram in Biomedicine. Annual symposia and plug. This process is crucial to limit post- conferences are held for scientists from M. Lohse traumatic blood loss, but may also lead to medicine and the natural sciences. Gradu- Lorenz, K., Schmitt, J.P., Schmitteckert, E.M., Lohse, M.J. (2009) A new type of pathological thrombus formation, causing ate students at the Center are members of ERK1/2-autophosphorylation causes car- diseases such as myocardial infarction or the in the graduate program “Virchow Grad- diac hypertrophy. Nature Medicine. 15, stroke. The group uses genetically modified uate Program „ that belongs to the Section 75-83. mouse lines in combination with disease Biomedicine of the “Graduate School of Life models to identify new strategies to inhib- Sciences”. B. Nieswandt Berna-Erro, A., Braun, A., Kraft, R., Klein- it the thrombotic and/or pro-inflammatory schnitz, C., Schuhmann, M.K., Stegner, D., activity of the cells, while preserving their Wultsch, T., Eilers, J., Meuth, S.G., Stoll, hemostatic function (see also 3.25, page G., Nieswandt, B. (2009) STIM2 regulates 112). capacitive Ca2+ entry in neurons and plays a key role in hypoxic neuronal cell death. Sci Signal, 2(93):ra67. Structural Biology: Protein Folding, H. Schindelin Function and Degradation Lee, I., Schindelin, H. (2008) Structural in- (H. Schindelin) sights into E1-catalyzed ubiquitin activation and transfer to conjugating enzymes. Cell. 134, 268-78. The group focuses on protein folding in the endoplasmic reticulum (ER) and degrada- A. Zernecke tion of mis-folded proteins via the ubiquitin- Zernecke, A., Bidzhekov, K., Noels, H., Shagdarsuren, E., Gan, L., Denecke, dependent protein degradation pathway. B., Hristov, M., Köppel, T., Jahantigh, Second, they are interested in the struc- M.N., Lutgens, E., Wang, S., Olson, E.N., ture and function of inhibitory neuronal re- Schober, A., Weber, C. (2009) Delivery of ceptors and the mechanism of their anchor- microRNA-126 by apoptotic bodies inducing at the postsynaptic membrane. There- es CXCL12-dependent vascular protection. Sci Signal, 2(100):ra81. fore the group uses a combination of complementary techniques for the biochemical and biophysical characterization in addition

152 5.2.2 Interdisziplinary Center for Clinical Research (IZKF)

Professor Dr. rer. nat. Thomas Hünig General A: Pathological Aspects of Inflamma- (Chair) Information tion

Institute of Pathology The IZKF Würzburg organizes the internal re- B: Tumor/Host-Interactions Josef-Schneider-Straße 2 search funding of the Medical Faculty. Its 97080 Würzburg major goal is to strenghten clincial research D: Transplantation and Tissue Engineer- Tel.: 0931/201-47794 based on interdisciplinary cooperations being Fax: 0931/201-47414 tween clinical research groups and groups E-mail: [email protected] of the biomedical sciences. The budget is E: Cardiac and Vascular Disorders www.izkf-wuerzburg.de fixed at approximately 5 millions Euro per annum. F: Imaging

CONTACT DETAILS CONTACT Professor Dr. med. Eva Bettina Bröcker (Vice Speaker) To carry out its mission the IZKF uses par- N: Clinical and Experimental Neurobiol- Tel.: 0931/201-26350 ticulary three instruments: ogy • Supporting cooperative research grants Dr. Andrea Thelen-Frölich (Office) in the fields of immunology/infectiology, Tel.: 0931/201-47794 oncology, cardiac and vasular disorders Junior Career as well as neurosciences; Programmes • Promoting education and advancement of young researchers in medicine Supporting young scientists in medicine is throughout all qualification phases; the second major commitment of the IZKF • Improving scientific infrastructure by that involves a wide spectrum of sponsor- centrally funded core facilities and local ing activities: research funding programmes. • MD/PhD-Programme The IZKF promotes research after internal Is funded by the IZKF since 1997. The MD/ and external peer review. In this way, the PhD-Programme is integrated in the Gradu- IZKF guarantees quality-based differentia- ate School of Life Sciences of the Universi- tion in the research funding of the Medi- ty (GSLS). Currently 15 doctoral candidates cal Faculty. are enrolled in this programme. • The General Assembly (“Zentrumskon- ferenz”), • Erstantragsteller-Programm (The • The Executive Board First Application) • The External Scientific Advisory Board. is awarded to young researchers of medicine who have completed their doctorate The IZKF Wuerzburg was founded in 1996 to carry out a clearly defined project. Sup- within the federal advancement program ported by mentoring over a period of two “Health Research 2000” of the Federal years it will help these scientists gaining ac- Ministry of Education and Research as one cess to external research funding. Current- of nine centers in Germany. Since 2004 it ly 8 young scientists are supported in this is completely funded by the Free State of programme. Bavaria. • Rotation Positions (“Rotationsstel- len”) Main Research ensures “protected” time for young physi- Interests cian scientists. The IZKF provides five rotation positions. This support proved a One major task of the IZKF is to select and successful measure to extempt these re- finance research projects in the main researchers from daily clinical duties. The ro- search fields of the Medical Faculty. A tation positions are granted for six to twelve unique feature of this research grant pro- months. gramme of the center is the concept of bringing together the expertise of basic and • Junior Research Groups clinical sciences to develop novel and effec- The implementation of junior groups is an tive diagnostics as well as therapeutic ap- integral part of the junior career programme proaches. A research grant can be used to of the IZKF. Excellent young scientists are fund staff, scientific instrumentation, con- selected and supported over a period of five sumables as well as most of the other finan- years including a substantial running bud- cial requirements of a research project. In get. In this time they are expected to estab- 2009 the IZKF supported 33 research proj- lish their scientific reputation and to qual- ects and three junior research groups in the ify for academic positions. Within the year following research fields: 2009 two IZKF junior group leaders have

153 completed the programme successfully. So, • Microarray-Unit at the beginning of 2010 one group is cur- • Early Clinical Trial Unit rently active in the IZKF. The following groups have been funded: Finally the center offers flexible funding moduls which are not available from to 1. Prof. Dr. Andreas Rosenwald, Gene Ex- major external funding research organisa- pression Profiling of Non-Hodgkin-Lym- tions. phomas (2004-2009) – In September • Start-up financing for innovative re- 2009 Andreas Rosenwald accepted search ideas the offer to become director of the de- • Central budget for reimbursements of partment of pathology at the University travel expenses Würzburg. • Visiting researcher programme for scientists coming from abroad 2. Prof. Dr. Dr. Thomas Thum, Cardiac • Organization and funding of symposia, Wounding and Healing, (2006-2009) workshops and other meetings in order – Since October 2009 Thomas Thum to encourage coooperation between directs the Institute of Molecular and scientists from domestic or internation- Translational Therapeutic Strategies at al universities. the Hannover Medical School. In 2010 the Center will offer consulting ser- 3. PD Dr. Jörg Wischhusen, TGF beta as vice for scientists, particulary young scien- a key mediator of the immune escape tists and groups of scientists, in applying of invasively growing tumors (2005- external research funding. 2010)

Other activities

To improve the scientific infrastructure in clinical research the Center maintains the following Core Facilities:

Fig.1: Research support via the IZKF in 2010.

154 For the Annual Progress Report: Please contact: IZKF-Office

Thum T, Gross C, Fiedler J, Fischer T, Kissler S, Just S, Rottbauer W, Bussen M, Galuppo P, Frantz S, Castoldi M, Mucken- thaler M, Soutschek J, Koteliansky, Rosen- wald A, Pena JT, Tuschl T, Martin GR, Bau- Fig. 2: Internalized antagomirs (microRNA-antagonists; red) in cardiac fibroblasts (in ersachs J, Engelhardt S. (2008) MiR-21 green; nuclei in blue) (from: T. Thum, Nature. 2008). derepresses fibroblast MAPkinase signalling and contributes to myocardial disease. Nature. 2008;456:980-4.

Leich, E., Salaverria, I., Bea, S., Zettl, A., Wright, G., Moreno, V., Gascoyne, R.D., Chan, W.C., Braziel, R.M., Rosenwald, A., et al. (2009). Follicular lymphomas with and without translocation t(14;18) differ in gene expression profiles and genetic alterations. Blood, 114, 826-834 SELECTED PUBLICATIONS Austinat, M., Braeuninger, S., Pesque- ro, J. .B., Bader, M., Stoll, G., Renné, T. and Kleinschnitz, C. (2009) Blockade of Bradykinin Receptor B1 but not Bradyki- nin Receptor B2 Provides Protection from Brain Edema and Cerebral Infarction. Stroke, 40, 285-293

Schön, M., Wienrich, B.G., Kneitz, S., Schlickum, S., Sennefelder, H., Vöhring- er, V., Hüttinger-Kirchhof, N., Stiewe, T., Ziegelbauer, K., and Schön, M.P. (2008). KINK-1, a novel small-molecule inhibitor of IKK�, and the susceptibility of melanoma cells to antitumoral treatment. J. Natl. Cancer Inst, 2008, 862-75

Wiktorowicz K, Peters K, Armbruster N, Steinert AF, Rethwilm A. (2009) Genera- tion of an improved foamy virus vector by dissection of cis-acting sequences. J Gen Virol 90: 481-487.

Guckenberger M, Sweeney RA, Wilbert J, Krieger T, Richter A, Baier K, Mueller G, Sauer O, Flentje M. (2008). Image-guided radiotherapy for liver cancer using respiratory-correlated computed tomography and cone-beam computed tomography. Int J Radiat Oncol Biol Phys. 71(1):297-304 Galimberti, D., Scarpini, E., Venturelli, E., Strobel, A., Herterich, S., Fenoglio, C., Guidi, I., Scalabrini, D., Cortini, F., Breso- lin, N., Lesch, K.-P., Reif, A. (2008). As- sociation of a NOS1 promoter repeat with Alzheimer‘s disease. Neurobiol Aging 29, 1359-1365. 155 5.2.3 Research Center for Infectious Diseases

Professor Dr. med. Matthias Frosch General information ly encountering parasite drug resistance. (Speaker) and structure It is the main research goal of the Pradel group to gain deeper insight into the molec- Josef-Schneider-Str. 2 Infectious diseases still cause global health ular mechanisms underlying reproduction of 97080 Würzburg problems. In this regard, the ”Research Cen- the malaria parasite, which takes places in Tel.: 0931/201-46160 ter for Infectious Diseases“ (ZINF) was al- the midgut of the blood-feeding mosquito Fax: 0931/31-82578 ready established at the University of Würz- and which plays a major role for disease E-mail: [email protected] burg in 1993. This interdisciplinary research transmission. Sexual stage proteins may www.uni-wuerzburg.de/infektionsbiologie centre includes young investigator groups represent promising candidates for trans- as well as other groups of the University of mission blocking strategies, which aim to Würzburg working on infectious diseases. inhibit parasite development in the mosqui-

CONTACT DETAILS CONTACT The Research Centre belongs to the Medi- to vector and thereby reduce the spread of cal Faculty and the Faculty of Biology of the the disease. University of Würzburg. One of the first objectives of the centre was to represent a link between these two faculties. An inten- Genetically attenuated malaria liver sive scientific and organizational relation- states as an experimental malaria vac- ship has been built to the faculties of phar- cine macy, chemistry and physics. The research (A.-K. Müller, 2007-2008) of the centre aims at the elucidation of fundamental aspects of infection processes. A major area of interest in the lab is the The young investigator groups are associ- characterisation of protective immune re- ated with the Institute for Molecular Infec- sponses to malaria induced by genetically tion Biology. attenuated parasites (GAP). Genetically attenuated uis3(-) and uis4(-) parasites that constitute a reproducible and standardized Major Research source of potent live-attenuated parasites Interests have been recently generated and characterised. Immunization with GAP elicits Marine Symbioses- New Antiinfectives sterilising immunity, but so far the antigen- (U. Hentschel, 2004-2009) ic specificity and the effector mechanisms of this protective immune response have Marine sponges have considerable poten- not been carefully characterised. The group tial for drug discovery. Marine demosponges combines molecular and cell biological re- are associated with phylogenetically com- search on GAP with studies aimed at un- plex, yet highly sponge-specific microbial derstanding the immunological correlates consortia that are responsible for the proof protection elicited by GAP. duction of many important marine natural product classes, (i.e., polyketides and non- ribosomal peptides). The research goals of the group are to (i) characterize the microbial diversity associated with sponges, (ii) to investigate aspects of symbiosis and function and, (iii) to identify new antimicrobial substances from sponge-associated microbiota. The overall aim of this research is to provide a basic understanding of the sponge-microbe association and to use this natural resource for small molecule discovery.

Molecular mechanisms of malaria transmission (G. Pradel, since 2005)

The tropical disease malaria, which is caused by the protozoan parasite Plasmodi- Fig. 1: Exflagellating male Plasmodium um, is a major health threat and one of the microgametocyte with microgametes, de- most important infectious diseases world- picted by fluorescence-labelling of protein wide. Currently, there is no vaccine in cir- alpha-tubulin II (shown green). During ex- culation for the treatment of malaria, and flagellation the motile microgametes stick pharmaceutical approaches are increasing- to human erythrocytes (in red).

156 a severe and often life threatening complication for the immunocompromised individual, with knowledge of factors that support fungal growth inside the host being scarce. Research activities are focussed on specific aspects of nitrogen metabolism, such as regulation of extracellular proteolysis or transport of breakdown products from the surrounding proteinaceous matrix. This is complemented by studies on hematoge- nous dissemination of the fungus as well as its impact on hemostasis. Furthermore, we investigate the differentiation of sexual fruiting bodies using improved methods of molecular biology for gene targeting in A. fumigatus.

Teaching

The junior groups offer lab courses and lectures for students in medicine and biology. The center organizes regularly conferences on topics of infectious diseases. Further- more, the groups contribute to the education of graduate students.

Fig. 2: Filamentous cell protrusions of a Plasmodium macrogamete (shown in red via fluorescence-labelling of protein Pfs25), mediating contact to gametocytes (shown in green via fluorescence-labelling of protein Pfs230).

Virulence determinants of the human Siegl, A., Hentschel, U. 2009. PKS and pathogen Aspergillus fumigatus NRPS gene clusters from microbial symbi- ont cells of marine sponges by whole ge- (S. Krappmann, since 2007) nome amplification. Environ Microbiol Re- ports: in press Major research goal is the identification of novel factors that support pathogenicity of Simon, N., Scholz, S.M., Moreira, C.K., Aspergillus. Infection with this saprophyte is Templeton, T.J., Kuehn, A., Dude, M.A., Pradel, G. 2009. Sexual stage adhesion proteins form multi-protein complexes in the malaria parasite Plasmodium falciparum. J. Biol. Chem. 284:14537- 14546.

Bergmann, A., Hartmann, T., Cairns, T., Bignell, E.M., Krappmann, S. 2009. A regulator of Aspergillus fumigatus extracellular proteolytic activity is dispensable for virulence. Infect. Immun. 77:4041-4050.

SELECTED PUBLICATIONS Taylor MW, Thacker RW, Hentschel U. 2007. Genetics. Evolutionary insights from sponges. Science. 316:1854-5.

Bayram O, Krappmann S, Ni M, Bok JW, Helmstaedt K, Valerius O, Braus-Stromeyer S, Kwon NJ, Keller NP, Yu JH, Braus Fig. 3: Marine sponges (A) and associated microbiota (B) are rich sources of secondary GH. 2008. VelB/VeA/LaeA complex coor- metabolites, such as the novel macrolactam cebulactam A1 (C). dinates light signal with fungal develop- mentand secondary metabolism. Science. 320:1504-6. 157 5.2.4 Center for Experimental and Molecular Medicine (ZEMM)

Professor Dr. rer. nat. Albrecht Müller General (Head) Information

Zinklesweg 10 The ZEMM is a facility of the Medical Fac- 97078 Würzburg ulty to provide a platform for experimental Tel.: 0931/201-45848 research in the field of Molecular Medicine. The ZEMM comprises two parts: an animal unit and a research unit. The building was Dr. med. vet. Heike Wagner completed in 2008. In the research unit, (Head of Animal Facility) well-equipped laboratories are temporar- Tel.: 0931/201-44077 ily provided to research groups in biomedi- Fig. 1: DNA pronuclear microinjection.

CONTACT DETAILS CONTACT cine upon request. The animal facility is in Dr. med. vet. Bettina Holtmann charge of the central breeding, husbandry (Head of Transgenic Technology) and supply of non-infectious laboratory ani- cleus colonies that are currently not in use Tel.: 0931/201-44078 mals used by research institutions in the and protects against loss due to colony con- area of medicine and biomedicine. In addi- tamination (health or genetic). A mouse em- tion, the animal unit has the tasks to pro- bryo bank will therefore be developed which vide clean animal holding areas and to gen- provides a collection and storage service to erate gene-modified animals. Furthermore, researchers. several operating rooms for small and large animals are available. The lab-zone and Also, sperm freezing and in vitro fertilization the animal facility are available for defined procedures are currently being developed. time periods to research groups engaged in clearly defined biomedical research ac- The rederivation of mouse lines by embryo tivities. transfer has started in 2009. To ensure the microbiological security of the SPF area embryo transfers are performed under sterile Major Research conditions in laminar flow benches while Interests preparation of embryos is performed within a separated small animal operating room. The animal facility of the ZEMM is in charge of the central breeding, maintenance and A total of 166 requests for embryo rederi- supply of clean laboratory animals for re- vation from clinical (90.2%) and non-clini- search units from medicine and biomedical (9.2%) institutions has been submitted cine. and 113 mouse lines could successfully be transferred into the clean area. Breed- The unit Transgenic Technology supports in- ing colonies under specific pathogen- free terdisciplinary research by providing a wide (SPF) conditions could be established and range of services associated with the gener- maintained from all these mouse lines. In ation of genetically modified mice, embryo- summary, the Transgenic Technology unit cryopreservation and rederivation of mouse provides a platform of advanced technol- lines by embryo transfer for the entire net- ogies to successfully support and perform work of biomedical research at the Univer- biomedical research programs. sity of Würzburg.

For the generation of genetically modified mice conventional transgenic (DNA pronuclear microinjection) and knock-out (blastocyst injection of genetically modified ES cells) technologies are provided.

The production of transgenic mice is currently performed in the Institute of Pharma- cology and Toxicology. A total of 15 projects have passed through our lab in 2009 and a total of 30 transgenic founder mice could be generated. The blastocyst injection technology (gene- targeting) is currently being established in the animal facility of the ZEMM.

Cryopreservation provides a less expensive and efficient alternative for maintaining nu-

158 Fig. 2: Mice in the open area of the animal facility.

Fig. 3: Blastocyst injection in a small animal operating room.

159 5.2.5 Interdisciplinary Center for Addiction Research (ICAW)

Professor Dr. med. Andreas Fallgatter General ciated with the beginning of the smoking (Chair) Information ritual, increase craving while others, especially those associated with the end of the Füchsleinstrasse 15 ICAW has developed in 2000 from the inter- smoking ritual, inhibit craving. An under- 97080 Würzburg disciplinary BMBF addiction research net- standing of the latter process seems espe- Tel.: 0931/201-77100 work (1996-2001) focusing on neurobio- cially important since it may help to create Fax: 0931/201-77120 logical and behavioral foundations of alco- environments in which smokers have only E-mail: [email protected] hol-addiction. The objectives are enduring little urge to smoke. development and encouragement of clini- PD Dr. med. Christian Jacob cal and neurobiological research on addic- (Vice-chair) tion. Advancement of traineeship, teaching, Molecular mechanisms of alcohol toler- CONTACT DETAILS CONTACT Tel.: 0931/201-77810 qualification in addiction associated topics, ance in Drosophila melanogaster inpatient and outpatient interventions and (A. Scholz, Institute for Genetics and Neu- political decision guidance are additional robiology) topics. For this purpose an outpatient and consultation-liaison program for the treat- With molecular genetic, genetic and ana- ment of alcohol and nicotine addiction has tomical methods we investigate ethanol in- been established at the department of psy- duced behaviors in the genetic model or- chiatry, psychosomatics and psychotherapy ganism Drosophila melanogaster. With our in 2008 in connection with the reestablish- behavioral assays we analyze the influence ment of a full professor position in psychi- of learned behavior and/or alcohol prefer- atry focusing on addiction medicine (Prof. ence on the development of alcohol tol- Fallgatter). Additionally, the Dept. of Psy- erance and alcoholism. We are interested chology I established a full professorship for in identifying networks that mediate these Interventional Psychology (Prof. A. Kübler) behaviors. In addition we try to understand with a focus on addiction research. how ethanol affects the brain on the cellular level. Previously we have identified a new cellular mechanism that is important Major Research for the development of ethanol tolerance. Interests This mechanism is similar to a cellular stress response. The hangover gene plays Neurophysiological assessment of ce- an important process in this process and rebral cue reactivity in substance de- the human homologue of this gene can be pendence associated with clinical alcohol dependence (A. J. Fallgatter, M.M. Schecklmann, L. (DFG-Einzelförderung und Graduiertenkol- Ernst, A. Dieler, Dept. of Psychiatry) leg, Thyssen Stiftung).

Event-related potentials (ERP), functional Magnetic Resonance Imaging (fMRI) Genetics of alcohol addiction and Near-Infrared Spectroscopy (NIRS) are (K.P. Lesch, Psychiatry, Psychobiology) used to investigate addiction memory as well as topographical aspects of emotional Neurobiological and psychobiological pro- and cognitive processes in alcohol and to- cesses such as reward-related behavior, bacco dependency. Other areas of research cognitive-executive dysfunction, stress cop- are the reversibility of disturbances in brain ing or anxiety that are involved in the devel- function in alcohol-dependent patients and opment of alcohol addiction are presumably the application of repetitive Transcranial under the influence of genetic variation. Magnetic Stimulation (rTMS) in tobacco de- Traits, e.g. impulsivity, sensation seeking, pendent patients. or aggressive behavior, as well as dysfunctional cognitive styles, anxiety, emotional la- bility, and stress vulnerability are directly or Biopsychological mechanisms of nico- indirectly related to morbidity. As evidenced tine craving by a plethora of research, most of these (P. Pauli, R. Mucha, M. Winkler, Department psychobiological domains are modulated by of Psychology) a functional serotonin transporter polymor- phism. These findings demonstrate the in- Within the DFG funded research group creasing relevance of translational research (Forschergruppe) “Emotion and Behavior“ and molecular-functional imaging studies in we examine the addiction specific question order to describe neurobiological founded how emotional learning processes modu- endophenotypes, thereby bridging the gap late the significance of environmental cues between molecular variation and clinical di- for craving to smoke. We expect that some agnoses. environmental cues, especially those asso-

160 The endogenous neurotoxine TaClo a) Addiction as automatic behavior and (C. Bringmann, D. Feineis, Institute for Or- failure of executive control ganic Chemistry) Although the concept of automaticity is not sufficient to explain the emergence and Chemical reactive compounds that people maintenance of addiction, there is no doubt are in contact with due to environmental that addictive behavior shows components pollution, drug abuse, medical treatment of automaticity. Addiction could be seen as or workplace conditions are suspected to a failure to instantiate executive control to be involved in the etiology of neurodegen- overcome cue-induced automatic behavior. erative processes. The investigations focus To investigate this hypothesis, we developed upon highly chlorinated tetrahydro-beta- a visual search task that allows us to inves- carbolines such as „TaClo“ that originates tigate automatization, automaticity and rein man from endogenous tryptamine („Ta“) establishment of executive control within and chloral („Clo“), e.g., after intake of the few training sessions. In cocaine addicts we hypnotic chloral hydrate, or, due to addic- could show, that dorsolateral prefrontal cor- tion, after occupational exposure to the in- tex is less activated than in healthy subjects dustrial solvent trichloroethylene (TRI), or when executive control is required after au- as a consequence of solvent abuse („sniff- tomatization. We are currently adapting the ing“). visual search task to specific addictions and eating disorder. (DFG Graduiertenkolleg)

ADHD as a risk factor for the develop- b) Deficits in reward learning as a com- ment of addiction ponent of addiction (C. Jacob, Dept. of Psychiatry) In addicted subjects positive reinforces such as food, sex, or other pleasurable ac- 60%-80% of the childhood manifestations tivities lose their rewarding qualities; the of ADHD persist into adulthood. There is brain reward centres such as the Nucleus a variety of co-morbid disorders including accumbens remain silent when confronted substance use disorders. The treatment of with such stimuli. It could thus be hypoth- ADHD with stimulants is protective against esized that a deficit in reward learning could substance use disorders. The clinical re- be a component of addiction. In a group of search group ADHD which is supported by smokers such deficits in implicit and explicit the DFG performs a multilayered evaluation learning could be shown. We are current- of the endophenotypes working memory ly investigating whether such deficits can and response inhibition. be shown in non-addicted social drinkers, women with restrained eating behavior, addicted smokers, non-smokers and smokers Addiction and Mental Disorders in the state of withdrawal. (J. Deckert, Dept. of Psychiatry, Psychoso- matics and Psychotherapy)

The relevance of substance abuse and de- Teaching pendence other than alcohol (caffeine, nicotine, amphetamine and cannabis) and its The seminary “neurobiology of addiction“is Bringmann G, Feineis D, Münchbach M, God R, Peters K, Peters E-M, Mössner R, neurobiology for the pathogenesis and ther- an advanced training for young scientists Lesch K-P (2006). Toxicity and metabo- apy of mental disorders has developed as and students of medicine, psychology and lism of the chloral-derived mammalian alan additional research topic, partly within biology. The annual basic and advanced kaloid 1-trichloromethyl-1,2,3,4-tetrahy- the context of the SFB-TRR58 on “Fear, training convention of addiction medicine dro-beta-carboline (TaClo) in PC12 cells. Z. Naturforsch. 61c, 601-610. Anxiety and Anxiety Disorders”. It focuses is an additional teaching activity. Research on the modulation of mental disorders by projects are presented on the annual meet- Domschke K, Dannlowski U, Ohrmann P, substance abuse– related genetic factors ings of the ICAW. Lawford B, Bauer J, Kugel H, Heindel W, and the consequences of substance abuse Young R, Morris P, Arolt V, Deckert J, Su- for the therapy of mental disorders employ- slow T, Baune BT (2008). Cannabinoid receptor 1 (CNR1) gene: impact on antide- ing drug monitoring as well as genetic and pressant treatment response and emotion imaging techniques. processing in major depression. Eur Neu- ropsychopharmacol. 18: 751-759.

Kübler A, Dixon V, Garavan H (2006). Au- Substance and behavioural addiction: tomaticity and re-establishment of execu- executive function and learning tive control – an fMRI study. Journal of

(Kübler, A. Meule, Y. Paelecke-Habermann, SELECTED PUBLICATIONS Cognitive Neuroscience 18: 1331-1342. Dept. of Psychology I) Scholz H, Franz M, Heberlein U (2005). The hangover gene defines a stress pathway required for ethanol tolerance. Nature 436, 845-847. 161 5.2.6 Interdisciplinary Center for Familial Breast and Ovarian Cancer

General rule, BRCA1 and BRCA2 related breast can- Professor Dr. med. Tiemo Grimm Information cers are early onset cancers, with an aver- (Speaker) age age of onset of around 43 years - some Since 1996, women at risk for familial 20 years prior to the age of onset in the Division of Medical Genetics breast and ovarian cancer are offered spe- general population. Thus, primary and sec- Theodor-Boveri-Weg 11 cialized counselling in Germany. Currently, ondary prevention represents a major chal- 97074 Würzburg there are twelve interdisciplinary centres for lenge. International and national data of Tel.: 0931/318-4076 familial breast and ovarian cancer (Zentren the joint project show that mutation carriers Fax: 0931/318-4434 für Familiären Brust- und Eierstockkrebs - can reduce their overall breast and ovarian E-mail: [email protected] Deutsche Krebshilfe). These centres offer cancer risks to less than 5% via prophylactic www.humgen.biozentrum.uni-wuerzburg.de/ a structured approach by which women not bilateral mastectomy, in combination with krebszentrum/ CONTACT DETAILS CONTACT only receive an answer to their concerns bilateral salpingo-oophorectomy. 0opho- www.frauenklinik.uni-wuerzburg.de/brustzen- about personal and familial cancer risk, rectomy alone has been shown to reduce trum/familiaerer_brustkrebs.htm but also receive counselling and assistance the risk of breast cancer by at least 50%. of how to deal with an increased risk. The Currently, only 1 in 10 carrier women in Ger- Professor Dr. med. Johannes Dietl Würzburg centre is known as “Interdisciplin- many opt for prophylactic mastectomy, but (Speaker) ary Centre for familial breast and ovarian an increasing number of women undergo cancer” and includes the following institu- oophorectomy. As an alternative to radical Department of Obstetrics and Gynecology, tions: Division of Medical Genetics; Univer- breast removal, within the framework of the Josef-Schneider-Str. 4 sity Women‘s Hospital; Department of Psy- joint project 80 percent of women partici- 97080 Würzburg chotherapy and Medical Psychology, and In- pate in the programme of intensive early Tel.: 0931/201-25251 stitute of Diagnostic Radiology. detection. In regular intervals, these wom- Fax: 0931/201-25406 en utilize a combination of mammography, E-mail: [email protected] The results of the national pilot testing and magnetic resonance imaging and sonogra- www.frauenklinik.uni-wuerzburg.de evaluation phase were so positive that the phy. The question of how successful such statutory health insurance companies (in a conservative strategy will finally turn out 2005) and the majority of private insurers to be cannot be answered at this time. In agreed to include a “Hereditary breast can- order to evaluate the performance of the cer comprehensive care package” as part twelve hereditary breast centres, a data- of their regular coverage. The services pro- base was established at the University of vided are interdisciplinary – i.e. genetics, Leipzig. Each centre contributes all relevant gynaecology, diagnostic radiology, and psy- data to this anonymous database financed cho-oncology. Genetics includes computer- by the German Cancer Society. The hope assisted risk estimates and quality-assured is that the final analysis of this dataset will molecular genetic analysis of the prinicipal permit a comparison between the different BRCA and other susceptibility genes. Op- strategies of primary and secondary preven- timal use of resources and assurance of tion. So far, there is a clear benefit of pro- high quality care has been achieved through phylactic mastectomy in primary preven- close cooperation within the local centre. tion, but acceptance of this procedure is comparatively low. More data are needed Breast cancer is the most common can- for the evaluation of enhanced early detec- cer for women in Germany. Approximately tion using sonography, mammography and ten to twelve percent are affected during complementary magnetic resonance imag- their lifetime, with an average age of onset ing (MRI). A major goal of early detection is of 63 years. For the small group of wom- to reduce mortality caused by breast and en with a hereditary predisposition, risk is ovarian cancer. considerably higher: the lifetime probability of these women amounts to 80 percent Another focus of the work of the German for breast cancer and 20 to 50 percent for consortium concerns molecular genetics. In ovarian cancer. It is currently estimated that about half of the families in whom breast at least five percent of breast cancers and and ovarian cancer appears to follow a up to ten percent of ovarian cancers are monogenic pattern, no predisposing muta- due to mutations in single genes. BRCA1 tions in the two BRCA genes are found. This and BRCA2 figure most prominently among could be due to undetected mutations or the high-risk genes. Over 800 of these fam- mutations in other genes known to be as- ilies were followed in the Würzburg centre. sociated with breast cancer, including ATM, Mutations in either BRCA1 or BRCA2 were BRIP1, PALB2, and others. Some of these identified in many of these families. The af- lower penetrance genes are studied in par- fected women were offered a comprehen- allel in the Fanconi anemia research lab- sive care package. BRCA-associated breast oratory of the Department of Human Ge- and ovarian cancers have different charac- netics. Recently, rare pathogenic mutations teristics such that effective prevention must in RAD51C were identified in families with be adjusted to the individual patient. As a breast and ovarian cancer. Another possibil-

162 ity which needs to be explored is the interaction of several low-penetrance susceptibility genes. The differentiation between these alternatives is subject of current re- Graeser MK, Engel C, Rhiem K, Gadzicki search efforts. Furthermore, modifying fac- D, Bick U, Kast K, Froster UG, Schlehe B, tors need to be investigated since there are Bechtold A, Arnold N, Preisler-Adams S, obvious inter- and intrafamilial differenc- Nestle-Kraemling C, Zaino M, Loeffler M, es in the clinical presentation of BRCA1- Kiechle M, Meindl A, Varga D, Schmutzler /BRCA2-mutation families which may be RK (2009) Contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers. J caused by environmental factors and/or by Clin Oncol. 27:5887-5892. modifier genes. Antoniou AC, Sinilnikova OM, McGuffog L, Healey S, Nevanlinna H, Heikkinen T, Si- mard J, Spurdle AB, Beesley J, Chen X; Kathleen Cuningham Foundation Con- sortium for Research into Familial Breast Cancer, Neuhausen SL, Ding YC, Couch FJ, Wang X, Fredericksen Z, Peterlongo P, Peissel B, Bonanni B, Viel A, Bernard L, Radice P, Szabo CI, Foretova L, Zikan M, Claes K, Greene MH, Mai PL, Rennert G, Lejbkowicz F, Andrulis IL, Ozcelik H, Glen-

SELECTED PUBLICATIONS don G; OCGN, Gerdes AM, Thomassen M, Sunde L, Caligo MA, Laitman Y, Kontorov- ich T, Cohen S, Kaufman B, Dagan E, Ba- ruch RG, Friedman E, Harbst K, Barba- ny-Bustinza G, Rantala J, Ehrencrona H, Karlsson P, Domchek SM, Nathanson KL, Osorio A, Blanco I, Lasa A, Benítez J, Ha- mann U, Hogervorst FB, Rookus MA, Col- lee JM, Devilee P, Ligtenberg MJ, van der Luijt RB, Aalfs CM, Waisfisz Q, Wijnen J, van Roozendaal CE; HEBON, Peock S, Cook M, Frost D, Oliver C, Platte R, Evans DG, Lalloo F, Eeles R, Izatt L, Davidson R, Chu C, Eccles D, Cole T, Hodgson S; EM- BRACE, Godwin AK, Stoppa-Lyonnet D, Buecher B, Léoné M, Bressac-de Pailler- ets B, Remenieras A, Caron O, Lenoir GM, Sevenet N, Longy M, Ferrer SF, Prieur F; GEMO, Goldgar D, Miron A, John EM, Buys SS, Daly MB, Hopper JL, Terry MB, Yassin Y; Breast Cancer Family Registry, Singer C, Gschwantler-Kaulich D, Staudi- gl C, Hansen TO, Barkardottir RB, Kirch- hoff T, Pal P, Kosarin K, Offit K, Piedmonte M, Rodriguez GC, Wakeley K, Boggess JF, Basil J, Schwartz PE, Blank SV, Toland AE, Montagna M, Casella C, Imyanitov EN, Al- lavena A, Schmutzler RK, Versmold B, En- gel C, Meindl A, Ditsch N, Arnold N, Nie- deracher D, Deissler H, Fiebig B, Suttner C, Schönbuchner I, Gadzicki D, Caldes T, de la Hoya M, Pooley KA, Easton DF, Chenevix-Trench G; CIMBA (2009) Com- mon variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers. Hum Mol Genet. 18:4442-4456.

Reim F, Dombrowski Y, Ritter C, Buttmann M, Häusler S, Ossadnik M, Krockenberger M, Beier D, Beier CP, Dietl J, Becker JC, Hönig A, Wischhusen J (2009) Immunose- lection of breast and ovarian cancer cells with trastuzumab and natural killer cells: selective escape of CD44high/CD24low/ HER2low breast cancer stem cells. Cancer Res. 69:8058-8066.

Krockenberger M, Engel JB, Häusler S, Di- etl J, Honig A (2009) Prolonged clinical benefit from platinum-based chemotherapy in a patient with metastatic triple negative breast cancer. Eur J Gynaecol Oncol. 30:449-451. 163 5.2.7 Transplant Center (TPZ)

Clinical The German Foundation of Organ Trans- Professor Dr. med. Rainer G. Leyh Transplantation plantation (DSO) educates physicians, (Speaker) health care workers and the general public The Transplant Centre Würzburg (TPZ) is one on brain death and organ explantation. With Department of Thoracic and Cardiovascular of several German transplant centres. Since the support of the hospitals in Aschaffen- Surgery the ratification of the German Transplant burg, Schweinfurt, Coburg and other hospi- Oberdürrbacher Str. 6 Act between 35 and 45 transplantations tals in the region, the registration of poten- 97080 Würzburg per year could be achieved in the kidney tial organ donors has been successfully op- Tel.: 0931/201-33001 transplant program. The number of trans- timized and more people in the lower Fran- E-mail: [email protected] plantations is thereby depending on the size conia area are willing to donate organs. of the waiting list. Due to the ever increas- Professor Dr. med. Hermann Einsele CONTACT DETAILS CONTACT ing discrepancy between organ demand (Vice-Speaker) and supply the living donation program was Clinical and Experimental Transplanta- Tel.: 0931/201-40000 enforced on the one hand, furthermore far tion Research more organs with expanded donor criteria were accepted (for example in the Eu- All specialities mentioned above are in- rotransplant Senior program). Fluctuations volved in multiple multicenter studies, ei- are mostly due to the number of accept- ther investigator-driven or with industrial able living donors, until the end of 2009 sponsoring. Diverse dissertations and pub- 68 living kidney-transplants of related and lications originate from this work. Wuerz- unrelated donors were performed. Altogeth- burg is one of the few places in Germany er 817 kidneys were transplanted in close supporting experimental transplantation re- cooperation of the Division of Nephrology search including xenotransplantation. This and the Department of Urology since the research is coordinated by a W2 professor start of the program in 1984. Furthermore for experimental transplantation immunolo- 13 combined kidney-pancreas-transplanta- gy. Transplantation of nearly all vascularised tions and one combined kidney-liver-trans- organs in both rat and mice models can be plantation were performed together with the performed in a well equipped modern labo- Department of Surgery I. Actually 213 pa- ratory for microsurgery. Close cooperations tients are waiting for a kidney graft in Wuer- exist with the universities in Oxford / UK, zburg. Boston / USA, Rochester / USA, Sydney / Australia and the Ludwig Maximilian Univer- Since 1989 also 30 heart transplantations, sity in Munich. two of them in 2009, were conducted by the Department of Thoracic and Cardiovas- cular Surgery in collaboration with the De- Further Activities partment of Internal Medicine I. At present 7 patients are admitted to the waiting list. Every two years the Transplant Centre organizes a local transplantation workshop Between 1992 and 2007 71 liver trans- (Franconian Transplant Workshop) focusing plants had been performed by the colon the operative and conservative aspects leagues of the Department of Surgery and of kidney transplantation, the next meeting the Department of Internal Medicine II (Divi- will take place in autumn 2010 for the 11th sions of Hepatology and Gastroenterology). time. In regular yearly intervals seminars for It is planned to reactivate the liver program patients and resident (“fit for transplanta- in 2010. In 2009 225 stem cell transplant tion”) physicians are arranged with great were performed at the Universitätsklinikum success, in 2009 more than 250 partici- Würzburg for adult patients. Thus the stem pants attended. cell transplantation programme in Würzburg is the second largest in Germany. Our SCT programme includes novel approachies like cord blood transplantation, haploidentical stem cell transplantation and adoptive T cell therapy.

All patients of the programs mentioned above are served by the outpatient departments of the involved sections, most of them together with resident practitioners in the vicinity. Also involved is the Depart- ment of Dermatology with a special out-patient clinic for patients transplanted with a solid organ.

164 Frei U, Noeldeke J, Macold-Fabrizii V, Ar- bogast H, Margreiter R, Fricke L, Voicules- cu A, Kliem V, Ebel H, Albert U, Lopau K, Schnuelle P, Nonnast-Daniel B, Pietruck F, Offermann R, Persijn G, Bernasconi C: Prospective age-matching in elderly kidney transplant recipients – a 5-year analysis of the Eurotransplant Senior Program. Am J Transplant 8, 50-57, 2008.

Matuschek A, Ulbrich M, Timm S, Sch- neider M, Germer C, Ulrichs K, Otto C: Analysis of parathyroid graft rejection suggests alloantigen-specific production of nitric oxide by iNOS-positive intragraft macrophages. Transpl Immunol 21(4), 2009: 183-191.

Schnuelle P, Gottmann U, Hoeger S, Bo- esebeck D, Lauchart W, Weiss C, Fisch-

SELECTED PUBLICATIONS ereder M, Jauch KW, Heemann U, Zeier M, Hugo C, Pisarski P, Kraemer B, Lopau K, Rahmel A, Benck U, Birck R, Yard BA. Effects of Donor Pretreatment With Dopa- mine on Graft Function After Kidney Trans- plantation: A Randomized Controlled Trial. JAMA 302, 2009: 1067-1075.

Steger U, Denecke C, Sawitzki B, Karim M, Jones ND, Wood KJ: Exhaustive differentiation of alloreactive CD8+ T cells: critical for determination of graft acceptance or rejection. Transplantation 85 (9), 2008:1339-1347.

Steger U, Ensminger S, Bushell A, Wood KJ: Investigation into the onset and progression of transplant arteriosclerosis in a mice aortic retransplantation model. Mi- crosurgery 28(3), 2008:182-186. 165 5.2.8 Comprehensive Cancer Center Mainfranken

General sis. The CCC Mainfranken offers the struc- Information tural framework for an efficient cooperation. Experts from all involved departments par- The Comprehensive Cancer Center Main- ticipate in weekly interdisciplinary tumour franken developed from the 1983 founded conferences. They discuss and decide ther- „Interdisciplinary Tumour Center at the Uni- apy concepts based on most recent guide- Professor emerit. Dr. med. Klaus Wilms versity Wuerzburg“. The CCC Mainfranken is lines reflecting the evidence based knowl- (Director) a multidisciplinary cancer therapy and can- edge for a successful treatment. cer research centre with the primary func- Josef-Schneider-Straße 6 tion to treat patients with tumour diseases Further offers for patients and the com- 97080 Würzburg in an optimal way and accordingly to the munity:

CONTACT DETAILS CONTACT Tel.: 0931/201-35150 most recent level of medical knowledge. All • Psychological support during all phases Fax: 0931/201-35952 involved disciplines like prevention, diag- of disease by qualified psycho-oncolo- E-mail: [email protected] nostics and therapy cooperate in the treat- gists www.ccc.medizin.uni-wuerzburg.de ment of oncologic diseases. The medical • Social service specialists work closely together with biolo- • Information about self-help groups Professor Dr. med. Michael Flentje gists and other scientists to perform cancer • Palliative care network (Deputy Director – Clinical Care) research on an international and competi- • Information about different tumour dis- Tel.: 0931/201-28890 tive level. eases

Professor Dr. rer. nat. Dr. h. c. Manfred The University Hospital Würzburg, the clin- The clinical cancer registry collects long Schartl ical-theoretical and the theoretical insti- term follow-up data and mortality informa- (Deputy Director – Oncologic Research) tutes of the medical faculty are part of the tion of tumour diseases. This is an impor- Tel.: 0931/888-4148 CCC Mainfranken. Research cooperation is tant tool to monitor the quality of treatment. maintained also with other faculties of the The cancer registry is also entrusted with Professor Dr. med. Dr. phil. Hermann Faller University. the epidemiological cancer registration for (Deputy Director – Outreach and Education) the bavarian population based cancer reg- Tel.: 0931/31-82713 Members of the CCC Mainfranken are also istry (www.krebsregister-bayern.de). This the Academic Teaching Hospitals (Julius- registry aims to discover regional and tem- PD Dr. rer. biol. hum. J. Riese Spital and Medical Mission Hospital in Würz- poral differences of cancer incidences and (Managing Director) burg as well as the Hospitals in Aschaffen- provides useful data for cause studies and Tel.: 0931/201-35151 burg and Schweinfurt), additional hospitals healthcare research. and specialists in private practices of the region Mainfranken. Major Research Inter- The medical care of patients suffering from ests and Research In- cancer is provided at the University Hospital frastructure and its affiliates on an interdisciplinary ba-

166 At the CCC Mainfranken, the oncologic re- focus on new concepts of a better GvHD search is intensively carried out on three lev- prophylaxis and B-cell-reconstitution follow- els - basic research, translational and clinical ing allogeneic stem cell transplantation, as research - in order to be able to offer patients well as improving diagnostics and therapy of the most recent knowledge and advances of fungal infections in immune-compromised medicine as soon as possible. Main research patients. Aspects of umbilical cord blood interests are therapies of malignant diseas- transplantation are examined of a project es by using defence mechanisms of the im- supported by the Carreras foundation. mune system, the description of new targets to control tumour diseases and investigation KFO 216 (Characterisation of the Oncogen- of the molecular mechanisms of metasta- ic Signalling Network of the Multiple Myelo- sis. The latest technology and special animal ma: Development of Targeted Therapies) is models are used for research. one of the clinical research groups (scientific leadership: Prof. Dr. med. R. Bargou) A special facility of CCC Mainfranken is the supported by the DFG who are working on Early Clinical Trial Unit where clinical trials of oncological subjects. Twenty scientists of phases I and II a/b are offered for patients six different departments of the University with advanced tumour diseases. Since es- of Wuerzburg are participating. Apart from tablishing this trial unit in 2007, 15 phase the Dept. of Internal Medicine II the follow- I/II studies testing several novel compounds ing institutes are cooperating: the Institute could be initiated. This unit aims on the defor Pharmacy and Food Chemistry, the Insti- velopment of targeted molecular and im- tute for Organic Chemistry, the Institute for munological therapies. Virology and Immunobiology, the Institute for Pathology and the Dept. of Physiologi- The clinical and laboratory research of sev- cal Chemistry. In addition there is a close eral departments embedded in the CCC cooperation with scientists and clinicians of Mainfranken were and are substantially the Dept. of Internal Medicine II at the Uni- funded through third-party grants. versity of Ulm.

Several EU projects of the Department of Six interdisciplinary teams of the clinical re- Internal Medicine II focus on further devel- search group KFO 124 (The Tumor Microen- opment of immunotherapy for cancer dis- vironment: Target and Immune Modulator eases and fighting infections in affected pa- of the Immune Response; scientific lead- tients. (Euro Net Leukämie, MANASP. Allo- ership: Prof. Dr. med. J. Becker) are ded- Stem, NANO II). Additional projects of this icated to analyse ongoing anti-tumor im- Department, funded by DFG, the German mune responses in situ in the context of Krebshilfe, Mildred Scheel Foundation, the tumor microenvironment. The results Carreras Foundation, International Myelo- can be applied to clinical aspects in order ma Foundation and by Sanderstiftung are to improve the efficacy of immune therapy working on the induction of tumour-specific for malignant disease and to establish new immune response and the improved treat- anti-cancer vaccines directed at the tumor ment of myeloma patients. The scientists micromilieu.

167 5.2.9 Comprehensive Hearing Center Würzburg

Hearing Research Major Research Professor Dr. med. Rudolf Hagen Interests (Head) Experimental and applied research provides the latest information in all aspects of hear- Middle ear biology Josef-Schneider-Str. 11 ing, which is integrated into treatment stra- (R. Mlynski, M. Schmidt, A. Radeloff, R. Ha- 97080 Würzburg tegies. Networking with local as well as in- gen) Tel.: 0931/201-21701 ternational research groups allows for the Fax: 0931/201-21248 actual state of knowledge, being integrat- Histological morphometry and surface char- E-mail: [email protected] ed into patient´s care. In order to intensi- acteristics of middle ear implants; immu- www.hno.uni-wuerzburg.de fy the interdisciplinary research concepts, a nology and immunohistology of choleste- foundation professorship on “Experimental atomas for research of origin and mainte- Dr. Heike Kühn (Office) CONTACT DETAILS CONTACT hearing research“ shall be established. The nance of chronic otitis media, expression of Tel.: 0931/201 21777 Wuerzburg CHC concept lead to a worldwide bone morphogenetic protein-2, MMP-9 and network of cochlea implant centers, which cytokines in cells of cholesteatoma. Deve- are in close cooperation under the roof of lopment of coated electrode carriers for “Hearring“ (www.hearring.com). medicamentous treatment of middle and inner ear.

Development of innovative instruments Biophysics of middle ear Together with partners of the biomedical (J. Müller, S. Brill, F. Kraus, R. Hagen) industry new instruments are developed with a special focus on a practical design LASER-vibrometrical measures of middle at the CHC. This further development com- ear mechanics in petrous bones. Clinical prises diagnostical instruments as well as and experimental investigations of middle improved implant systems. The possibilities ear implants and transplants using EDP of intense testing of new devices and in- supported documentation. Intraoperative struments in an optimized clinical setting monitoring of transmission function in ac- keep the CHC attractive for new co-operative middle ear prostheses. tion partners.

Inner ear biology Interdisciplinary Treatment (R. Mlynski, K. Rak, N. v. Wasielewski in cooperation with the Institute of Neurobiology, Mission Hearing disorders often have a difficult M. Sendtner) and Structure pathophysiological background, which ne- cessitates an interdisciplinary diagnosis In vitro and in vivo investigations of neuro- The Comprehensive Hearing Center Würz- and treatment. Starting with the first hea- trophic substances (FGFs, NT-3, CNTF, LIF) burg (CHC) is an interdisciplinary, integra- ring tests in newborn babies, developmental on survival and growth patterns of hair cells tive center for diagnosis, counselling and aspects are included as well as non-medi- and spiral ganglion neurite extension in research regarding all aspects of hearing. It cal support. Furthermore direct involvement the mammalian cochlea; effects of recom- is spatialized to the Department of Oto-Rhi- of companies offering specialized supplying binant adenoviruses on cochlear cells to no-Laryngology, Plastic, Aesthetic and Re- service is part of the treatment concept. transducer cochlear tissues for future gene constructive Head and Neck Surgery. Pa- therapy, inner ear and hearing development tients with hearing disorders and their rel- in CNTF and LIF knockout mice, creation of atives a comprehensive counselling on all Follow-up Care and Rehabilitation transgenetic mice with a cell specific gene- possible diagnostic measures and thera- knock-out in cochlear and spiral ganglion peutical options is offered. In many cases surgical therapy has to be followed by a highly specialized support ser- The combination of different diagnostic and vice, especially in hearing implants. First fit- therapeutic institutes comprising hearing ting of the implant processor normally takes research, care units, supporting compa- place in the implanting clinic, for further af- nies and rehabilitation institutes allows for ter-care and rehabilitation CHC has close a comprehensive expertise on all aspects contact to all important rehab institutes in of hearing. Germany. This guarantees an optimal and individualized support with the necessary Patient´s care takes place in an interdisci- feed-back to the hearing center. plinary setting, according to the latest developments in science and medical techniques. Postclinical treatment is adjusted individually with all cooperating rehabilita- Fig. 1: Neuronal differentiation of adult tion partners. stem cells for application in the inner ear (guinea pigs).

168 Pedaudiological tests and newborn Further development of diagnostic tools for hearing screening objective frequency specific measurement (W. Shehata-Dieler, D. Ehrmann, R. Keim in of the absolute threshold of hearing. Objec- cooperation with the Center of Pre-speech tification of binaural hearing in normal hea- Development and Developmental Disor- ring and hearing impaired persons. ders, K. Wermke)

Development of new objective test proce- Hearing research dures for frequency specific examination (M. Vollmer, T. Bremer in cooperation with of newborns. Investigation of pre-speech the University of California, San Francisco, sounds in infants as a new tool for pedaudi- R. Beitel, and the Ludwig-Maximilians Uni- Fig. 2: Active migration of stained stem ological testing. versity Munic, B. Grothe) cells (pink) from basal cochlear turn (guinea pigs). Electrophysiological basic research on cen- Cochlear- and brain stem implants tral-neuronal processing of acoustic and (J. Müller, W. Shehata-Dieler, A. Radeloff, S. electric stimulation of auditory pathway in cells; investigations of function of vasodi- Brill, S. Kaulitz in cooperation with the De- an animal model. lator stimulated phosphoproteins (VASP) in partment of Neurosurgery, C.Matthies, and terminal hair cell innervation. Univ. of Innsbruck, P. Nopp)

Evaluation of new stimulation strategies for Impact of stem cells in auditory path- further improvement of speech intelligibility way following cochlear and brain stem implan- (A. Radeloff, K. Rak, R. Mlynski) tation. Advancement of intraoperative tele- metry and monitoring systems. Detection of adult stem cell populations in inner ear and central auditory pathway. In-vivo application of cultured stem cells Experimental audiology to damaged inner ear in animals (guinea (M. Cebulla, R. Keim, W. Harnisch in co- pigs). operation with the Department of Psychia- try, Psychosomatics and Psychotherapy, A. Fallgatter)

Radeloff A, Unkelbach MH, Mack MG, Settevendemie C, Helbig S, Mueller J, Ha- gen R, Mlynski R (2009) A coated electrode carrier for cochlear implantation reduces insertion forces. The Laryngoscope 119:959-963.

Brill S, Müller J, Hagen R, Möltner A, Brockmeier S, Stark T et al (2009) Site of cochlear stimulation and its effect on electrically evoked compound action potentials using the MED-EL standard electrode array.BioMedical Engineering OnLine 8:40-49.

Tolsdorff B, Petersik A, Pflesser B, Pom- mert A, Tiede U, Leuwer R, Höhne KH(2009) Individual models for virtual bone drilling in mastoid surgery Computer Aided Surgery 14:21-27. SELECTED PUBLICATIONS Mlynski R, Volkenstein S, Hansen S, Bro- ros D, Ebmeyer J, Dazert S: (2007) Inter- action of cochlear nucleus explants. Laryn- goscope 117:1216-1622.

Vollmer M, Hartmann M, Tillein J (2010) Fig. 3: Collateral sprouting of neuronal cells on semiconductor-material. Neuronal responses in cat inferior colliculus to combined acoustic and electric stimulation. Adv.Otorhinolaryngol 67:61-69. 169 5.2.10 Center for Intestinal Medicine

The University of Würzburg’s Center for In- PD Dr. med. Joerg Pelz testinal Medicine was first certified by the (Coordinator) German Cancer Society and the Southern Technical Inspection Authority in Septem- Professor Dr. med. Christoph-Thomas Germer ber 2008. (Head) Since then, the number of patients has in- Department for General, Visceral, Vascular creased by 40%. Our aim is to provide the and Pediatric Surgery highest quality of therapy for each individual Oberdürrbacher Str. 6 patient. Different clinics and departments 97080 Würzburg work together to ensure the best possible

CONTACT DETAILS CONTACT Tel.: 0931/201-31170 care. We provide medical care in coopera- www.darmzentrum-wuerzburg.de tion with the patients’ physicians, nutrition counselling and psychological and social services. Individual therapy plans are developed in the weekly tumour board meetings. The high quality of care is also a result of the proximity of the doctors and care givers involved in the Centre for Intestinal Medi- cine. Physicians in private practice and other partners in the region perform the outpatient examinations wherever possible and, when necessary, refer patients to the Cen- tre for Intestinal Medicine. Here they benefit from having all their therapies in one place. We offer several cancer therapies along with specialty services in prevention and rehabilitation. An effective pain therapy and counselling for patients with a colostomy are other important services available.

Because we are certified, we have an increasing number of patients involved in clinical studies.

The Center for Intestinal Medicine passed the reassessment for certification with flying colours in August 2009. This seal of quality, based on strict guidelines of the Ger- man Cancer Society, acknowledges the high quality of our care for patients with colon cancer.

Participating Clinics and Institutes: • Clinic for General, Visceral, Vascular and Pediatric Surgery (Surgery I) • Clinic for Radiation Therapy • Institute for Diagnostic Radiology • Medical Policlinic II (Hematology and Oncology) • Institute of Pathology • Institute for Psychotherapy and Clinical Psychology???

Appointments for prevention and therapy of colon cancer can be made through the central patient management unit (ZPM) in Sur- gery I, Tel. (0931) 201-39999.

170 5.2.11 Center for Rheumatic Diseases

General Information

The diagnosis and treatment of immune mediated diseases is one topic at the medical faculty of the university of Wuerzburg. The Center of Rheumatic Diseases founded in 2003 is an association of different institutes and clinical centers that are dedicated Prof. Dr. med. Hans-Peter Tony to rheumatic diseases. In addition to mem- (Speaker) bers of different medical, surgical, diagnos-

CONTACT DETAILS CONTACT tic or research specialities of the university Medizinischen Klinik und Poliklinik II hospital also hospitals and physicians in pri- Oberdürrbacher Str. 6 vate practice outside the university are in- 97080 Würzburg tegral parts. The aim of the Center of Rheu- Tel.: 0931/201-40 100 matic Diseases is to improve the health Fax: 0931/201-640 100 care of patients suffering from rheumatic E-mail: [email protected] diseases in the greater area surrounding the university hospital of Wuerzburg. Par- Dr. med. Stefan Kleinert (Vice-Speaker) ticularly the interdisciplinary cooperation in Tel.: 0931/201-40 100 teaching, science and clinical care will be improved. The Center of Rheumatic Diseas- Frau Vera Castro (Office) es is a member of the working group of Cen- Tel.: 0931/201-40105 ters for Rheumatic Diseases within the Ger- man society of rheumatology.

Major Research Interests

The Center for Rheumatic Diseases by itself does not institute scientific projects. However it promotes scientific interactions and cooperation programs of its members and sustains scientific projects dealing with rheumatic diseases. For that purpose the center organises interdisciplinary meetings and regular informal scientific workshops. At national level the Center for Rheumatic Diseases contributes regularly to the Ger- man epidemiological register for rheumatic diseases.

Teaching

The Center for Rheumatic Diseases is particularly involved in teaching. It coordinates the lectures, seminars and internships for clinical immunology/ rheumatology in the graduate program. In addition it commis- sions relevant continuing education for doctors in training and rheumatology specialists.

171 5.2.12 Center for Stem Cell Therapy

Activities tant subproject of the „Immune reconstitu- Professor Dr. med. Christian P. Speer FRCP tion-program“ are the multifacetted interac- (Edin.) The stem cell therapy unit was established tions between human hematopoietic stem (Speaker) in 2005. In 2009, we offered a graft to 239 cells and Notch-ligand expressing stroma adult and paediatric patients. 154 received cells. Emphasis of the investigations are Department of Pediatrics an autologous and 85 an allogeneic trans- the lymphoid differentation pathways re- Josef-Schneider-Straße 2 plant. To accomplish this program, the „Ge- sulting from these interactions under vari- 97080 Würzburg meinsame Stammzell-Labor“, which means ous conditions. Tel.: 0931/201-27830 a high end stem cell processing unit joined by the Medizinischen Klinik II and the Uni- Professor Dr. med. Hermann Einsele versitätskinderklinik, is of paramount impor- Novel cellular therapies for malignant (Speaker) CONTACT DETAILS CONTACT tance. Here, most elaborated techniques brain tumors are utilized to visualize, isolate and cryo- Department of Internal Medicine II preserve discrete cell populations in order Under the umbrella of a newly established, Oberdürrbacher Str. 6 to create the optimal cellular composition EU-wide network innovative cellular thera- 97080 Würzburg of the graft. The production process is per- pies for patients with malign brain tumors Tel.: 0931/201-40001 formed under good manufacturing practice. are developed, validated and finally tested Based on these competences, the major fo- in clinical trials. One of these approaches cus of the joined research program lies in includes the vaccination of glioblastoma pa- Dr. med. Matthias Wölfl modular cellular therapy and accompanying tients with autologous, tumor-lysate pulsed (Department of Pediatrics) translational research. dendritic cells (DCs) with subsequent appli- Tel.: 0931/201-27640 cation of in vitro generated, tumor-specific T cells. In preparation of a phase I/II clini- Professor Dr. med. Matthias Eyrich Immune reconstitution after allogeneic cal trial, comprehensive validation experi- (Department of Pediatrics) stem cell transplantation ments for clinical grade and scale produc- Tel.: 0931/201-27640 tion of DCs and antigen-specific T cells are After launching the allogeneic stem cell currently carried out. The implementation Professor Dr. med. Paul-Gerhardt Schlegel transplantation program in 2005, analysis of production procedures compatible with (Department of Pediatrics) of immune reconstitution after stem cell regulatory constraints in a GMP-facility rep- Tel.: 0931/201-27888 transplantation over HLA-barriers has been resent a particular challenge of these con- one of our major research activities. Aim of cepts. Once established, these clinical trials PD Dr. med. Stephan Mielke the project is to increase safety and effi- will underline the dedicated immunothera- (Department of Internal Medicine II) cacy of established immunotherapeutic ap- peutic emphasis of our stem cell transplan- Tel.: 0931/201-44945 proaches like donor-lymphocyte infusions tation program. (DLIs) as well as augmenting the anti-leu- Dr. med. Götz-Ulrich Grigoleit kemic potential of the graft. Another impor- (Department of Internal Medicine II) Tel.: 0931/201-40042

PD Dr. med. Gernot Stuhler (Department of Internal Medicine II) Tel.: 0931/201-40052

Fig.1: The building D30 hosts the Center for Stem Cell Therapy.

172 In cooperation with researchers from Hei- delberg and Düsseldorf, we carefully investigate the hematological and immunological reconstitution of bone marrow function after cord blood transplantation. To this end and supported by the Deutsche Jose Carre- ras Leukemia Foundation, we successfully established a clinical and scientific protocol within a multicenter phase I/II study.

Haploidentical stem cell transplant program

Our haploidentical stem cell transplant program focuses clearly on the reduction of transplantation related mortality (TRM). We are chairing an international multicenter trial (Study Chair Europe and Wuerzburg: S. Mielke; Sponsor Kiadis Pharma, The Neth- Fig. 2: The stem cells are stored in liquid erlands) on the use of selectively allodeplet- nitrogen at minus 196 °C. ed donor lymphocytes as a novel method of an adoptive immune transfer after T cell depleted haploidentical blood stem cell trans- Immune therapy of chronic CMV infec- plantations to cut down on TRM. In a first tion step donor lymphocytes are ex vivo co-cul- Straathof KC, Rao K, Eyrich M, Hale G, tured with irradiated patient-derived periph- Bird P, Berrie E, Brown L, Schlegel PG, In the first DC vaccination trial after allo- eral blood mononuclear cells. In a second Goulden N, Gaspar HB, Gennery AR, Lan- geneic SCT, we treated 24 patients suf- step patient-reactive donor-derived lympho- dais P, Davies EG, Brenner MK, Veys P, fering from chronic CMV infection. The DC cytes are eliminated by the photodepletion and Amrolia P. Haematopoietic stem cell vaccination was tolerated without any rel- pocess. This trial is associated with respec- transplantation with antibody-based minimal intensity conditioning: a phase 1/2 evant toxicities. Vaccination led to a signifi- tive translational scientific program studying study. Lancet, 374:912-920, 2009. cant benefit compared to a historic control the specific immune reconstitution follow- group. ing haploidentical transplantation. Eyrich M, Wiegering V, Lim A, Schrauder A, Winkler B, and Schlegel PG. Immune function in children under chemotherapy for standard risk acute lymphoblastic leu- Adoptive immune transfer of streptam- kemia- a prospective study of 20 paedi- er selected T cells atric patients. Br J Haematol, 147:360- 370, 2009. We are chairing a national multicenter tri- Kuball J, Hauptrock B, Makina V, Antunes al investigating the safety and efficacy of E, Voss RH, Wölfl M, Strong R, Theobald streptamer selected CMV specific T cells in M, Greenberg PD. Increasing functional

chronic CMV infection after allogeneic SCT. SELECTED PUBLICATIONS avidity of T-cell receptor (TCR)-redirected The CMV specific T cells are selected from T-cells by removing defined N-glycosyl- ation sites in the constant domain. Jour- an unstimulated leukapheresis of the stem nal of Experimental Medicine, 206:463- cell donor or, in case of a seronegative stem 475, 2009. cell donor, from a CMV seropositive third party donor. Schöttker B, Feuchtinger T, Schumm M, Klinker E, Handgretinger R, Einsele H, Stuhler G: Five donors - one recipient: modeling a mosaic of granulocytes, natu- Cord blood transplantation ral killer and T cells from cord-blood and third-party donors. Nature Clin Pract Oncol Cord blood transplantation is an alternative 2008; 5:291-5. option for patients who urgently need an Mielke S, Nunes R, Rezvani K, Fellowes allogeneic stem cell graft but lack a suit- VS, Venne A, Solomon SR, Fan Y, Gos- able donor. Well established in the paediat- tick E, Price DA, Scotto C, Read EJ, Bar- ric setting, cord blood grafts are increasingly rett AJ. A clinical-scale selective allodeple- employed for adults. Central fort the broad tion approach for the treatment of HLA- mismatched and matched donor-recipient applicability of cord blood is the finding that pairs using expanded T lymphocytes as cord blood derived T lymphocytes are highly antigen-presenting cells and a TH9402- active against leukemia without inducing an based photodepletion technique. Blood overt risk for graft versus host reactions de- 111:4392-402, 2008. spite HLA discrepancies.

173 5.2.13 Cleft Lip and Palate Center

General course of this research project. The objec- Professor Dr. med. dent. Angelika Stellzig- Information tive is to analyze three-dimensionally the Eisenhauer (Speaker) presurgical molding of the external nose In the Cleft Lip and Palate Center of the Uni- with orthodontic pads and to assess longi- Department of Orthodontics versity of Wuerzburg patients were treated tudinal progress. Pleicherwall 2 with congenital anomalies and syndomes in 97070 Würzburg the maxillo-facial region. The treatment se- Tel.: 0931/201-73330 quence is characterized by interdisciplinary Development and testing of non-inva- cooperation with the Maxillo-Facial Surgery, sive orthodontic plate appliances to the Otorhinolaryngology, the Pediatric Clinic, treat obstructive apnea in neonates the Gynecology and the Institut for Human with Pierre Robin sequence.

CONTACT DETAILS CONTACT Genetics. The treatment starts immediately (U. Bareis, A. Stellzig-Eisenhauer in coop- after birth and continues to adulthood. eration with the Pediatric Clinic)

A nationwide unique Center for Prespeech Development & Developmental Disorders Identification of early indicators of later (Prof. K. Wemke) is integrated in the Cleft speech and language disorders in ba- Lip and Palate Center. Approximately 40 bies with cleft lip and palate newborns a year with a cleft lip palate were (K. Wermke) newly attended for treatment in the Center for an orthodontic consultation. Research activity at the Center for Pre- speech Development & Developmental Dis- orders (ZVES), Department of Orthodontics, Major Research University of Würzburg aims to identify ear- Interests ly indicators from early baby sounds that might be used to detect specific risks of speech development disorders. Based on Three-dimensional stereophotogram- the results of an interdisciplinary longitudi- metric diagnostics of the face of babies nal project, the German Speech Develop- with congenital cleft lip and palate ment Study, which was sponsored by the Establishing and three-dimensional DFG (German Research Foundation) and evaluation of a non-invasive dynamic the Max Planck Institute of Cognitive and treatment method for presurgical naso- Brain Sciences, Leipzig, we were able to alveolar orthopedic molding identify suitable risk markers in the 2nd (P. Meyer-Marcotty, U. Bareis, A. Stellzig- and 4th month of life (incl. Wermke et al., Eisenhauer) 2007; Denner, 2008; Wermke et al., submitted). We are currently in the process of Three-dimensional data for the facial soft testing these risk markers in babies with tissues of babies and infants with cleft lip orofacial clefts for their suitability in clini- and palate will be generated during the cal practice.

Fig. 1: Preoperative nasoalveolar molding with an orthopedic plate in a newborn with a cleft lip and palate.

174 Fig. 2: Orthopedic appliance with a nasal stent.

Language development disorders in Interdiciplinary consultation-hours cleft children with congenital cleft lip and lip and palate: palate Tuesdays, 2:00 to 4:00 PM, contact: (Longitudinal study in cooperation with D. 0931/201-73330 or –73320, Department M. Hansen and A. Jurkutat, University of of Orthodontics, Professor Dr. med. dent. Würzburg, Philosophy Faculty III, Depart- Angelika Stellzig-Eisenhauer, Pleicherwall ment of Special Needs Education III, Speech 2, 97070 Würzburg Therapy Education and the Department of Ear, Nose and Throat Diseases, Plastic and Cosmetic Surgery)

Children with congenital cleft lip and palate, owing to their complex damage in the oro- nasopharyngeal area, display physiological functional impairment which results in secondary developmental disabilities. These include impairment of articulation, phonation and respiration in the children concerned. The causal connection between organic defect and the resulting speech characteristics is obvious. However, the question of whether language-systematic development Kochel J, Meyer-Marcotty P, Wirbelauer J, abnormalities additionally exist in children Böhm H, Kochel M, Bareis U, Thomas W, with cleft deformities has not yet been ad- Hebestreit H, Speer C, Stellzig-Eisenhau- er A. Treatment modalities of infants with equately resolved. In view of the heteroge- upper airway obstruction – review of the neity of the research results on language literature and presentation of novel ortho- development in children with cleft lip and pedic appliances. Cleft Palate Craniofac J palate, starting with a doctoral thesis proj- 2009; accepted. ect based on selected models for language Meyer-Marcotty P, Stellzig-Eisenhauer acquisition, various hypotheses about the A. Dentofacial self-perception and so- etiology of language development disorders cial perception of adults with unilater- are being put forward and empirically test- al cleft lip and palate. J Orofac Orthop. ed. Suitable test methods for evaluating the 2009;70:224-36. language skills of children with cleft lip and Mampe B, Friederici AD, Christophe A, palate aged 4–5 years will be deduced from Wermke K. Newborns‘ cry melody is the results and applied in subsequent longi- shaped by their native language. Curr Biol tudinal studies. 15;19:1994-7,2009.

SELECTED PUBLICATIONS Wermke, K., Robb, M. Fundamental Fre- quency of Neonatal Crying: Does Body Size Matter? J Voice. 2009 Aug 5.[Epub ahead of print]. 175 5.2.14 Level I Perinatal Center

births with 51 very low birth weight infants Antenatal inflammation induced TGF-β1 Professor Dr. med. Johannes Dietl with a birth weight below 1500 g. but suppressed CTGF in preterm lungs

Department of Obstetrics and Gynecology TGF-β1 and CTGF are key regulators of lung Josef-Schneider Strasse 4 Major Research development, airway- and vascular-remod- 97080 Würzburg Interests eling. We asked whether chorioamnionitis- Tel.: 0931/201-25251 associated antenatal inflammation would Fax: 0931/201-25406 Possible role of imbalance of angio- regulate TGF-β1and CTGF expression in E-mail: [email protected] poietin-1 and endostatin in the patho- preterm lamb lungs. It could be shown that www.frauenklinik.uni-wuerzburg.de genesis of bronchopulmonary dysplasie antenatal inflammation-induced TGF-β1, (BPD) but decreased CTGF expression in preterm Professor Dr. med. Christian P. Speer, FRCP CONTACT DETAILS CONTACT lung. This dysregulation may inhibit vascular (Edin.) Chorioamnionitis and funisitis have been development or remodeling and limit lung shown associated with preterm labor and fibrosis during remodeling. These effects Department of Pediatrics postnatal pulmonary morbidity of preterm may contribute to the impaired alveolar and Josef-Schneider-Straße 2 infants. A systemic inflammatory response pulmonary vascular development that is a 97080 Würzburg of the fetus is a risk factor for BPD. Impaired hallmark of BPD. Tel.: 0931/201-27830 pulmonary angiogenesis accompanied by Fax: 0931/201-27833 simplification and rarification of alveoli is a E-mail: [email protected] histological hallmark of BPD. Angiopoietin- Thymic changes after chorioamnionitis www.kinderklinik.uni-wuerzburg.de 1 mediates vascular development, matu- induced by intraamniotic LPS in fetal ration, and stabilization. Endostatin mainly sheep acts as an angiostatic factor. In a cohort of extremely premature infants funisitis was Regulatory T-cells (Treg) mediate homeo- associated with decreased concentrations stasis of the immune system and differen- of endostatin and angiopoietin-1 in airways tiate under the control of the transcription during the very early phase of premature factor FoxP3 in the fetal thymus. Using an life. Infants, who developed BPD, had a de- animal model of chorioamnionitis we as- creased ratio between angiopoietin-1 and sessed if fetal inflammation caused by cho- endostatin suggesting an imbalance toward rioamnionitis would modulate thymus de- inhibition of pulmonary angiogenesis. velopment. Results show that antenatal inflammation during fetal life induces thymus changes and influences Treg development. Long time effect of BPD on physical ac- Possible consequences of these temporary tivity and exercise capacity in children changes in the immune system in postnatal Mission life remain to be studied, but accumulating and structure In this current study the long time effects of evidence suggests an important role for an- BPD on lung function, physical activity and tenatal inflammation in fetal programming The Mother- and Children-Centre (Level I exercise capacity of school age children are and subsequent disease development. Perinatal Centre) is a joint institution of the analysed. departments of Obstetrics and Gynecolo- gy and of Pediatric comprising two obstet- Fetomaternal interface rical wards, 5 labour and delivery rooms, Serum and glucocorticoid-inducible ki- an operating room for caesarean sections nase (SGK1) in pulmonary tissue of pre- The interactions between the maternal im- and outpatient clinics for obstetrics, repro- term fetuses exposed to chorioamnio- mune system and the placenta that lead ductive medicine and prenatal diagnostics. nitis. to tolerance of the fetus are analyzed. A For healthy newborns there exit a nursery subproject studies the effect of soluble fac- room. Furthermore, the Perinatal Centre The purpose of this set of studies was to tors, such as cytokines, growth factors and has a special care unit for moderately pre- analyse if the expression of SGK1 is influ- hormones, which influence cellular interac- mature infants and newborns, who must enced by chorioamnionitis by studying lung tions. As part of a clinical research group be observed, and a neonatal intensive care tissue sections of stillborn fetuses with or (KFO 124, cooperation with the depart- unit for extremely preterm baby’s und criti- without chorioamnionitis. SGK1 stimu- ment of dermatology, J. Becker), placenta- cally ill newborns. On the neonatal intensive lates epithelial Na(+) channel ENaC and tion serves as a model system for tumours. care unit preterm infants and newborn with the Na(+)/K(+)-ATPase activity, an effect Under a new “first applicant” programme by severe disorders and congenital malforma- presumably participating in the regulation the IZKF Wuerzburg, a project on the role of tions are treated on state of the art technol- of transepithelial Na(+) transport. It could thrombopoietin in early pregnancy is pro- ogy and by highly qualified staff. This is done be shown that exposure to chorioamnion- moted. in close cooperation with the departments itis is associated with a downregulation of of Pediatric Neurosurgery, Pediatric Surgery, SGK1 in fetal lung tissue. The possible con- Urology with Pediatric Urology, Ophthalmol- sequences of a decreased rate of SGK1 Therapeutic strategies for the treat- ogy, Oto-Rhino-Laryngology, Thoracic and could be an impaired ability to clear the ment of premature labour Cardiovascular Surgery, Orthopaedics and lungs from excessive fluid immediately af- Orthodontics. In 2009 there were 1482 ter preterm birth. Tocolytic drugs have different mechanisms

176 Fig. 1: Extremely low birth weight preterm infant with a birth weight of 450 g. of action. During long-term treatment, however, it comes to a rapid loss of effect, and often a premature birth cannot be avoided. In a collaborative project with the institute Thomas W, Seidenspinner S, Kramer BW, of pharmacology, fundamental mechanisms Kawczynska-Leda N, Chmielnicka-Kopac- of these substances at the myometrium of zyk M, Marx A, Wirbelauer J, Szymankie- pregnant uteri are elucidated. The goal is wicz M, and Speer CP. Airway concentra- to identify new and to optimize established tions of angiopoietin-1 and endostatin in therapeutic strategies to reduce fetal mor- ventilated extremely premature infants are decreased after funisitis and unbalanced bidity and mortality due to preterm delivery with bronchopulmonary dysplasia/death. caused by premature labour. Pediatr Res 65: 468-473, 2009.

Wirbelauer J, Schmidt B, Klingel K, Cao L, Lang F, and Speer CP. Serum and glucocorticoid-inducible kinase in pulmonary Teaching tissue of preterm fetuses exposed to chorioamnionitis. Neonatology 93: 257-262, The Mother- and Children-Centre offers 2008. several courses for medical students. In a Kunzmann S, Speer CP, Jobe AH, and “skill`s lab” students have the opportuni- Kramer BW. Antenatal inflammation in- ty to train clinical situations and to handle duced TGF-beta1 but suppressed CTGF in

diagnostic equipment. Once a week, there SELECTED PUBLICATIONS preterm lungs. Am J Physiol Lung Cell Mol is an interdisciplinary conference between Physiol 292: L223-231, 2007. the department of Obstetric and Pediatric Rieger L, Segerer S, Bernar T, Kapp M, as part of the Perinatal Centre. In addition, Majic M, Morr AK, Dietl J, and Kammerer regular scientific meetings and symposia U. Specific subsets of immune cells in hu- are organized in Würzburg, e.g. every 3rd man decidua differ between normal preg- year the international symposium “Recent nancy and preeclampsia--a prospective observational study. Reprod Biol Endocri- Advances in Neonatal Medicine” with par- nol 7: 132, 2009. ticipants from more than 45 nations. Out- side of the United States of America this Segerer SE, Muller N, van den Brandt J, symposium represents the largest scientific Kapp M, Dietl J, Reichardt HM, Rieger L, and Kammerer U. Impact of female sex forum for neonatology. hormones on the maturation and function of human dendritic cells. Am J Reprod Im- 177 munol 62: 165-173, 2009. 5.2.15 Cardiovascular Center

General ease development – from the clarification Information of basic mechanisms leading to heart failure to the advanced and terminal stages of Cardiovascular and cerebrovascular diseas- heart failure and its complications and co- es are the major cause of death in Germa- morbidities. The spectrum of research ob- ny. Thus, cardiovascular research is one of jectives will include diagnostics, treatment the most important scientific as well as clin- and health care strategies. The following ical topics at the Medical University of Würz- themes for research into diagnostic, thera- Professor Dr. med. Georg Ertl burg. In the cardiovascular center of Würz- peutic and management strategies of heart (Speaker) burg University the medical faculty and the failure have been defined: 1. Advancement university hospital unite the clinical and sci- of Diagnostics and Management; 2. Heal-

CONTACT DETAILS CONTACT Cardiovascular Center entific competence of different institutions ing, Remodeling, Protection; 3. Rare Heart Oberdürrbacher Strasse 6 regarding prevention and treatment of car- Diseases and Genetic Principles; 4. Endo- 97080 Würzburg diovascular diseases, their risk factors, and crince System and Metabolism; 5. Cardio- Tel.: 0931/201-39001 complications. It uses existing structures for renal Cross-talk; 6. Heart Failure: Emotion, this interdisciplinary approach of cardiovas- Cognition, Cerebral Dysfunction; 7. Ad- Professor Dr. med. Rainer Leyh cular disease management and establish- vanced/End-stage Heart Failure, Tissue En- (Vice-Speaker) es new collaborations with local physicians gineering and Regenerative Medicine. Tel.: 0931/201-3301 and national institutes. Due to the multi- factorial etiology and treatment of cardio- The cardiovascular center has also an im- Professor Dr. med. Martin Lohse vascular diseases this interdisciplinary ap- portant role in continuing medical educa- (Vice-Speaker) proach to science is mandatory. Treatment tion. Interdisciplinary student education Tel.: 0931/201-48401 of cardiovascular diseases also benefits and meetings have been organized includ- from interdisciplinary networks (“compre- ing a corollary course of Experimental Med- PD Dr. med. Stefan Frantz (Office) hensive medical management”). Innovative icine, cardiologic-cardiovascular surgery Tel.: 0931/201-43542 diagnostics and therapeutics can promptly seminars, cardiovascular imaging semi- be transferred in patient care. This increas- nars, cardiologic-paediatric seminars, and es attractiveness for patients, scientists, medical pathology conferences. Numer- and physicians. ous meetings have taken place discussing for example acquired diseases of the aortic The central interest of the cardiovascu- valve, cardiovascular healing, quality man- lar center lies in the prevention and treat- agement in the cath lab, and the Mainfrank- ment of heart failure and its complications. en Heart Attack Net. Physician-patient sem- However, while mortality from coronary ar- inars continue to be organized in collabora- tery disease is decreasing, mortality from tion with the Deutsche Herzstiftung. congestive heart failure is increasing. Thus, to investigate basic mechanisms and new therapeutic options for heart failure numer- Interdisciplinary Network Heart Failure ous projects have been funded by the DFG, and National Competence Net Heart IZKF, SFB 688 and by the Rudolf-Virchow- Failure Zentrum. Results from molecular biology, genetics and physics are transferred into Prof. Ertl is co-chair of the national compe- clinical research and practice. It is our goal tence net heart failure. The cardiovascular to integrate basic science and clinical re- center contributes 5 out of 20 projects and search (cardiology, endocrinology, nephrol- has collaborations with several others, as ogy, psychiatry, neurology, psychology) to for example SP6a “New diagnostic strate- improve patient care. This led to the “In- gies – Cardiac imaging and serum-/plasma- terdisciplinary Heart Failure Network” (sup- markers”, C. Angermann/G. Ertl, SP6b “Eti- ported by funds of the BMBF) as well as ology and prognostic relevance of beta1-re- the “Mainfranken Heart Attack Net” (see ceptor autoantibodies in human myocardial below) fostering interdisciplinary research, diseases”, R. Jahns/C. Angermann, SP15 teaching and patient care, and the initia- Disease manifestation and management tive for an “Integrated Centre for Research in chronic heart failure (Randomized INH and Treatment Heart Failure”. The latter Study), C. Angermann/G. Ertl. More than has proposed a Comprehensive Heart Fail- 3,000 patients have been included in reg- ure Center (CHFC), which has been posi- istries, cohort studies and trials of the local tively evaluated in three rounds (final vote Interdisciplinary Network Heart Failure in or- pending). The principal research objective der to test the efficacy and effectiveness of at the CHFC will be the comprehensive ad- disease management programmes includ- vancement of care for patients with heart ing cardiologic as well as psycho-educative failure thus improving their quality of life interventions to monitor and educate pa- and life expectancy. The CHFC aims to pur- tients with heart failure. The translation into sue preventive strategies on all levels of dis- patient care is being developed. Associat-

178 ed to the competence net is the MOOD-HF collaborations as demonstrated by a large techniques for mitral and aortivc valve sur- study (funded by the BMBF). In this study number of publication. Many of them are gery are currently beeing established. Thus, the effect of a serotonin reuptake inhibitor supported by the IZKF (see separate chap- thoracic and cardiovascular surgery has be- on morbidity and mortality in patients with ter 5.2.2, page 153). come a decisive contributor for the research heart failure and depression is tested in as- focus Heart Failure. sociation with the department of psychiatry. Furthermore, the connection of rheumatic Department of Thoracic and Cardiovas- and cardiac diseases is tested in collabora- cular Surgery tion with the Medizinische Klinik II. Another large project has been launched in March Prof. Rainer G. Leyh was appointed new di- 2010: The ETiCS study (R. Jahns/G. Ertl) rector of the department on April 1 2007. will investigate the role of activating autoan- Apart from a dramatic increase in the case tibodies directed against the cardiac beta- load for open heart surgery various oper- adrenergic receptor in a series of cross-sec- ative procedures have been introduced in tional and longitudinal studies. ETiCS is a Würzburg: Complex aortic procedures like collaborative effort of the competence net, Ross, David and Yacoub operations and also involving several other European uni- emergency operations of aortic dissections versitary centers investigating the bioma- have been established on a large scale. In terials and clinical data sets of more than addition the department offers help with 1,300 patients and healthy subjects. The operative techniques e.g. for bi-ventricular main aim is to elucidate the pathogenet- pacing devices to surrounding hospitals who ic role of these antibodies in human heart embark on these new procedures. In close disease also utilizing high-end diagnostic cooperation with the departments of anes- tools that were developed at the University thesiology and internal medicine I the car- of Würzburg. diovascular surgery department facilitates transferral of patients in cardiogenic shock with the life-bridge-system (a miniaturized Mainfranken Heart Attack Net and portable heart-lung support system). This measure will continue to strengthen the impact of the Mainfrank Heart Attack Net and the clinical management of these high risk patients.

Furthermore, the cardiac transplantation program has been reinstituted, supporting interdisciplinary research in the field of heart failure and strengthening the coope- aration with the Interdisciplinary Network Heart Failure. Scientific interest is centered The Mainfranken Heart Attack Net was around improvement of donor acceptance funded in 2007 to connect emergency phy- criteria for heart and lung transplantations sicians with cardiologists and cardiothoracic and basic and clinical research into trans- surgeons in order to minimize the time for plant vasculopathy. Selected patients with cardiac interventional therapy. If coronary end-stage heart failure benefit from ventric- artery intervention appears not to be fea- ular mechanic support system (assist de- sible or useful the department of thoracic vices) and/or complex cardiosurgical pro- and cardiovascular surgery offers emergen- cedures as, e.g., reconstruction of the left cy operations 24 hours a day. The Main- ventricle. Finally, minimally invasive surgery franken Heart Attack net has diminished the time to coronary interventions within a few months and allows to collect data for quality management as well as clinical research.

SFB 688

The SFB 688 „Mechanisms of cardiovascular cell-cell interactions, and molecular and functional imaging of these interactions“ integrates cardiovascular basic with clinical science (please find more information in chapter 5.1.6, page 140). Besides the SFB there are numerous interdisciplinary

179 5.3 Research Training Groups 5.3.1 Research Training Group 520, Immunomodulation

General joint study of a modern immunology text- Professor Dr. rer. nat. Thomas Hünig Information book, miniprojects to learn new techniques, (Speaker) journal clubs, and progress reports. The DFG funded Graduate College Immuno- Institute for Virology and Immunobiology modulation completed a full term of three 2009 saw the 4th joint retreat with two oth- Versbacher Str. 7 times three years at the end of 2008, er graduate colleges, GRK 592 “Lympho- 97078 Würzburg and received funding for a limited num- cyte Activation” (Erlangen) and the GRK Tel.: 0931/201-49951 ber of graduates for an additional year. In 794 “Cell Biology of immune-associated Fax: 0931/201-49243 the meantime, the popularity of this gradu- processes” (Tübingen), and we plan to con- E-mail: [email protected] ate college led to an increase in associat- tinue this fruitful tradition. Funding for this www.gk-520.uni-wuerzburg.de/ ed members, allowing its continuation as retreat is now provided by the GSLS, and

CONTACT DETAILS CONTACT a graduate training programme within the a limited number of GSLS graduates from class “Infection and Immunity” of the Grad- other training programmes is offered free uate School for Life Sciences with more participation. than 30 participants.

Major Research Interests

Graduates from all research groups at the University of Würzburg working on immunological topics are welcome in the graduate training programme. Basic immunology performed in rodent models is complemented by infection biology, tumor immunology and clinical immunology.

Teaching

The wide spectrum of research within the framework of immunology provides the training programme with specialist teachers who guarantee a comprehensive education. During the period of the DFG funded graduate college, a versatile training programme has been developed in which teaching modules vary each semester. These include the

180 5.3.2 Research Training Group 1048, Molecular Basis of Organ Development in Vertebrates

development or understanding stem cell development for regenerative medicine. Teaching After a very successful first period (4/04- 9/08) the GRK 1048 is now in its sec- The participating research groups repre- ond funding term by the German Research sent various fields ranging from stem cell Foundation (DFG). biology to single molecule microscopy. This has its impact on the breadth of the teaching program. The research training group is Major Research part of the “Graduate School of Life Sci- Professor Dr. rer. nat. Dr. h. c. Manfred Interests ence (GSLS)”. Structures of supervision Schartl (Speaker) such that each student has a Thesis Advi-

CONTACT DETAILS CONTACT The research program addresses questions sory Committee that mentors her/him dur- Chair of Physiological Chemistry I in the field of Developmental Biology with ing the entire training period his have been Biocenter, a special emphasis of organogenesis and established. On an annual basis the project Am Hubland provides collaborations that offer Ph.D. stu- of each student is evaluated and restruc- 97074 Würzburg dents a broad interdisciplinary training ba- tured as necessary to guarantee a success- Tel.: 0931/31-84148 sis. It is focused on vertebrate organogen- ful completion. The qualification program of Fax: 0931/31-84150 esis, which allows the use of related model GRK 1048 offers PhD students a broad in- E-mail: [email protected] organisms by all participants. The restric- terdisciplinary training in up to date meth- www.gk-1048.uni-wuerzburg.de tion to vertebrates is also of advantage for ods and concepts of modern biomedical re- education and training as students have search with a thematic focus on develop- Professor Dr. med. Manfred Gessler more closely related scientific projects, mental biology, cell differentiation and or- (Vice Speaker) which will foster the exchange of ideas, re- ganogenesis. In order to optimally prepare Tel.: 0931/31-84159 agents and technical protocols. Transgen- the students for a career in research, the ic mouse technology has broadened the qualification programs combine seminars, study field for developmental biologists and lectures and retreats with workshops, soft serves the above-mentioned goals, as do skills and practical training modules. The the other recently emerging study objects, participants are also exposed to selected the small aquarium fish models zebrafish topics of clinically oriented research that is and medaka. The research program focuses ongoing in the medical faculty of Würzburg on the role of key molecules or molecular with the aim to broaden the scope of young complexes (signaling molecules, transcrip- scientist. Together with the strong internation factors, splicing factors, micro RNAs) in tional links this program ensures that stu- organogenesis of vertebrates. Major topics dents will be well equipped for an indepen- include neurogenesis, cardiovascular devel- dent and successful scientific career. opment and germ cell development. Experi- ments are done in four model organisms (mouse, frog, zebrafish and medaka) and cover a wide range of techniques. An important methodological aspect of the GRK 1048 is the inclusion of modern imaging techniques such as confocal microscopy and SPIM.

General Information

The aim of the research training group GRK 1048 is to provide a structured PhD research and training environment in Devel- opmental Biology. The scientific goal is to contribute to a better understanding of the molecular mechanisms of morphogenesis, patterning, cell specification and cell differentiation as the basis for the establishment of a fully functional, healthy organism. Un- der the paradigm that normal and pathological development often uses the same molecules and pathways, the topic of the GRK Fig. 1: Double staining of spermatocytes from wildtype and lamin C2 deficient (∆C2) 1048 is of immediate relevance to medi- mice for the synaptonemal complex (SC). The axial element protein SYCP3 is stained in cine. Consequently several projects address green and the lateral element protein SYCP1 in red. Spermatocytes from ∆C2 mice have questions that are directly linked to disease univalent sex chromosomes and show unpaired axes (arrowheads).

181 5.3.3 International Research Training Group 1141, Signal Transduction: Where Cancer and Infection Converge

In Würzburg the GK1141 was affiliated to the generation of synergies between these the class of „Infection and Immunity“ of the scientists for establishment of novel ther- Graduate School of Life Sciences (GSLS) apeutic approaches against infections and in 2006. The GK 1141 receives addition- cancer. al funding by the German-French College (http://www.dfh-ufa.org), which is used for exchange programs and student education. This education is performed with a focus on Teaching interdisciplinarity, teaching a broad practi- Professor Dr. med. Ulf R. Rapp cal and theoretical knowledge in a number The student training encompasses project (Speaker Würzburg) of scientific areas. specific and general aspects. During week-

CONTACT DETAILS CONTACT ly seminars the members of the GK 1141 Professor Dr. rer. nat. Thomas Rudel have to teach each other on current scien- (Speaker) Major Research tific ‚hot topics‘, current publications, text- Interests book chapters or overviews and insights Chair of Microbiology of general scientific interest. During these Biocenter One of the major similarities between the seminars the student members in addition Am Hubland pathogenesis of some infectious pathogens invite and host external speakers. During a 97074 Würzburg and cell transformation leading to cancer retreat once a year distinct topics are high- Tel.: 0931/31-84400 are pathological alterations in cellular sig- lighted and examined in detail. Furthermore Fax: 0931/31-84402 nalling processes. In this teaching program courses dealing with complex lab methods E-mail: [email protected] emphasis is placed on the similarities be- or science theory are conducted. Due to the wuerzburg.de tween infection and cancer. Three major re- affiliation with the GSLS the members of the search areas are covered: GK1141 may participate in the courses and Professor Dr. Emmanuel Lemichez seminars offered by the International Grad- (Speaker Nice) 1) Regulation of the MAP-Kinase-Pathway uate School Würzburg. Tel.: (+33) 4 93 37 77 09 under physiologic conditions and in disease The student members are supervised during 2) Manipulation of cellular signalling dur- their thesis by an individual committee. This ing the infection by pathogens committee consists of scientists from the 3) Utilization of bacteria as trojan horses Universities of Würzburg and Nice. At least for therapeutic manipulation of the cel- once a year all committee members meet lular signalling cascades or direct trig- with the student to discuss the status quo gering of anti-tumor responses and the future focus of the thesis.

This research training group connects scientists from different scientific areas such as immunology, microbiology and cancer research. The overall aim of this group is

General Information

The German-French DFG research training group GCWN (GK 1141) is a collaboration between the universities of Würzburg and Nice. The funding agency is the German Re- search Foundation (DFG) and the program runs from February 2005 until July 2010. Currently about a dozen PhD participate in the education program of this graduate college. Nine students have already acquired their PhD in the GK 1141.

182 5.3.4 Research Training Group 1156, From Synaptic Plasticity to Behavioural Modulation in Genetic Model Organisms

General Major Research Professor Dr. med. Michael Sendtner Information Interests (Speaker) The Research training Group 1156 was set The major scientific research topic of the GK Institut für Klinische Neurobiologie up in 2005 as a joint interdisiplinary educa- 1156 is the relation between brain and be- Versbacher Str. 5 tional programme by the University of Würz- haviour. Based on the research foci of the 97078 Würzburg burg, the Institute of Neuroscience, Shang- Faculties of Biology and Medicine in the Tel.: 0931/201-44000 hai, and the Institute of Biophysics, Beijing. field of neuroscience which are funded and Fax: 0931/201-44009 Highly skilled students from both countries organized via the “Collaborative Research E-mail: [email protected] in the disciplines of biology and medicine Center 554, Behavior of Arthropods” and www.gk-1156.uni-wuerzburg.de/main/ are offered an interdisciplinary training pro- the “Collaborative Research Center 581,

CONTACT DETAILS CONTACT gramme aimed to study the genetic and Molecular Models for Diseases of the Ner- cellular basis of synaptic plasticity using a vous System”, the students should work on methodologically broad approach. The re- basic topics concerning synaptic plasticity search training group provides funding for in the nervous system. All projects address 12 students from the Faculties of Biology the main question, how synaptic plasticity and Medicine at the University of Würzburg. on the molecular, synaptic and cellular level An integral part of the training programme modulates the function of the nervous sys- is a stay of at least 3-6 months at the re- tem and forms behaviour. From the meth- spective partner institutes, allowing the odological point of view, model organisms students from Würzburg to become famil- like Drosophila and mouse models with mu- iar with the research structures of both Chi- tations in molecules relevant for the regula- nese elite institutes and to use the meth- tion of synaptic plasticity, are in the center ods established there in their own research of interest. The analysis of the relation of projects. The students of this International structural alterations to behavioural mod- Research Training Group are also members ulations is one of the biggest challenges of the class “Neuroscience” of the Interna- in current neuroscience. This challenge tional Graduate School at the University of can only be met by a broad interdisciplin- Würzburg. ary approach going beyond faculty frontiers in Würzburg and including international co-

Fig. 1: Brain of an adult fly (red; in green the mushroom bodies, the associative center for odour learning).

183 operations with the groups at the Chinese Academy of Science.

Teaching

Central courses of the Graduate College are methodological courses to the generation and analysis of model organisms, introduction into modern microscopy (Life Imaging, confocal and STED microscopy), introduction into modern cell culture techniques, special classes and annual symposia in which the students from the groups from Würzburg and the Chinese partners participate. The PhD program will extent over three years and will be adapted to the current level of education and the progress in the experimental work of the graduate students. The concomitant educational programme of the Graduate College is an integral part of the education of graduate students in the class “Neuroscience” of the In- ternational Graduate School of Life Science at the University of Würzburg.

Fig. 2: Presynaptic clustering of N-type Ca-channels in growth cones of isolated mouse motoneurons. Motoneurons form clusters of Ca-channels (green) with other components of the active zone (piccolo, stained in red), this process is disturbed in motor neuron diseases such as spinal muscular atrophy.

184 5.3.5 Research Training Group 1253, Emotions

Professor Dr. rer. soc. Paul Pauli (Speaker)

Department of Psychology I Marcusstr. 9-11

CONTACT DETAILS CONTACT 97070 Würzburg Tel.: 0931/31-82843 Fax: 0931/31-82733 E-mail: [email protected] www.gk-emotions.uni-wuerzburg.de

Professor Dr. med. Klaus-Peter Lesch (Vice-Speaker) Tel.: 0931/201-77600 Fig. 1: Principal Investigators and structure of the RTG.

General tive Sciences will be advanced by guest sci- molecular basis for the processing of affec- Information entists, summer-schools with international tive stimuli, the morphology and anatomy scholars and the mandatory presentation of of the involved neural systems, normal and The GK is part of the International Graduate results at international meetings. pathological emotional behavior on a cogni- School of the University of Würzburg and tive, behavioral and physiological level, and follows its rules for the supervision of doc- modulating self-regulation processes and toral students. An interdisciplinary supervi- Major Research contexts (Fig. 1). Special interests of the sion is ensured by doctoral committees for Interests GK are to evaluate the role of the serotonin each student with members from different system and the amygdala in the processing research groups. The three year curriculum The present Graduiertenkolleg (GK) aims at of affective stimuli on several work levels is organized to allow an intensive interdis- identifying important mediators and mod- and to identify interactions between levels. ciplinary training on theories and methods erators influencing the processing of af- The philosophy project provides a theoreti- of the Affective Sciences and to provide re- fective stimuli. To reach this goal, nine re- cal framework for the empirical-experimen- search experiences in different laboratories. search groups from philosophy, psychology, tal projects, and itself focuses on the epis- Independence of students and professional psychiatry, neurology, anatomy, and physi- temological, anthropological and ethical di- academic skills will be ensured by special ology closely collaborate in order to devel- mension of research on emotion. workshops. The integration in international op excellent and internationally visible in- networks of scientists working in the Affec- terdisciplinary research opportunities for doctoral students within the Affective Sci- ences. The projects of the GK converge on Teaching four levels, each addressed by human or animal research: the neurobiological and Internet: http://www.gk-emotions.uni-wuerzburg.de/teaching/ The weekly Jour Fixe (Journal Club) provides the possibility to discuss both new results and the research project of the PhD students. International guest speakers are invited for seminars, lectures and the two meetings, i.e. the spring and the summer schools outside Würzburg. The PhD students take part in lab rotation as well as attend soft skills courses, provided free by the RTG and the GSLS. The students can participate on external events any time. Every Fig. 2: Lateral Amygdala (LA). Double Flu- year the work of the PhD students is evalu- orescence in situ hybridization in the later- ated by their three principal investigators, al nucleus of the rat amygdala. Red: neu- who work in interdisciplinary institutions. ropeptide y mRNA; green: serotonin recep- Fig. 3: Sagittal view of a human brain. tor 2C mRNA; yellow: colocalization; blue: Red-yellow shadings indicate activation in nuclear staining with DAPI; magnification: the amygdala due to the view of a threat- 20x; scale bar: 20µm. ening stimulus.

185 5.3.6 International Research Training Group 1522, HIV/AIDS and Associated Infectious Diseases in Southern Africa

General monitoring on antiretroviral therapy information Scientist: Prof. Dr. Hartwig Klinker Project 2: Study of drug-resistant HIV The principal aims of the International Re- Scientist: Dr. Jochen Bodem search Training Group 1522 are to translate Project 3: Molecular Epidemiology of HIV clinical into basic research on infectious dis- Scientist: Prof. Dr. Axel Rethwilm eases (ID) in South Africa (SA), to acquaint Project 4: Influence of different HIV sub- German PhD and medical students with types on HIV dementia conditions of transmissible diseases that Scientists: Prof. Dr. Eleni Koutsilieri and PD are currently only very rarely seen in Ger- Dr. Carsten Scheller many (GE), and to broaden the fields of ba- Project 5: Targets, mechanisms and conse-

CONTACT DETAILS CONTACT Professor Dr. med. Axel Rethwilm sic research currently undertaken at Würz- quences of regulated T cell pre-mRNA splic- (Speaker Würzburg) burg (WÜ) University by adding a new quality ing and their relevance as genetic markers into the spectrum of infectious agents/in- of virally induced or general T cell suppres- Institute of Virology and Immunobiology fectious diseases under study on an inter- sion. Versbacher Str. 7 national level. The background of this pro- Scientist: Prof. Dr. Sibylle Schneider- 97078 Würzburg posal is the understanding that whilst Africa Schaulies Tel.: 0931/201-49554 has the highest burden of ID of all conti- Fax: 0931/201-49553 nents, SA as the most developed country on Area II: E-mail: [email protected] the continent has excellent research facili- Project 6: Epidemiology, diagnosis, and mo- www.gk-1522.uni-wuerzburg.de/ ties and an infrastructure that enables the lecular mechanisms of multidrug resistance research of this programme to be conduct- in Candida albicans and its impact on host- Professor Dr. med. Wolfgang Preiser ed at the same level with German institu- fungus interactions (Speaker Kapstadt and Stellenbosch) tions. Taking advantage of the excellent re- Scientist: Prof. Dr. Joachim Morschhäuser Tel.: +27 21 938 9353 search conditions at the participating facili- Project 7: Characterization of the influence ties in Cape Town (CT) and the experience of excretory/secretory products from Echi- and broadness of ID research at WÜ Uni- nococcus multilocularis larvae on dendritic versity, a programme is conducted that (a) cell maturation and the interaction of Echi- allows the analysis of clinical samples with nococcus E/S products with TLR and CTL methods currently not available in SA, (b) surface receptors complements ongoing research activities in Scientist: Prof. Dr. Klaus Brehm WÜ by adding novel scientific aspects, (c) Project 8: Staphylococcus aureus popula- fosters basic research in SA in fields which tion structure and host cell interaction in are of utmost importance and in which ex- chronic infections pert teams are not currently present in the Scientist: Prof. Dr. Dr. Bhanu Sinha Western Cape region, and (d) guides young Project 9: Generation and characterization scientists through an organised postgradu- of candidates for malaria/HIV combination ate student education and exchange pro- therapy gramme into basic research and into the Scientist: Dr. Gabriele Pradel medically important clinical conditions of ID in SA. In particular, the student exchange Area III: programme is central to this proposal. The Project 10: Characterization of the role of research topics are divided into three main C-type lectins in dendritic cell interactions areas: In the focus of area I are clinical and with Leishmania parasites basic research on HIV/AIDS and on general Scientist: Prof. Dr. Heidrun Moll mechanisms of virus-induced immunosup- Project 11: Protective and productive in- pression. AIDS-associated opportunistic inflammatory responses induced by micro- fections will be investigated in area II, while bial products studied at the level of den- area III covers questions on the immunol- dritic cells ogy of ID. There are numerous interconnec- Scientist: Prof. Dr. Manfred Lutz tions within one and between different ar- Project 12: The role of CD28 mediated co- eas, which foster inter-project scientific ex- stimulation in the control of secondary im- change between the groups involved. On mune responses to infectious agents the SA side the corresponding speaker is Scientist: Prof. Dr. Thomas Hünig (WÜ) Prof. Dr. Wolfgang Preiser (Virology) at the University of Stellenbosch.

Research topics:

Area I: Project 1: The impact of therapeutic drug

186 5.4 Research Units 5.4.1 Clinical Research Unit 103, „Osteogenic Stem Cell Differentiation and Therapy of Bone Loss“ and Orthopedic Center for Musculoskeletal Research

Professor Dr. med. Franz Jakob General Professor Dr. med. Maximilian Rudert Information

Orthopedic Center for Musculoskeletal The Clinical Research Unit 103 „Osteogen- Research ic stem cell differentiation and therapy of Orthopedic Department bone loss“ (KFG103) was funded by the Brettreichstr. 11 German Research Society from 2001 to 97074 Würzburg 2009 to foster research at the Orthopedic Tel.: 0931/803-1580 Department. A full research professorship Fax: 0931/803-1599 for Experimental and Clinical Osteology was E-mail: [email protected] established at the same time and was taken over by Prof. Franz Jakob. During the two

CONTACT DETAILS CONTACT E-mail: [email protected] www.orthopaedie.uni-wuerzburg.de funding periods the KFO103 was the core Fig. 1: Mesenchymal stem cells in culture. www.mcw.medizin.uni-wuerzburg.de institution to establish the Orthopedic Cen- Fluorescence staining of nuclear Oct4 ex- ter for Musculoskeletal Research. The Cen- pression (A = specific antibody, B = sec- ter consists of 4 sections developed from ond antibody control) (B. Klotz). Morphol- the 4 in-house KFO103 projects, which ogy of young versus presenescent mesen- are lead by independent scientists. These chymal stem cells (C and D) (P. Benisch, are dealing with stem cell biology, molecu- R. Ebert). lar orthopedics and cell biology, tissue engineering, regenerative medicine and gene ing molecules of the CCN family of proteins therapy. The state of Bavaria, represented are important topics. We characterize sub- by the district of Unterfranken, generous- populations of mesenchymal stem cells us- ly provides the infrastructure and overhead ing genome wide array analyses to enhance costs for this Center. The facility is run in a our knowledge about the basics of regener- 600 sq. m. environment at two different lo- ative strategies and to translate this knowl- cations with working and laboratory space edge into standard operating procedures equipped for S1, S2 and radioactivity work- and quality control in cell based therapies. ing procedures. The Medical faculty decid- Scientists are involved in research networks ed to promote research on Musculoskeletal funded by the DFG (FOR793 Osteoporot- Diseases and Trauma as an emerging field ic Fracture Healing), the BMBF (Networks at the Research Campus Wuerzburg, in or- Osteopath and Preeclampsia), the Ministry der to establish a new Research Focus for of Economics (EXIST Phase I), the Bavar- Wuerzburg University. The Musculoskeletal ian Research Foundation (Network on cell Center Würzburg MCW, founded in 2007, based therapies in the elderly FORZEBRA) combines all clinics and institutes dealing and the European Union (Networks ADIPOA with Musculoskeletal Diseases and Trauma and VASCUBONE on cell based strategies in in research and patient care. The core in- bone and cartilage regeneration), and also stitutions of the MCW are the chairs for Or- the local IZKF of the Medical Faculty. thopedic Surgery, Trauma Surgery, Orofacial Surgery, Regenerative Medicine and Mate- rial Sciences in Medicine.

Major Research Interests

The Orthopedic Center for Musculoskeletal Research (KFG103) is an interactive platform, which combines basic science with translational research and clinical implementation of innovative therapeutic strategies. Major Research interests are the biology and differentiation pathways of mesenchymal stem cells and their offspring. We Fig. 3: Application of mesenchymal stem focus on morphogenesis and cellular age- cells for treatment of femoral head necro- ing to meet the needs of translation of e.g. sis. A mixture of cells and scaffold mate- guided differentiation induction and quality rial is transferred to the necrotic site of the control in regenerative therapeutic strate- femoral head via two bore holes using a gies. The signaling pathways for FGFs, vita- special plastic funnel (A and B). The pe- min D, the wnt/frz pathway of differentiation, ripheral part of the bore holes is sealed TGF� receptors and their ligands like GDFs with bone substitute material (C and D) (U. and BMPs and also the matricellular signal- Nöth).

187 • Practical Course in Orthopedics (bedside teaching in small groups, demonstrations in physiotherapy, plaster techniques and orthopedic technical devices and corselets) • Clinical ward Rounds, x-ray discussions, orthopedic colloquia • Molecular Aspects of Bone Diseases – Genes and Cell Biology • Molecular Methods for osteology in basic science • Integrated Seminar on the Molecular Basis of Musculoskeletal Diseases • TecFun, Technology of Material Scienc- es

Fig. 2: Immunofluorescence staining of the cytoskeleton and nuclei of mesenchymal stem cells grown on a collagen type II nanofiber scaffold 24 h after seeding (green = actin, red = tubulin, blue = nuclei) (R. Hallinger, L. Rackwitz).

Key Issues in Research • Osteology Outpatient Clinic with a focus Reichert JC, Heymer A, Berner A, Eulert J, Nöth U. Fabrication of polycaprolactone on osteoporosis and rare bone diseases collagen hydrogel constructs seeded with • Biology of Mesenchymal Stem Cells, (F. Jakob, L. Seefried, K. Osterhage, G. mesenchymal stem cells for bone regener- Signaling pathways for FGFs, TGFβ/BMP, Baron) ation. Biomed Mater. 2009 16;4:65001. vitamin D, cellular ageing, fracture heal- • Rickets, Special Project on Calcium De- ing after trauma and in osteoporosis (F. ficiency Rickets in Nigeria (F. Jakob, P. Ebert R, Zeck S, Krug R, Meissner-Weigl J, Schneider D, Seefried L, Eulert J, Ja- Jakob, R. Ebert, B Mentrup, P. Benisch, Raab, R. Ebert, J. Eulert, C. Kitz (Child- kob F. Pulse treatment with zoledronic acid B. Klotz, N. Raijmaakers, S. Müller-Deu- rens Hospital), B. Sponholz (Geographic causes sustained commitment of bone bert, L. Seefried) Department) marrow derived mesenchymal stem cells • Mechanobiology and Biomechanics (F. • Genetics and Molecular Biology of Hy- for osteogenic differentiation. Bone. 2009 May;44(5):858-64. Jakob, L. Seefried, M. Hoberg, R. Ebert, pophosphatasia (F. Jakob, C. Beck S. Müller-Deubert, A. Steinert) (Childrens Hospital), B. Mentrup, C. Goebel S, Lienau J, Rammoser U, Seefried • Molecular Orthopedics and Cell Biol- Marschall) L, Wintgens KF, Seufert J, Duda G, Ja- ogy, Matricellular Proteins of the CCN • Molecular Mechanisms of metastatic kob F, Ebert R (2009) FGF23 is a putative family in Morphogenesis and Tissue En- Bone Disease (F. Jakob, R. Ebert, N. marker for bone healing and regeneration. J Orthop Res. 2009 Sep;27(9):1141-6. gineering (N. Schütze, T. Schilling, K. Schütze)

Schlegelmilch, R. Laug, A. Noll, S. Hilp- SELECTED PUBLICATIONS Steinert AF, Palmer GD, Pilapil C, Nöth U, ert) Evans CH, Ghivizzani SC. Enhanced • Regenerative Medicine/Tissue Engineer- in vitro chondrogenesis of primary mesenchymal stem cells by combined gene ing/Translational Cell Therapy (U. Nöth, Teaching transfer. Tissue Eng Part A. 2009 L. Rackwitz, R. Hallinger, M. Haddad- May;15(5):1127-39. Weber, M. Hoberg, M. Rudert) • Course in clinical examination tech- • Gene Therapy in Musculoskeletal Re- niques for operative and conservative Kunzmann S, Seher A, Kramer BW, search and Therapy (A. Steinert, M. orthopedics Schenk R, Schütze N, Jakob F, Sebald W, Speer CP. Connective tissue growth fac- Kunz, P. Prager, N. Armbruster, C. We- • Lectures in Basics of Orthopedics (also tor (CTGF) does not affect TGF-�1 induced ber) accompanying the practical course) Smad3 phosphorylation and T lymphocytes proliferation inhibition. Int Arch Aller- 188 gy Imm 2008; 147(2):152-160. 5.4.2 Clinical Research Unit 124, The Tumor Microenvironment: Target Structure and Modulator of Immune Responses

General Professor Dr. med. Eva-Bettina Bröcker Information (Speaker) The Clinical Research Group 124 (KFO124) Josef-Schneider-Str. 2 was founded in 2004 under the guidance 97080 Wuerzburg of Prof. Broecker and Prof. Becker at the Tel.: 0931/201-2635 Department of Dermatology. Other subproj- Fax: 0931/201-26462 ects (SP) are localized at the gynecologi- E-mail: [email protected] cal hospital, the Medical clinic II and the www.tumor-microenvironment.de Virchow Centre. In September 2007, since the prolongation of its term, 3 further sub- Fig. 1: Cellular components of the tumor

CONTACT DETAILS CONTACT Professor Dr. med. Jürgen C. Becker projects at the Dermatology, Neurology, stroma and analysis of different aspects in (Head) and the Medical clinic I were added to the the KFO124 subprojects. Tel.: 0931/201-26396 KFO124.

The KFO124 attends to fundamental research and clinical orientated problems result of immune response to solid tumors. concerning tumor-stroma interactions. The Moreover, the tumor microenvironment may obtained knowledge should allow to bet- serve as an additional source for targets of ter understand immune responses in sol- therapeutic immune responses. Hence, the id tumors. Subsequently, this information subprojects of the KFO 124 focus on differ- can be transferred to clinical aspects to im- ent cell types and interaction aspects in the prove the efficacy of immune therapies for tumor micromilieu. malignant diseases and to establish new anti-cancer vaccines targeting the tumor micromilieu. SP Becker

In this project stroma-associated antigens Major Research are preclinically and clinically evaluated for Interests anti cancer therapy by eliciting a vaccination induced immune response attacking Malignant tumors are complex tissues com- the tumor stroma and thereby inhibiting tu- posed of cellular and structural components mor progression. In this regard, we not only interacting with and influencing each other. have identified immunogenic peptides of Indeed, many steps in cancerogenesis, e.g. tumor-stroma-associated antigens survivin, proliferation, invasion, angiogenesis, re- CD105 and S100A4, but also performed modeling of the extracellar matrix and me- the first clinical tests with these peptides. tastasis depend on microenvironmental factors that are produced by stroma cells, e.g. fibroblasts, endothelial cells and infiltrating SP Fassnacht/Reichardt inflammatory cells. In addition, the tumor microenvironment is an important modula- This project investigates the interaction of tor of ongoing tumor-specific immune re- glucocorticoids and the immune system in sponses. The modulation is both direct, patients with adrenocortical carcinoma. The i.e. inflicting the activity of tumor infiltrating group cares for a large number of these pa- lymphocytes, as indirect, e.g. changing the tients. Of particular interest is the tumor- function of antigen presenting cells. Inter- induced immune suppression in glucocorti- estingly, very similar mechanisms seem to coid-secreting tumours. In addition, the ef- be involved in several physiologic situations fects of exogenous glucocorticoids on regu- such as maintaining peripheral tolerance latory T cells will be analysed. to self antigens or avoiding immune reactions to the semiallogenic fetus during pregnancy. Therefore, analyses of immune eva- SP Friedl sion mechanisms in placentation may help to better understand immune reactions in Immunological control of progressive tu- cancer patients and vice versa. mors activation and expansion of tumor specific cytotoxic T lymphocytes (CTL) fol- Within the scope of the KFO124 anti-tumor lowed by an efficient effector phase in the immune responses ongoing in situ in the tumor microenvironment. We established context of the tumor microenvironment are a real-time 3D matrix-based model of CTL analysed. The goal is to obtain a compre- function that allows the observation of ac- hensive understanding of the immunologi- tive migration, interaction, dissociation and cal relevant processes, which determine the serial killing of CTL with target cells over up

189 to 24 hours. Using this model, we presently address whether factors present in the tumor microenvironment interfere or enhance of anti-tumor CTL response and serial killing. Ongoing experiments aim at imaging serial killing in vivo using orthotopic melanoma lesions in syngenic mice using adop- tively transferred CTL. These studies will help to understand local and cellular determinants of effective, or defective, CTL function in cancer disease.

SP Kaemmerer

The placenta could be regarded as a natural model system for invasive tumours. In this project the interaction of the tumour- like invasive fetal trophoblasts with maternal immune cells are studied focussing on mechanisms which lead to the induction of tolerance and allow the cytotrophoblasts to escape the maternal immune system.

SP Wiendl

The main emphasis of the project is on the detailed characterization of membrane transfer of immune-tolerogenic molecules, such as the non-classical MHC molecule HLA-G or the coinhibitory B7 molecule B7-H1, using trogocytosis as a mechanism of immune- modulation in the milieu of the tumor. Friedl P, Weigelin B: Interstitial leucocyte migration and immune function. Nat.Im- munol.2008, Sept 9: 960-969.

SP Schrama Hofmeister-Müller V, Vetter-Kauczok CS, Ullrich R, Meder K, Lukanidin E, Bröck- The project addresses the role of the na- er EB, Straten P, Andersen MH, Sch- rama D, Becker JC. Immunogenicity of ture of the antigen on the development of HLA-A1 restricted peptides derived from immune responses. Currently, the impact of S100A4 (metastasin 1) in melanoma pa- natural regulatory T cells on different an- tients. Cancer Immunol Immunother. tigen specific immune responses is inves- 2009;58:1265-1273. tigated. The specific immune responses Rieger L, Segerer S, Bernar T, Kapp M, are directed against antigens which are ex- Majic M, Morr AK, Dietl J, Kämmerer U. pressed a) ubiquitary b) localized, or c) af- Specific subsets of immune cells in human ter induction primarily on stroma-associat- decidua differ between normal pregnancy ed fibroblasts. and preeclampsia--a prospective observational study. Reprod Biol Endocrinol. 2009 23:132. SELECTED PUBLICATIONS Waschbisch A.,,Meuth SG,Herrmann Teaching AM, Wrobel B, Schwab N, Lochmüller H, Wiendl H. Intercellular exchanges of membrane fragments (trogocytosis) between The groups participating in the KFO124 su- human muscle cells: a potential mecha- pervise medical and biological dissertations, nism fort he modulation of muscular im- as well as biomedical master theses in fun- mune responses. J Neuroimmunol 2009, damental and clinical research. The supervi- 209: 131-138. sion of dissertations partly is done within the Weismann D, Briese J, Niemann J, Grüne- Graduate School of Life Sciences. In addi- berger M, Adam P, Hahner S, Johanssen tion, the group leaders participate in lectures S, Liu W, Ezzat S, Saeger W, Bamberger for the students of different specialisations AM, Fassnacht M, Schulte HM, Asa SL, Al- lolio B, Bamberger CM. Osteopontin stim- (medicine, biomedicine, and biology). ulates invasion of NCI-h295 cells but is not associated with survival in adrenocortical carcinoma. J Pathol. 2009;218:232- 190 40. 5.4.3 Clinical Research Unit 125, Attention-Deficit/Hyperac- tivity Disorder - Translational Research Focus on Mo- lecular Pathogenesis and Treatment Across the Life Cycle

Professor Dr. med. Klaus-Peter Lesch of neuropsychology, psychobiology as well allow better understanding of both the mo- (Speaker and Coordinator) as child and adolescent, and adult psychia- lecular and cellular foundation of ADHD and try will strengthen the connections between the relevance of genetic variation for dis- Department of Psychiatry, Psychosomatics the individual disciplines by establishing ease-related behavior such as hyperactivity, and Psychotherapy new research groups, who will investigate attentional and cognitive deficits, emotional Füchsleinstr. 15 common topics. In that, new opportunities dysregulation, and drug use. Finally, the de- 97080 Würzburg for the study of the molecular foundations in sign of novel therapeutic strategies requires www.psychobiologie.uni-wuerzburg.de/ the etiopathogenesis and long-term course translational approaches with interdisciplin- Tel.: 0931/201-77600 of ADHD have been put into practice. ary cooperation of basic research and clini- Fax: 0931/201-77620 cal medicine. E-mail: [email protected]

CONTACT DETAILS CONTACT Major Research The KFO 125 is divided into ten tightly in- Professor Dr. med. Andreas Warnke Interests terconnected subprojects: Two subprojects (Coordinator) (SP 1 and 2) focus on clinical aspects in- Department of Child and Adolescent Psychia- ADHD (MIM 143465) is the most common cluding diagnostic evaluation of ADHD and try, Psychosomatics and Psychotherapy behavioral disorder in childhood with a prev- co-morbid disorders across the life cycle Tel.: 0931/201-78000 alence of 4-8% and with substantial herita- as well as ascertainment of patients and E-mail: [email protected] bility which is likely due to multiple genes of their families for genetic study (Jacob et small effect size. Longitudinal studies dem- al. 2007). In addition, these two subpro- onstrated persistence into adulthood with jects assess etiological heterogeneity, clin- a lifetime prevalence estimated at approxi- ical symptoms of subtypes and outcome, General mately 2-4%. Epidemiological studies sug- as well as psychosocial impact of ADHD Information gested high co-morbidity with other psychi- within the framework of a family-centered atric disorders; lifetime prevalence rates of outpatient unit. In contrast to previous lon- The molecular pathogenesis of Attention- anxiety disorders in adult ADHD approach gitudinal studies, a multi-layer analysis fa- Deficit/Hyperactivity Disorder (ADHD) and 50%. Affective disorders and alcohol/drug cilitates a novel approach in follow-up re- the significance of its endophenotypes and dependence also display a remarkable fre- search which is likely to provide a more pro- comorbid disorders, such as substance quency (Fig. 1). A co-morbidity with anti- found understanding of the interaction be- abuse, affective disorders, and antisocial social personality disorder was reported tween genetic disposition and environmen- personality disorders, for the course of ill- to be increased in several clini- ness is both clinically and health politically cal cohorts. The burden of dis- a highly relevant but largely unsolved prob- ease cannot be overestimated by lem. The Clinical Research Program (KFO accounts of social and economic 125), as a joint facility of the Departments problems as well as impaired aca- of Child and Adolescent Psychiatry, Psy- demic achievement and work per- chosomatics and Psychotherapy (KJPPP) formance. Particularly, disruptive and Psychiatry, Psychosomatics and Psy- family environment may harm off- chotherapy (PPP), deals with the interde- spring development. pendent relationships between the molecular and functional-structural mechanisms By integrating the concepts of mo- of the pathogenesis of ADHD and its sig- lecular genetics, neurobiology, and nificance for its long-term course using in- cognitive psychology, the psychiat- terdisciplinary and translational research ric neurosciences have witnessed strategies. The primary goals are based on remarkable progress in the under- the following concept: By joining preclinical standing of the relationship be- Fig. 1: Chromosome 7p15.2-15.3 duplication and and clinically oriented research groups, who tween neurodevelopment, neural neuropeptide Y. Segregation of the chromosome work on ADHD-specific molecular mecha- function, and behavior related to 7p15.2-15.3 duplication (D) in a multigeneration- nisms of nerve cell function as well as mo- ADHD. In this context particular- al family with ADHD is depicted. Affected members lecular genetic and developmental biolog- ly animal models such as geneti- are symbolized by solid black symbols when the du- ical essentials of brain function, and on cally modified mice or nonhuman plication is present, and by solid grey when absent; structural-functional basis of the complex primates contributed important in- unaffected members are identified by open sym- behavior of ADHD, predictors and differen- sight. On the other hand improve- bols. Moreover, the correlation between neuropep- tial strategies for therapy during the long- ment of methodological tools in tide Y (NPY) plasma concentrations and body mass term course of illness are being developed. psychology and psychiatry permit- index (BMI) in 7p15.2-15.3 duplication carriers Moreover, evolutionary conserved ADHD- ted the accumulation of new infor- with ADHD, non-carriers with ADHD, and healthy relevant principles of structure and function mation on the psycho- and neu- family members is plotted. F numbers allow alloca- of the brain as well as syndrome-typical be- robiological basis of behavior and tion to the pedigree. Finally, neural activation in the havior (e.g., hyperactivity, attention-defi- its alteration in ADHD. The human ventral striatum during the anticipation of large re- cit, impulsivity, aggression, substance use) genome project and the sequenc- wards (upper panel) and in the posterior insula dur- are being defined by comparative investiga- ing of mouse and rhesus macaque ing the anticipation of large losses (lower panel) for tions of different species (humans, nonhu- genomes shifted the focus also to 7p15.2-15.3 duplication carriers with ADHD (n = man primates, mice). Finally, the preexist- investigations of gene function in 4) and healthy controls (n = 21) is shown (Lesch ing areas of convergence between the fields psychiatry. This development will et al. 2010).

191 2009, Conzelmann et al. 2009). Finally, all aspects of the clinical and neurobiological research program are integrated by a subproject on genetic epidemiology/biostatistics (SP 9) and by a junior research group on imaging of genetic variation (SP 10 - JRG). The primary goal of the JRG is the elucidation of the effects of genetic variation on the functional neuroanatomy of attention, impulsivity as well as emotion and its rel- Fig. 2: Delay discounting in ADHD. Dysfunctional evance for ADHD using different reward processing, accompanied by a limited ability brain imaging techniques like EEG, to tolerate reward delays, is a prominent feature in NIRS, fMRI and PET. ADHD. Using fMRI, brain activation in adult patients with ADHD and healthy controls was examined dur- The basis for the pursuit of these ing a series of choices between two monetary re- concepts and goals is the interdis- ward options that varied by delay to delivery. Com- ciplinary composition of KFO 125 pared with healthy controls, hyporesponsiveness and its integration into the re- of the ventro-striatal system was demonstrated in search structures of the University patients with ADHD and was evident for both im- of Wuerzburg (e.g. SFB 581, GRK mediate and delayed rewards. In contrast, delayed 1156, GRK 1263, GSLS, IZKF) as rewards evoked hyperactivation in dorsal caudate well as into a wide spectrum of nucleus and amygdala of ADHD patients. In both national (e.g. BMBF Multicentre Jacob CP, Romanos J, Dempfle A, Heine M, structures, neural activity toward delayed rewards Study, Nationales Schwerpunkt- Windemuth-Kieselbach C, Kruse A, Reif A, was significantly correlated with self-rated ADHD netzwerk ADHS, MPI für Moleku- Walitza S, Romanos M, Strobel A, Brocke B, symptom severity. The findings support the con- lare Genetik) and international Schäfer H, Schmidtke A, Böning J, Lesch KP cept of a diminished neural processing of rewards collaborations (e.g. EU Newmood (2007) Co-morbidity of adult attention-deficit/hyperactivity disorder with focus on per- in ADHD and are in accordance with predictions of Network, NIMH, NHGRI, NIDA, sonality traits and related disorders in a ter- the delay aversion hypothesis (Plichta et al. 2009). NIAAA, Tgen Research Institute). tiary referral center. Eur Arch Psychiatry Clin This resulted in a specific and Neurosci 257:309-317. long-term configuration of competence at the Clinical Institute of the Romanos M, Freitag C, Jacob C, Craig DW, Dempfle A, Nguyen T, Halperin R, Walitza tal influences on the course of juvenile and University of Wuerzburg with focus on fu- S, Renner TJ, Seitz C, Romanos J, Palma- adult ADHD. In synergy to SP 1 and 2 a ture-oriented translational research of etio- son H, Reif A, Heine M, Windemuth-Kie- BMBF-supported study entitled “Effects and pathogenetic mechanisms and novel thera- selbach C, Vogler C, Sigmund J, Warnke A, Mechanisms of Psychotherapy in the Treat- peutic options of ADHD. Schäfer H, Meyer J, Stephan DA, Lesch KP (2008) Genome-wide linkage analysis of ment of ADHD in Children and Adults – The ADHD using high-density SNP arrays: novel First Randomized Multicentre Study” exclu- loci at 5q13.1 and 14q12. Mol Psychiatry sively focuses on the treatment of ADHD 13:522–530. across the life cycle. Teaching SELECTED PUBLICATIONS Lesch KP, Selch S, Renner TJ, Jacob C, Nguyen TT, Hahn T, Romanos M, Shoichet Three subprojects (SP 3-5) represent an The unique configuration of competence for S, Dempfle A, Heine M, Boreatti-Hümmer A, integrated approach toward elucidation of translational research of the KFO 125 to- Walitza S, Romanos J, Gross-Lesch S, Zer- specific molecular genetic and neurobiolog- gether with the SFB 581, SFB TRR 58 and laut H, Allolio B, Heinzel S, Fassnacht M, ical mechanisms of complex behavior relat- Graduate Programs within the Internation- Fallgatter A, Wultsch T, Schäfer H, Warnke A, Reif A, Ropers HH, Ullmann R (2010) Ge- ed to ADHD. Genome-wide linkage scans al Graduate School of Life Sciences (GSLS) nome-wide copy number variation analysis are being performed on extended multigen- provides an excellent platform for compe- in ADHD: association with neuropeptide Y erational families with high density of ADHD tent education and training of a wide vari- gene dosage in an extended pedigree. Mol and a sample of affected sib pairs. In ad- ety of junior researchers including Bachelor Psychiatry, Jan 25 [Epub ahead of print] dition, identification of SNP variants and and Master students, M.D. and Ph.D. stu- Conzelmann A, Mucha RF, Jacob CP, Wey- copy number variation (CNVs) in genome- dents as well as Postdocs from the Faculties ers P, Romanos J, Gerdes AB, Baehne CG, wide association (GWA) studies will provide of Medicine, Biology, Physics, and Humani- Boreatti-Hümmer A, Heine M, Alpers GW, a basis for subsequent studies on geneti- ties. The enhancement of the interdiscipli- Warnke A, Fallgatter AJ, Lesch KP, Pauli P cally modified mouse models of ADHD (Fig. narity of teaching in the psychiatric neuro- (2009) Abnormal affective responsiveness in attention-deficit/hyperactivity disorder: sub- 1) (Lesch et al. 2008, 2010). Furthermore, sciences is therefore a central goal of the type differences. Biol Psychiatry 65:578- three subprojects (SP 6-8) attempt to de- KFO 125. Complex approaches to neurobi- 585. fine endophenotypes of ADHD by electro- ological questions and the joint use of tech- physiological and neuropsychological para- niques and methods derived from genetics, Plichta MM, Vasic N, Wolf C, Lesch KP, digms as well as functional magnetic reso- cell biology, and imaging are the hallmarks Brummer D, Jacob C, Fallgatter AJ, Grön G (2009) Neural hypo- and hyper-respon- nance imaging (fMRI) (Fig. 2) (Plichta et al. of Molecular Psychiatry, thus being interdis- siveness on immediate and delayed reward ciplinary by definition. processing in adult ADHD. Biol Psychiatry 192 65:7-14. 5.4.4 Clinical Research Unit 216: Characterization of the Oncogenic Signaling-Network in Multiple Myeloma: Development of Targeted Therapies

Professor Dr. med. Hermann Einsele General ment of different genetic mouse models to (Speaker) Information study and to verify the oncogenic pathways in primary human myeloma samples in vivo. Klinische Forschergruppe 216 The Clinical Research Unit 216 is funded These animal models will eventually serve in Versbacher Str. 5 by the Deutsche Forschungsgemeinschaft preclinical studies of novel therapeutic ap- 97078 Würzburg (DFG) and the Medical Faculty since 2009. proaches. Tel.: 0931/201-45141 The leading institution is the Department of Fax: 0931/201-70090 Internal Medicine II. The speaker of the CRU Our previous work has led to the identifi- E-mail: [email protected] is Prof. Hermann Einsele, the scientific head cation of a number of signaling systems www.uk-wuerzburg.de/forschung-lehre/forsc- is Prof. Ralf Bargou. The CRU 216 focuses that are activated in myeloma cells, such hung/forschergruppen/klinische-forschergrup- on key aspects of the molecular pathogen- as Ras-, NF-kB-, and stress-response-path- CONTACT DETAILS CONTACT pe-216.html esis of multiple myeloma an uncurable can- ways (e.g. the heat shock protein pathway). cer of the hematopoietic system. The ulti- Our aim is to appraise the functional impor- Professor Dr. med. Ralf Bargou mate goal of this research work is to iden- tance of these pathways in myeloma as ac- (Head) tify target structures for the development of curately as possible and to analyze if and Tel.: 0931/201-40014 novel molecular therapies. The CRU 216 is to what extent they co-operate with each closely linked to the Early Clinical Trial Unit other. In a complementary approach we Frau Eiselein (Office) of the Comprehensive Cancer Center Main- plan to screen for still unknown signalling Tel.: 0931-201-45141 franken which will facilitate rapid translation pathways by using shRNA-based screening of knowledge in basic research into clinical techniques. Finally, we will try to identify the trials. Within the framework of this Clinical genetic lesions that might lead to the acti- Research group 20 scientists from 6 differ- vation of these pathways. To this end we will ent institutes of Wuerzburg University coop- apply novel genetic technologies such as for erate in 6 subprojects and 3 core facilities (z example high-throughput sequencing. The projects). This includes the Department for results should help to obtain a better un- Internal Medicine II, the Institute for Pathol- derstanding of the functional and molecular ogy, the Department for Biochemistry II, the heterogeneity of this disease. They should Department for Immunology, the Institute also promote identification of novel thera- for Pharmacy, and the Institute for Organic peutically relevant targets and implemen- Chemistry. There is also a close cooperation tation of novel treatment approaches that with physicians and scientists from the De- may be designed to specifically target suit- partment of Internal Medicine II at Ulm Uni- able myeloma subgroups. versity. Another important aim of the CRU is to implement novel structures for clinical research and to strengthen translation- Subproject Chatterjee/Bargou al research in hematology and oncology at Wuerzburg University. Aim of this project is the analysis of Raf- dependent pathways and the interaction of these pathway with the oncogenic sig- Major Research naling network in myeloma cells. This work Interests will clarify whether Raf-dependent signaling pathways might constitute relevant thera- The underlying hypothesis for the Clinical peutic targets. Research Unit is the assumption that in multiple myeloma the malignant phenotype results from deregulation not of a single but of a number of signaling pathways, and that these collectively constitute an oncogenic signalling network. Consequently, we as- sume that differences in this network may permit functional definition of novel subgroups of this disease.

It is therefore the aim of this Clinical Re- search Unit to attempt an extensive functional characterization of the oncogenic signalling network to permit the development of novel and effective therapeutic options. This aim will be pursued via two complementing methodical approaches: (1) a combination of functional, molecular and genetic ex vivo characterizations of pri- Fig. 1: Pathways of the Oncogenic Signal- mary myeloma cells, and (2) the developing Network identified in multiple myeloma

193 tiple myeloma. Targeted Z Project Eilers/Rosenwald therapy of shared signaling pathway of multiple myelo- Aim of this z project ist the development and ma and T cells may there- implementation of novel genetic and func- fore have the potential to tional screening technologies for the iden- eradicate minimal residu- tification of novel oncogenic pathways. This al disease after allogeneic includes shRNA-based sreening approach- stem cell transplantation es as well as high-through-put sequencing and to control GvHD. technologies.

Subproject Holzgrabe/ Sotriffer/Bringmann

Previous work of this project has demonstrated that the heat-shock-protein patheay is frequently activated in myeloma cells and critically contributes to the maintenance of the oncogenic signaling network. Aim of this project is therefore to develop novel pharmacological inhibitors of the heat-shock-protein Chatterjee, M., Rancso, C., Stühmer, T., Eckstein, N., Andrulis, M., Gerecke, G., pathway. This project fo- Lorentz, H. Royer, H.D., Bargou, R.C. Fig. 2: Immunohistochemical analysis of HSP90ß Expres- cuses on HSP90, HSP70, The Y-box binding protein YB-1 is associ- sion in primary Myeloma cells compared to benign MGUS and the transcription factor ated with progressive disease and medi- plasma cells (bone marrow biopsies). HSF-1 (heat-shock-stimu- ates survival and drug resistance in mul- lating-factor-1). tiple myeloma. Blood, 111: 3714-3722, 2008.

Stühmer, T., Zöllinger, A., Siegmund, Subproject Berberich/Hünig Subproject Stühmer/Wajant/Siegmund D., Chatterjee, M., Grella, E., Knop, S., Kortüm, M., Unzicker, C., Jensen, M.R., Quadt, C., Chène, P., Schoepfer, J., Car- CD28 is an important co-stimulatory pro- There is increasing evidence that the NF- cia-Echeverria, C., Einsele, H., Wajant, H., tein that plays a key key role in T cell acti- kB system is a central regulator of the on- and Bargou, R.C.: Signaling profile and vation. Expression of CD28 is also found in cogenic signaling network in multiple my- anti-tumor avtivity of the novel HSP90 in- myeloma cells and is associated with diseae eloma that integrates the signals of various hibitor NVP-AUY922 in multiple myeloma. progression and poor prognosis. Aim of this other pathways. Aim of this project is there- Leukemia, 22(8): 1604-12, 2008. project is to analyze the role role of CD28- fore to analyze the interaction of NF-kB with Zöllinger, A., Stühmer, T., Chatterjee, M.,

dependent signaling in myeloma in vitro as other signaling pathways. SELECTED PUBLICATIONS Gattenlöhner, S., Haralambieva, E., Mül- well as in transgenic mouse models. ler-Hermelink, H-K., Andrulis, M., Greiner, A., Wesemeier, C., Rath, J., Einsele, H., and Bargou, R.C. Combined functional Z Project Haralambieva/Einsele and molecular analysis of tumor cell sig- Subproject Bommert/Beilhack/Bargou naling defines two distinct myeloma sub- This core facility is responsible for isolation, groups: Akt-dependent and Akt-indepen- In vitro experiments indicate that the cold processing and organization of the analy- dent multiple myeloma. Blood, 112(8): shock domain protein YB-1 plays a key role sis of primary tumor samples which are 3403-11, 2008. in the development of resistance to apop- obtained through diagnostic bone marrow Knop, S; Gerecke, C; Liebisch, P; Topp, tosis and chemotherapy. Aim of this project trepanations. Another duty of this core fa- MS; Platzbecker, U; Sezer, O; Vollmuth, C; is to analyze the role of YB-1 within the on- cility is the analysis of signaling pathways in Falk, K; Glasmacher, A; Maeder, U; Ein- cogenic signaling network in vivo in various situ in primary tumor samples by immuno- sele, H; and Bargou. RC. Lenalidomide (Revlimid®), adriamycin and dexametha- transgenic mouse models. histochemistry. sone (RAD) in patients with relapsed and refractory multiple myeloma: A report from the German Myeloma Study Group DSMM Subproject Topp/Einsele Z Project Langer/Döhner (Deutsche Studiengruppe Multiples Mye- lom). Blood, 113:1160-71, 2009.

The proposed study will focus on the iden- This z project performs a comprehensive ge- Stühler, C, Mielke, S, Chatterjee, M, Duell, tification of common signaling pathways netic analysis of primary myeloma samples J, Lurati, S, Rückert, F, Einsele, H, Bargou, shared by primary MM cells and activated by FISH analysis and SNP Chip Arrays. RC, and Topp, M. Selective depletion of al- alloreactive T cells for the dual therapy of loreacting T cells by targeted therapy of heat shock protein 90: A novel strategy for graft-versus-host disease (GvHD) and mul- control of graft versus host disease. Blood, 114: 2829-36, 2009. 194 5.5 Research Alliances 5.5.1 Rehabilitation Research Network of Bavaria

Professor Dr. med. Dr. phil. Hermann Faller General Implementation Phase (Speaker) Information In order to effectively employ the knowledge Institute of Psychotherapy and Medical Psy- The Rehabilitation Research Network of gained through rehabilitation research in chology Bavaria (RFB) was founded in 1998 with practice, several transfer projects were es- Marcusstr. 9-11 funding from the „Rehabilitation Sciences“ tablished. The goals of the ongoing project 97070 Würzburg program of the German Ministry of Educa- “Center of Patient Education” are the opti- Tel.: 0931/31-82713 tion and Research (BMBF) and the Germa- mization of patient education and the dis- Fax: 0931/31-2078 ny Statutory Pension Insurance. The main semination of research results within reha- E-mail: [email protected] reasons for its establishment were the in- bilitation practice (see Fig. 1). Descriptive www.rehawissenschaft.uni-wuerzburg.de creasing medical and economical impor- and evaluative criteria for patient education tance of chronic disorders and the con- were designed and consented, the conduc- CONTACT DETAILS CONTACT sequent need for a more scientific orien- tion of patient education was measured on tation in medical rehabilitation. The RFB’s a national level, and the findings were sys- main tasks are to provide well-coordinat- tematically analyzed and made available in ed and high-quality research, to contribute an online database. Criteria for quality man- to the efficient transfer of research results agement and qualification of educational into practice, and to improve the regional staff were also developed. research infrastructure on a long-term basis. The premises for these tasks have been The second implementation focus was on funded through the Foundation Professor- occupational orientation within medical re- ship for Rehabilitation Sciences at the Uni- habilitation. A generic screening instrument versity of Würzburg’s Section of Rehabilita- was developed to identify professional prob- tion Sciences and through the Network of lem areas and to ascertain the need for oc- Rehabilitation Research of Bavaria (NRFB), cupational rehabilitation services. A second which comprises rehabilitation researchers, project in this area focused on surveying clinics and agencies. and analyzing occupational interventions in rehabilitation clinics and providing appropriate constituents for rehabilitative inter- Main Research ventions. A current follow-up project at the Interests Section of Rehabilitation Sciences concentrates on the dissemination of professional- The main theme of the RFB is “Patients in ly oriented measures in medical rehabilita- Rehabilitation: Disease-specific and Gener- tion into practice. al Approaches to Motivation, Coping, Inter- vention and Evaluation”. During two separate stages of funding through the BMBF Funding Program on Chronic Disorders and the Germany Statutory Pension Insur- and Patient Orientation ance, a total of 25 projects were established (22 research projects and 3 cross- The Section of Rehabilitation Sciences is sectional projects). The research coordina- currently conducting five scientific projects tion, including the research methods con- in cooperation with rehabilitation clinics as sultation, was carried out by the Section of part of a health services research program Rehabilitation Sciences at the Institute of on patient orientation (funded by BMBF, Psychotherapy and Medical Psychology at Pension Insurance, Health Insurance). The the University of Würzburg. topics of these projects include an evaluation of innovative concepts for the follow-up Examples of research projects conducted at care of adipose patients (telephone-based the Institute or in its cooperation: sensitivity follow-up) and chronic pain patients (live to change of generic health-related quality online follow-up) as well as the develop- of life questionnaires; validation of the Ger- ment and evaluation of an integrated pa- man version of the Short Musculoskeletal tient education concept for chronic back Function Assessment Questionnaire (SMFA) pain patients (in cooperation with the Uni- used to measure the functional state of or- versity of Erlangen-Nürnberg). Further topics thopedic patients; evaluation of a generic involve shared decision-making as a part of health promotion program for medical reha- medical rehabilitation and the validation of bilitation; meta-analytical analyses of pre- a generic assessment instrument for mea- dictors for success of patient education pro- suring the proximal effects of patient edu- grams based on pooled data; sociomedical cation onself-management and empower- assessments as part of the admissions pro- ment (Health Education Impact Question- cess for rehabilitation. naire, heiQ) (in cooperation with the medical school of Hannover and the Deakin Uni- versity, Melbourne, Australia).

195 Fig. 1: Goals and responsibilities of the Center of Patient Education

Networking Education One of the objectives of application-oriented rehabilitation research is the estab- The Section of Rehabilitation Sciences at lishment of a network consisting of various the Institute of Psychotherapy and Medical stakeholders in research and practice. The Psychology is responsible for the organiza- Section of Rehabilitation Sciences’ Center tion of lectures in the interdisciplinary area of Patient Education functions as the cross- 12, “Rehabilitation, Physical Medicine, Na- regional intersection of this network. On a turopathy”, and offers an optional semi- regional level, the close cooperation be- nar in rehabilitation sciences. In addition, tween the Section of Rehabilitation Scienc- it contributes to the interdisciplinary areas es and the Network of Rehabilitation Re- 3, “Health Economy, Health Care System, search of Bavaria (NRFB) allows for the de- Public Health”, and 10, “Prevention, Health Faller H, Reusch A, Ströbl V, Vogel H (2008) Patientenorientierung und Patien- velopment of various research projects as Promotion”. tenschulung. Rehabilitation 47:77-83. well as an interdisciplinary communication and collaboration (e.g. the joined confer- Faller H, Koch GF, Reusch A, Pauli P, All- ence “Patient Orientation in Rehabilitation” gayer H (2009) Effectiveness of education held in 2008 in Würzburg to commemorate for gastric cancer patients: a controlled prospective trial comparing interactive vs. 10 years of joined rehabilitation research in lecture-based programs. Patient Education Bavaria since the foundation of the RFB). and Counseling 76:91-98. Currently, a new initiative, “Bavaria’s Re- habilitation-Practice researches”, has been Krannich J-H, Weyers P, Lueger S, Schim- mer C, Faller H, Elert O (2008) The effec- implemented in cooperation of the NRFB tiveness of a motivation program for life- and the Section of Rehabilitation Sciences style change in the course of aortocoro- at the University of Würzburg. The new ini- nary bypass graft surgery. Clinical Rehabili- tiative will involve the development of prac- tation 22:3-13. tice-oriented research projects that will be Meng K, Seekatz B, Roßband H, Worrin- supported until sponsorship. A corporate gen U, Faller H, Vogel H (2009) Entwick-

model project for an enhanced rehabilita- SELECTED PUBLICATIONS lung eines standardisierten Rückenschu- tion process based on the collaboration of lungsprogramms für die orthopädische Re- business, rehabilitation clinics and reha- habilitation. Rehabilitation 48:335-344. bilitation agencies was also supported and Ströbl V, Küffner R, Müller J, Reusch A, evaluated by the Section of Rehabilitation Vogel H, Faller H (2009) Patientenschul- Sciences. ung: Qualitätskriterien der Schulungsum- setzung. Rehabilitation 48:166-173. 196 5.5.2 BMBF-Competence Network: Genome Research on Pathogenic Bacteria - PathoGenoMik-Plus

General dis (the meningococcus) and Streptococcus Information pneumoniae (the pneumococcus) which are both responsible for the vast majority of The „PathoGenoMik-Plus“ network is part of cases of acute bacterial meningitis world- the funding and research initiative “Genome wide, especially in young children. research on microorganisms” which was initiated by the German Federal Ministery of The research activities of the other two clus- Education and Research (Bundesministeri- ters focus on the causative agent of tuber- Professor Dr. med. Matthias Frosch um für Bildung und Forschung, BMBF). culosis in humans Mycobacterium tubercu- (Speaker) losis and on periodontitis as a model for During the funding period from 2006 to polymicrobial disease. Institute for Hygiene and Microbiology 2009 the participating groups of the “Pa- CONTACT DETAILS CONTACT Josef Schneider Str. 2 thoGenoMik-Plus” network focus on human 97080 Würzburg pathogenic bacteria that are of high socio- Tel.: 0931/201-46160 economic relevance for the public health Fax: 0931/201-46445 system in Germany due to their wide dis- E-mail: [email protected] semination in, e. g., hospitals or that pose www.genomik.uni-wuerzburg.de/patho- a particular threat for the health system due genomik-plus_2006_-_2009/ to their high rate of antibiotic resistance or their high virulence potential. Dr. rer. nat. Gabriele Gerlach (Office) Tel.: 0931/201-46901 While the “PathoGenoMik” initiative (2001- 2006) focused on the sequencing of entire genomes from a number of medically important bacterial pathogens the functional analysis of the sequenced genomes with respect to potential applications in the diagnosis, therapy as well as prophylaxis of infectious diseases is the main focus of the “PathoGenoMik-Plus” funding initiative.

The PathoGenoMik-Plus network is coordinated by Prof. Dr. M. Frosch from the Insti- tute for Hygiene and Microbiology from the University of Würzburg. Besides several research groups of the University of Würzburg further German research groups from eight different Universities, the Max-Planck-Insti- tute of Infection Biology (Berlin), the Ro-_ bert-Koch Institute and the Research Cen- ter Borstel are members of the network.

Major Research Hennig S, Ziebuhr W. (2008). A trans- Interests posase-independent mechanism gives rise to precise excision of IS256 from insertion sites in Staphylococcus epidermidis. Jour- According to the wide spectrum of infec- nal of Bacteriology 190:1488-1490. tious diseases investigated in the network the research groups collaborate in four clus- Schoen, C., Blom, B., Claus, H., Sch- ters. ramm-Glück, A., Brandt, P., Müller, T., Goesmann, A., Joseph, B., Konietzny, S., Kurzai, O., Schmitt, C., Friedrich, T., Linke, Cluster 1 is coordinated by Prof. Dr. Dr. h.c. B., Vogel, U., Frosch, M. (2008). Whole mult. J. Hacker (until 2008 head of the In- genome comparison of disease and car- stitute for Molecular Infection Biology at the riage strains provides insights into viru- University of Würzburg and is focussed on lence evolution in Neisseria meningitidis. Proc. Natl. Acad. Sci. U.S.A., 105: 3473- nosocomial infections with special empha- 34788. sis on the hospital-acquired bacterial species Staphylococcus aureus, Staphylococ- Schoen C, Tettelin H, Parkhill J, Frosch M. cus epidermidis and Pseudomonas aerugi- 2009 Genome flexibility in Neisseria meningitidis. Vaccine 27: B103-111. nosa. SELECTED PUBLICATIONS

Cluster 2 is coordinated by Prof. Dr. M. Frosch and works on Neisseria meningiti-

197 5.5.3 Network of Excellence EuroPathoGenomics

This task is accomplished by the Network strains was accomplished. It was demon- of Excellence “EuroPathoGenomics” (NoE strated that asymptomatic bacteriuria E. EPG) that is supported by the European coli isolated are frequently characterized Union with 6.7 million Euro for the duration by genome loss, i.e. the inability to express of five years (July 2005 – June 2010). The several genes due to the acquisition of point NoE EPG, comprising 38 top level laborato- mutations, genomic rearrangements and ries from 13 different nations, is co-ordinat- deletions. Furthermore, genomes of re-iso- ed by the University of Würzburg under the lates from deliberate colonization of human Professor Dr. rer. nat. Dr. h.c. mult. Jörg direction of Professor Jörg Hacker. patients with an asymptomatic-bacteriuria Hacker (Speaker) (ABU) isolate have been sequenced and compared to that of the parent strain. Ge-

CONTACT DETAILS CONTACT Deutsche Akademie der Naturforscher Major Research nomic alterations could be described in the Leopoldina - Interests re-isolates that mirror bacterial adaptation Nationale Akademie der Wissenschaften in response to bladder colonization. Thus, Emil-Abderhalden-Str. 37 One of the major objectives in the field of under certain circumstances uropathogenic 06108 Halle/Saale research is to organise the mass of geno- E. coli may evolve into harmless commen- Tel.: 0345/472 39 0 mic information that has become avail- sal-like variants. ABU strains acquire multi- Fax: 0345/472 39 19 able, regarding both microorganisms and ple genomic alterations upon in vivo coloni- E-mail: [email protected] their hosts, into schemes allowing one to zation of the human urinary bladder. decipher the cross talks between patho- Dr. rer. nat. Andreas Demuth (Office) gens and commensals and their host cell Tel.: 0931/31-82126 and tissue targets. Innovation in diagnostic Antibiotic resistance techniques and therapy, as well as the development of vaccines against pathogenic Lateral gene transfer through its implica- microorganisms, are expected to come out tion in the development and spread of an- of the joint research activities of these top- tibiotic resistance genes among bacterial level European research groups in the field pathogens is also a topic of major concern of genomic research. in the EPG network. Using Gram-negative and Gram-positive model systems, different Accordingly, several topics are in the focus aspects of the evolution and spread of an- of the EPG project: tibiotic resistances were analysed by com-

Comparative genomics/Biodiversity

Comparative genomics has been used to contribute to a better understanding of genome content and evolution of bacterial pathogens. Therefore, DNA-DNA hybridizations, sequencing as well as analysis of General genes and complete ge- Information nomes of different bacteria (e.g. Vibrio, Rick- Bacterial infections remain a major cause ettsia, Chlamydia, Liste- of disease and mortality in humans and ani- ria, Salmonella, Legio- mals throughout the world. Only the detailed nella, Bartonella, Esch- understanding of their pathogenic process- erichia, Staphylococ- es will provide us with innovative tools for cus, Helicobacter) were their prevention and treatment. The study of performed in the NoE infectious disease needs a multidisciplinary EPG. For instance, the approach that brings together the different comparative analysis of disciplines of molecular biology, immunol- the genome content of ogy, cell biology and structural biology. Al- uropathogenic E. coli though scientific collaborations within Eu- (UPEC) isolates from rope have been established to some extent, symptomatic, asymp- Fig. 1: Genotyping DNA chip for the simultaneous assessment there is a pressing need for more perma- tomatic as well as of antibiotic resistance and pathogenicity potential of extrain- nent links and structures between the dif- chronic cases of uri- testinal pathogenic Escherichia coli (false colour fluorescence ferent disciplines. nary tract infection (UTI) image). Source: T. Barl and T.T. Bachmann.

198 very difficult to combat. Therefore, to develop new strategies for diagnosis, prevention and control of microbial infections it is aimed to identify specific factors expressed within biofilms (e.g. Escherichia, Legionella, Pseudomo- nas, Staphylococcus). It could be shown that biofilm-forming Pseudo- mas aeruginosa bacteria undergo lipopolysac- charide (LPS) structural modifications inducing enhanced inflammatory cytokine response in human monocytes.

Fig. 2: FISH (fluorescence in situ hybridization) detection of Pathogen-host cell in- human epithelial bladder cells (T24), Citrobacter freundii and teractions Candida albicans. Source: H. Merkert. Microbial diseases are the result of the inter- parative genomics and functional studies. action of the parasite and its host. There- Furthermore, bacterial gene expression in fore, analysis of the interactions between response to exposure to antibiotics was in- bacterial pathogens and eukaryotic cells vestigated in order to get a deeper insight were accomplished in various cell culture into the effect of antibiotics on gene regu- and animal models and corresponding ad- lation. These approaches will result in an hesion assays as well as screening tests improved understanding of the molecular were established. For example, a global as- mechanisms contributing to the develop- sessment of host cell functions involved in ment and spread of antibiotic resistances the intracellular survival and replication of and to the discovery of novel anti-infectious Chlamydia trachomatis using RNA interfer- agents and their targets. ence in human cells has been performed. This analysis resulted in the identification of 59 host cell genes influencing C. trachoma- Putze J, Hennequin C, Nougayrède JP, Cellular microbiology tis infection and infectivity. Zhang W, Homburg S, Karch H, Bringer MA, Fayolle C, Carniel E, Rabsch W, Oel- The analysis of factors influencing the viru- schlaeger TA, Oswald E, Forestier C, Hack- lence of bacterial pathogens is one of the er J, Dobrindt U. (2009) Genetic structure and distribution of the colibactin ge- cornerstones of experimental infection biol- Teaching nomic island among members of the fam- ogy. Therefore, extensive analysis of regula- ily Enterobacteriaceae. Infect Immun. tory networks involved in the production of One of the main activities of the EPG proj- 77(11):4696-703. virulence factors and survival of pathogens ect is related to the education and train- Sjöström AE, Balsalobre C, Emödy L, (e.g. Mycobacteria, Pseudomonas, Listeria, ing of students in the field of pathogeno- Westerlund-Wikström B, Hacker J, Uhlin Legionella, Salmonella, Neisseria) in vitro mics. Therefore, the so-called “EuroPatho- BE. (2009) The SfaXII protein from new- and within the host was carried out in the Genomics Graduate Academy” (EGA) has born meningitis E. coli is involved in regu- EPG project. Whole genome expression and been established. The EGA provides young lation of motility and type 1 fimbriae ex- comparative gene profiling were performed scientists a broad-based interdisciplinary pression. Microb Pathog. 46(5):243-52. to allow the identification and quantitative study programme with a wide range of sem- Klasson L, Westberg J, Sapountzis P, Näs- analysis of network components that are inars, summer schools and practical work- lund K, Lutnaes Y, Darby AC, Veneti Z, parts of signalling pathways. shops. Furthermore, participants of the im- Chen L, Braig HR, Garrett R, Bourtzis K,

plemented exchange programme have the SELECTED PUBLICATIONS Andersson SG. (2009) The mosaic genome structure of the Wolbachia wRi opportunity to visit the laboratory of project strain infecting Drosophila simulans. Proc Microbe-microbe interaction partners in order to exchange expertise and Natl Acad Sci U S A. 7;106(14):5725-30. to gain new insights into particular areas Microbial communities such as biofilms of interest. Sahr T, Brüggemann H, Jules M, Lom- are involved in many infections in humans ma M, Albert-Weissenberger C, Cazalet C, Buchrieser C. (2009) Two small ncRNAs often resulting in chronic states that are jointly govern virulence and transmission in Legionella pneumophila. Mol Microbiol. 199 72(3):741-762. 5.5.4 Research program of the BMBF: Effects and Mecha- nisms of Psychotherapy in the Treatment of Attention Deficit-Hyperactivity-Disorder (ADHD) in Children and Adults

Professor Dr. med. Andreas Warnke General tistical analysis and monitoring will be pro- (Speaker) Information vided by the Centre for Clinical Trials and LabConsult in Freiburg. An advisory board is Department for Child and Adolescent Psy- This national network is part of a research supervising the projects. Treatment integrity chiatry, Psychosomatics and Psychotherapy program on psychotherapy in the treatment is assured by randomized videotaping and Füchsleinstr.15 of psychiatric disorders founded by the Ger- external supervision. The consideration of 97080 Würzburg man Ministry of Education and Research. scientific and ethical criteria based on the Tel.: 0931/201-78000 The need for a more intense study of psy- GCP document of the International Confer- Fax: 0931/201-78040 chotherapy in Germany had been stressed ence on Harmonization (ICH) is supervised E-mail: [email protected] by the advisory committee for evidence by a Data Monitoring Committee (DMC). www.klinik.uni-wuerzburg.de/kjp based psychotherapy (Wissenschaftlicher Our research program is strengthened by CONTACT DETAILS CONTACT www-i.klinik.uni-wuerzburg.de/deutsch/ein- Beirat Psychotherapie) of the German Psy- the cooperation with the Clinical Research richtungen/kliniken/kjp/forschung/ADHD/ chotherapeutic Association (Bundespsy- Group ADHD (KFG 125, founded by the Ger- ForschungsverbundPsychotherapieADHS/ chotherapeutenkammer) and the German man Research Association, DFG) in Wuerz- content.html Medical Association (Bundesärztekammer). burg and international cooperation. Our network focuses on the treatment of ADHD. ADHD in adults has long been un- recognized and underestimated. Random- Major Research ized controlled clinical trials including mor- Interests phological and genetic variables are still missing worldwide. Main issue of the child psychiatric study groups (principal investigator: A. Warnke, The aims of the present network are: CAPP Wuerzburg) is the project “Does the • to evaluate the effects of a structured treatment of maternal ADHD enhance disorder specific psychotherapy (group the effectiveness of parent management setting) in adult ADHD in a randomized, training for children’s ADHD?”. The ther- placebo-controlled multi-centre study apy of mothers includes a structured group- comparing the outcome of psychother- psychotherapy-program for adult ADHD in apy, psychopharmacological treatment combination with medication (methylpheni- (methylphenidate) and the combination date). The control intervention is psychiatric of both; counselling without the implementation of • to analyse whether the developed psy- specific therapeutic strategies (randomized chotherapy manual can be successfully trial). After 13 weeks all mothers and chil- transferred to the setting of child and dren receive parent management training adolescent psychiatry: does ADHD par- for children’s ADHD carried out on a one- ent (i.e. adult) treatment reinforce par- to-one basis. 144 mother-child-pairs will be ent (i.e. mother) training outcome in the randomized. Other research questions refer treatment of ADHD children; to the generalization, stability and prognosis • to examine whether there are specific of treatment outcome. neurobiological markers (such as striatal morphology and neurochemistry and The project “Evaluation of the efficacy genetic variations), which can differen- and effectiveness of a structured dis- tially predict therapeutic response to order specific psychotherapy in ADHD pharmacotherapy, psychotherapy or a in adults” (principal investigator: A. Phil- combination of both. ipsen, APP Freiburg) is a randomized controlled multicentre clinical trial including 4 The structure of the national network is in- conditions: “group psychotherapy + place- terdisciplinary and multicentre. 4 projects bo“, “group psychotherapy + medication are established in 13 study centres: recruit- (methylphenidate)“, “clinical management ing and manualized therapy are provided by + medication” and “clinical management clinics for adult psychiatry and psychother- + placebo“. apy (APP) and clinics for child and adolescent psychiatry and psychotherapy (CAPP) Both of these clinical studies are linked in Wuerzburg (APP, CAPP), in Freiburg with other projects. The project “Molecu- (APP, CAPP), Mannheim central institute lar imaging might predict therapeutic (APP, CAPP), Homburg (forensic psychia- response in adult patients with ADHD. try, CAPP), Berlin (APP, CAPP), Essen (APP), A pilot multimodal neuroimaging study” Mainz (APP) and Rostock (APP). The mul- (principal investigator: L. Tebarzt van Elst, timodal imaging studies will be conducted APP Freiburg) is designed to investigate by the recently established South German morphological and functional biological Brain Imaging Center (APP Freiburg). Ge- brain markers of treatment response using netic data will be collected and analyzed in MR spectroscopy. Wuerzburg (EPP). Data management, sta-

200 Fig. 1: Network structure.

The moleculargenetic project is entitled “The association of genetic variation with molecular imaging and the efficacy of cognitive behavioural therapy in adult ADHS” (principal investigator: K.-P. Lesch, APP Wuerzburg). Main study questions re- Jans Th, Philipsen A, Graf E, Ihorst G, Ger- fer to the prognosis of treatment outcome lach M, Warnke A (2009). Does the treat- and to associations between morphological ment of maternal attention deficit and hyperactivity disorder (ADHD) enhance the or neurochemical abnormalities and specif- efficacy of a behavioural parent training ic genetic variants. Genotyping and statis- for the treatment of their children’s ADHD? tical analysis will be performed in national - study protocol of a randomized con- (Institute of Human Genetics, Wuerzburg; trolled multicenter trail. ADHD Attent Def Institute of Medical Biometry and Epidemi- Hyperacti Dis, 1, 33–45. ology, University of Marburg) and interna- Konrad K, Dempfle A, Friedel S, Heiser P, tional (amongst others the National Human Holtkamp K, Walitza S, Sauer S, Warnke Genome Research Institute, NIH, Bethes- A, Remschmidt H, Gilsbach S, Schäfer H, da) cooperation. Hinney A, Hebebrand J, Herpertz-Dahl- mann B. (2010). Familiality and molecular genetics of attention networks in ADHD. During the second funding period of the net- Am J Med Genet B Neuropsychiatr Genet, work follow-up investigations and a health 5, 148-158. economic evaluation will be conducted in the clinical trials and the analyses of the Philipsen A, Richter H, Peters J, Alm B,

SELECTED PUBLICATIONS Sobanski E, Colla M, Münzebrock M, projects on neuroimaging and genetics will Scheel C, Jacob C, Perlov E, Tebartz van be extended. Elst L, Hesslinger B (2007). Structured group psychotherapy in adults with attention deficit hyperactivity disorder: results of an open multicentre study. J Nerv Ment Dis, 195, 1013-1019.

Philipsen A, van Elst LT, Lesch KP, Jans T, Warnke A (2009). Effects and mechanisms of psychotherapy in the treatment of attention deficit hyperactivity disorder (ADHD) in children and adults. Psychother Psychosom Med Psychol, 59,132-140.

Perlov E, Philipsen A, Matthies S, Drieling T, Maier S, Bubl E, Hesslinger B, Buechert M, Henning J, Ebert D, Tebartz Van Elst L (2009). Spectroscopic findings in attention-deficit/hyperactivity disorder: review and meta-analysis. World J Biol Psychiatr 201 10, 355-365. 5.5.5 Bavarian Immunotherapy Network (BayImmuNet): Generation of Clinical Grade Antigen-Specific T-cells with an Early Effector Phenotype for Adoptive T-cell Immunotherapy

General Information and Research Interests

Immunotherapy using antigen-specific T- Dr. med. Matthias Wölfl cells holds great promise as an addition- (Head) al strategy to complement standard cancer therapy. Among the patient groups in great- Department of Pediatrics est need for novel treatment strategies are Josef-Schneider-Str. 2 patients with glioblastoma, one of the most 97080 Würzburg malignant form of brain tumors occurring Tel.: 0931/201-27753 in children and adults. Preclinical data sug-

CONTACT DETAILS CONTACT Fax: 0931/201-27887 gest that immunotherapy for this patient- E-mail: [email protected] group may be beneficial. However, one ma- www-i.klinik.uni-wuerzburg.de/deutsch/ein- jor challenge arises from the low precursor richtungen/KinderklinikundPoliklinik/content. frequency of such antigen-specific T-cells html within the T-cell repertoire. We have developed a protocol, which allows the rapid ex- Professor Dr. med. Paul-Gerhardt Schlegel pansion of antigen-specific T-cells to signifi- (Vice-Head) cant numbers. This protocol is suitable for Tel.: 0931/201-27888 different tumor-associated antigens with a lower precursor T-cell frequency. In this project, we want to establish the clinical usability of such short term expanded T-cells with an early effector memory phenotype, by translating our preclinical findings into an up-scaled protocol that allows the expansion of antigen-specific T-cells to clinically relevant numbers while being in adherence with the current regulations for the production of cellular products within the Europe- an Union (AMG). This will be the basis for first clinical studies using adoptive transfer of antigen-specific T-cells to treat patients suffering from glioblastoma. Kuball J, Hauptrock B, Makina V, Antunes E, Voss RH, Wölfl M, Strong R, Theobald M, Greenberg PD. Increasing functional avidity of T-cell receptor (TCR)-redirected T-cells by removing defined N-glycosyl- ation sites in the constant domain. Journal of Experimental Medicine, 2009, Feb 16; 206(2): 463-475.

Wölfl M, Rutebemberwa A, Mosbruger T, Mao Q, Li H, Netski D, Ray SC, Pardoll D, Sidney J, Sette A, Allen T, Kuntzen T, Ka- vanagh DG, Kuball J, Greenberg PD, Cox AL. Hepatitis C virus Immune escape via Exploitation of a Hole in the T cell Reper- toire. Journal of Immunology, 2008, Nov 1; 181(9): 6435-46

Wölfl M, Kuball J, Ho WY, Nguyen HN, Manley T, Bleakley M, Greenberg PD. Ac-

SELECTED PUBLICATIONS tivation-induced expression of CD137 permits detection, isolation and expansion of the full repertoire of CD8+ T-cells responding to antigen without requiring knowledge of epitope-specificities, Blood, 2007 Jul 1;110(1):201-10.

Kuball J, Dossett M, Wölfl M, Ho WY, Fowl- er C, Greenberg PD. Facilitating matched pairing and expression of TCR chains introduced into human T cells. Blood, 2007, Mar 15;109(6):2331-8.

Ho WY, Nguyen HN, Wölfl M, Kuball J, Greenberg PD. In vitro methods for generating CD8+ T-cell clones for immunotherapy from the naive repertoire. J Immunol Methods. 2006 Mar 20;310(1-2):40. 202 5.5.6 German Research Foundation: SPP 1356, Pluripotency and Cellular Reprogramming

General Information

Research on cellular pluripotency is one of the most challenging and promising research fields in biomedicine. The potential Professor Dr. rer. nat. Albrecht Müller to reprogram cells into any type of adult Fig. 2: Pluripotent ES cells (Coordinator) stem cell for the purpose of cell replacement therapy holds tremendous therapeu- Zinklesweg 10 tic implications. Cell reprogramming may ed genes and factors regulating pluripoten- 97078 Würzburg circumvent current ethical considerations cy; (2) the determination of molecular in-

CONTACT DETAILS CONTACT Tel.: 0931 - 201 45848 surrounding the derivation of new human terconnections between the genetic and Fax: 0931 - 201 45148 embryonic stem cells for research and clin- epigenetic pathways regulating pluripoten- E-mail: [email protected] ical applications. The molecular pathways cy; (3) the determination of the association www.spp1356.de controlling pluripotency and cellular repro- between global and local chromatin nuclear gramming are now only beginning to be un- structure and the regulation of pluripotency derstood. A thorough understanding of reg- and (4) the identification of practical and ulatory pathways on the molecular level in effective strategies to induce and regulate pluripotent cells is essential for the develop- pluripotency by nuclear reprogramming, cell ment of effective and rational approaches fusion, and extrinsic factors. to induce pluripotential reprogramming and direct pluripotent cells into specific differentiation pathways. Work package 1: The priority program SPP 1356 focuses on two key areas crucial for the understanding Genetic and epigenetic networks that con- of pluripotency and reprogramming: trol pluripotent cells • Genetic and epigenetic signatures of a.) The identification and characterization pluripotent cells of genetic and epigenetic networks that • Identification and functional testing of control pluripotency, i.e. the molecular pluripotency factors basis for pluripotency; • Chromatin remodeling and nuclear b.) The mechanisms governing the rein- structure statement of pluripotency in a differentiated cell. Work package 2:

Major Research Induction of pluripotency by nuclear repro- Interests gramming • Analysis of natural reprogramming Therefore the work schedule of the inter- mechanisms disciplinary program group includes: (1) the • Somatic reprogramming induced by identification of novel as well as unsuspect- SCNT, cell fusion and nuclear extrinsic factors • Mathematical modeling of pluripotency

The SPP 1356 comprises 24 German research groups that are specialists in the molecular analysis of pluripotency, chromatin and cellular reprogramming.

Priority programmes represent topic-oriented funding programmes of the DFG. They provide the opportunity for interdisciplinary networking and nationwide coordination of research projects in fields of current research interest. Priority Programmes are established for a period of up to six years.

Fig. 1: Features that influence pluripotency and reprogramming. Depicted is a murine preimplantation blastocyst -the origin of pluripotent cells- and features that influence pluripotency and reprogramming.

203 5.5.7 BMBF Project, SARA: Systems Biology of PGI2 and ADP P2Y12 Receptor Signaling

Professor Dr. med. Ulrich Walter Members in physiological as well as pathological re- (Speaker Würzburg) Sickmann A., Institute for Analytical Sci- spect, platelets are tightly regulated by nu- ence, Dortmund merous factors acting either stimulatory or Institute for Clinical Biochemistry und Patho- Geiger J./Walter U., Institute of Clinical Bio- inhibitory and, occasionally, in both ways. biochemistry chemistry and Pathobiochemistry with Divi- Most of these factors bind to specific re- Oberdürrbacher Str. 6 sion of Laboratory Medicine ceptors thus governing distinct intracellular 97080 Würzburg Dandekar T., Institute of Bioinformatics, pathways . A strictly regulated equilibrium of Tel.: 0931/201-4500 Wuerzburg activatory and inhibitory signals is apparent- Fax: 0931/201-64500 Nollau P., Department of Clinical Chemistry/ ly essential for the physiological function of E-mail: [email protected] Central Laboratories, Hamburg platelets and vessel wall. Two endogenous http://sara.informatik.uni-tuebingen.de/ Timmer J., Freiburg Center for Data Analysis factors, namely adenosine-diphosphate

CONTACT DETAILS CONTACT and Modeling, Freiburg (ADP) and prostacyclin (PGI2), which play Professor Dr. rer. nat. Albert Sickmann Kohlbacher O., Center for Bioinformatics, a particular role in physiology and patho- (Speaker) Tuebingen physiology by maintaining the equilibrium Blankenberg S., Center for cardiovascular of platelet activation and inhibition are in ISAS - Institute for Analytical Sciences prevention, Mainz the focus of this project. Though ADP is re- Bunsen-Kirchhoff-Str. 11 Schinzel R., vasopharm GmbH, Wuerzburg garded a rather weak platelet agonist in re- 44139 Dortmund cent years it became evident that a complete platelet aggregation is only possibly General by activation of ADP stimulated pathways Information The sole inhibition of one of the three ADP receptors known for platelets is sufficient to The SARA project consortium is supported prevent thrombus formation. PGI2 is clearly by the research initiative „Medical Systems the most relevant and efficacious inhibitor Biology - MedSys“ in the framework of the of platelet aggregation. The short lived pros- BMBF program „Biotechnology”. taglandin is formed by the endothelium lining the vessel wall and acts directly on the Blood platelets play a key role in the regu- platelets passing by. As a matter of fact it lation of hemostasis and in the genesis of turned out that PGI2 and ADP are indeed thrombotic events. Platelets can attach al- direct opponents in the physiological regu- most instantly to injured vessel wall, sub- lation of platelet function. endothelial matrix or other, activated platelets and contribute considerably in devel- The SARA research consortium aims at a opment and progression of cardiovascular description of ADP and PGI2 evoked sig- diseases. As a result of their central role, naling pathways by applying molecular bio-

Fig. 1: Interaction of ADP and PGI2 signal transduction pathways.

204 Ulrich Walter / Jörg The project is composed of 5 phases: Geiger - Functional • Definition: defining the experimental analysis of plate- setting, methods, conditions lets, , Würzburg • Characterization: characterize pathways Thomas Dandek- and pathway components ar - Computational • Identification: identify regulatory com- interactomics and ponents kinomics, Bioinfor- • Quantification: quantify cellular respons- matics, Würzburg es, role of regulatory components Peter Nollau - SH2 • Prediction: testing predictions from bio- domain profiling, informatical models Universitätsklini- kum Eppendorf, Hamburg Jens Timmer - Mod- eling of signaling pathways, Freiburg Oliver Kohlbacher - Computational proteomics, Tübingen Stefan Blanken- berg – PREVENT- it (Gutenberg heart study), Uni- versitätsklinikum Mainz Reinhard Schinzel – industry partner, Fig. 2: Structure of the research consortium vasopharm GmbH, Würzburg logical, biomedical, biochemical and bioinformatical methods with respect to quan- Project C: Functional analysis of plate- tity and time course. In an iterative strat- lets egy protein phosphorylation, formation of messenger molecules as well as cellular This project aims at a comprehensive defi- responses such as secretion or aggrega- nition and description of the role of P2Y12 tion after stimulation of ADP and/or PGI2 ADP receptor and prostaglandin receptor induced pathways are investigated. Protein mediated pathways in platelets. phosphorylation is determined by innova- All biochemical experiments required for tive techniques allowing for identification of the further analysis by other partners in this phosphorylation sites – by means of SH2- consortium are designed, carried out and profiling – and an absolute quantification of analyzed in this project. As soon as avail- Lewandrowski U, Wortelkamp S, Lohrig phosphorylation by quantitative phospho- able, the bioinformatical models gener- K, Zahedi RP, Wolters DA, Walter U, Sick- proteomics. The findings are integrated in a ated by the collaboration partners will be mann A. Platelet membrane proteomics: a novel repository for functional research. bioinformatical model of the signaling cas- validated biochemically. In close collabora- Blood. 2009;114(1): e10-9. cades which will be further refined by ad- tion with both vasopharm and Roche Diag- ditional more specific analysis. Markers for nostics, established and novel phosphopro- Zahedi RP, Lewandrowski U, Wiesner J, platelet activation and inhibiiton identified tein markers will be verified and developed Wortelkamp S, Moebius J, Schütz C, Wal- coherently will then be verified in a large as diagnostic parameters for monitoring of ter U, Gambaryan S, Sickmann A. Phos- phoproteome of Resting Human Platelets. group of volunteers. Eventually a meaningfi- human platelet function and inhibition in J Proteome Res. 2008 7(2):526-34. ukl model of platelet function regulation will health and disease. Also, the data obtained be developed which will improve our under- will be used to characterize the quantitative Begonja AJ, Geiger J, Rukoyatkina N, standing of the genesis and development of biochemical effects of novel platelet ADP Rauchfuss S, Gambaryan S, Walter U. Thrombin stimulation of p38 MAP kinase atherothrombotic diseases. In addition it is receptor inhibitors developed by other in- in human platelets is mediated by ADP expected that the project will provide nov- dustry partners. Finally, the data obtained and thromboxane A2 and inhibited by el approaches for diagnosis and therapy of will be extended to the analysis of platelets cGMP/cGMP-dependent protein kinase. atherothrombosis. from selected patients of a large prospec- Blood. 2007;109(2): 616-8. tive clinical study which monitors the devel- The SARA consortium includes eight sub- opment of coronary artery disease and their SELECTED PUBLICATIONS projects: underlying risk factors. Albert Sickmann - Quantitative Phospho- proteomics, ISAS, Dortmund

205 5.5.8 BMBF Joint Project, CB-HERMES: Expansion of Cord Blood Stem Cells

Professor Dr. rer. nat. Albrecht Müller General means that allow significant HSC expansion (Coordinator) Information and better engraftment.

Zinklesweg 10 Lifelong blood production depends on hae- 97078 Würzburg matopoietic stem cells (HSCs) and their Major Research Tel.: 0931/201-45848 ability to self-renew and to differentiate. Interests Fax: 0931/201-45148 Cord blood (CB) banking is continually in- E-mail: [email protected] creasing due to the superior properties of Specific aims: 1) to develop rational and ro- www.cb-hermes.de CB compared to adult HSC. However our in- bust means of ex vivo CB-HSC expansion: ability to expand HSCs renders insufficient by novel growth factor cocktails, nano-struc- stem cell numbers, a major constraint in tured 3D surfaces, modification of inhibitory

CONTACT DETAILS CONTACT many settings of CB-HSC transplantation. pathways, induced epigenetic modifications Despite optimization of isolation and pro- and by specific stroma environments; 2) de- cessing techniques this restricts CB-HSC velopment of clinically applicable standard transplantation mainly to paediatric pa- operating procedures for CB-HSC expan- tients. New methods that generate suffi- sion using CD34+ cells isolated from um- cient numbers of HSCs from limited input bilical cord blood; 3) eludicate molecular cells are needed to make CB-HSCs avail- pathways and intercellular networks oper- able to adult patients and amenable to ad- ating in HSC ex vivo expansion cultures; 4) vanced cell and gene therapy approaches exploring genetic, epigenetic and functional in regenerative medicine. Therefore, the integrity of expanded cells in vivo. aim of this consortium is to open CB-HSCs to new therapeutic applications by developing controlled strategies for expansion and transplantation. Specifically we plan to apply novel growth factor cocktails, nano- structured 3D surfaces, modifications of inhibitory pathways and epigenotype and specific stroma environments in order to expand and regulate HSCs ex vivo. The first clinical application of novel strategies developed by us is in the context of allogeneic CB-HSCs transplantation for elderly patients suffering from haematopoietic disorders.

Overall goal: to broaden the therapeutic application of CB-HSCs by developing robust

Fig.1: Shown are human cord blood cells.

206 Fig. 2: HoxB4-expanded bone marrow cells.

No. Head of the project Institution Titel of the subproject 1 Dr. Bernd Schiedlmeier, Hannover Medical School Pathway discovery and Prof. Dr. Christopher Baum Dept. Experimental Hematology protocol development

2 Dr. Sabine Neuß-Stein, RWTH Aachen University Biomaterial scaffolds for Dr. Thomas Hieronymus, Institute of Pathology CB-HSC expansion Prof. Dr. Martin Zenke Helmholtz Institute for Biomedical Engineering

3 Prof. Dr. Albrecht Müller University Würzburg Epigenetic characterisa- Institute of Medical Radiation and Cell Research tion of CB-HSCs

4 Prof. Dr. Wolfgang Wagner RWTH Aachen University Expansion of CB-HSCs Helmholtz Institute for Biomedical Engineering with human MSCs

5 Prof. Dr. Arnold Ganser, Hannover Medical School Clinical Appli-cation of Prof. Dr. Eva Mischak- Dept. Hematology, Hemostasis, Oncology and Stem Cell Transplan- CB-HSCs Weissinger tation

207 5.6 MD/PhD-Program

Professor Dr. med. Axel Rethwilm Purpose and Objective (Speaker Medical Faculty) of the Program

Institute of Virology and Immunobiology The MD/PhD program is a joint training pro- Versbacher Str. 7 gram of the Medical Faculty and the Fac- 97078 Würzburg ulty for Biology of the University of Würz- Tel.: 0931/201-49554 burg. The MD/ PhD program is open for Fax: 0931/201-49553 medical students who are registered MDs. E-mail: [email protected] or Goal of the program is to earn the PhD de- [email protected] gree according to the rules of the the Inter- www.uni-wuerzburg.de/izkf national Graduate School of Life Sciences

CONTACT DETAILS CONTACT of the University of Würzburg. The MD/PhD Professor Dr. rer. nat. Jörg Schultz program consists of lab practica, a general (Speaker Faculty of Biology) (specializing) study and seminar program, graduate work with thesis and a graduate Chair of Bioinformatics defense with exam. Biocenter Am Hubland The MD/PhD study program includes lec- 97074 Würzburg tures, seminars, and practical courses in Tel.: 0931/888-4552 research labs. It lasts for approx. 6 months Fax: 0931/888-4552 and is followed by an oral examination. The E-mail: [email protected] graduate work starts after finishing the study wuerzburg.de program. Successful graduates of the curriculum “Experimental Medicine” may enter the MD/PhD program without passing the practical course phase.

The MD/PhD program started in summer 1997 and is funded and organized by the Interdisciplinary Center for Clinical Re- search Würzburg (IZKF). Until now, approx. 40 students were enrolled. Of these, more than 20 have already received their PhD, 6 obtained a medical specialization (“Facha- rztanerkennung”), 3 are in the USA as Post- docs, 5 obtained their “Habilitation” and 1 received a call for professorship. Although not very large, the MD/PhD-program of the Medical Faculty can be regarded to be a great success.

208 5.7 University of Würzburg Graduate Schools – Graduate School of Life Sciences

Professor Dr. rer. nat. Caroline Kisker General modern forms of graduate training culmi- (Dean) Information nated in the foundation of the “Internation- al Graduate School” (IGS) by the University DFG-Forschungszentrum für Experimentelle For many years the Faculties of Biology and Senate in December 2003. This “Interna- Biomedizin Medicine have offered high-level structured tional Graduate School” was initiated to en- Josef-Schneider-Str. 2 graduate training. Early experiences with compass the entire university, with separate 97080 Würzburg structured graduate training at the Univer- sections (“Klassen”) to cover the specific Tel.: 0931/31-80381 sity of Würzburg were achieved most no- scientific and training needs and cultures E-mail: [email protected] tably in the context of several DFG-funded of the diverse disciplines. wuerzburg.de graduate programs (Graduiertenkollegs). A prime example of graduate training is also

CONTACT DETAILS CONTACT Professor Dr. rer. nat. Dr. med. habil Heidrun the MD/PhD-program, which was initiated Section Biomedicine Moll (Vice Dean) by the Faculties of Biology and of Medicine in 1996/7 as the first such program in Ger- As a first step, a Section of Biomedicine Institut für Molekulare Infektionsbiologie many. These programs with several genera- was initiated in the IGS in 2003 by unify- Josef-Schneider-Str. 2 tions of basic and clinical scientists have ing several programs and their graduate 97080 Würzburg shown the effectiveness of such structured students: Tel.: 0931-31-82627 training programs and were therefore com- E-mail: [email protected] bined to found the Section Biomedicine in • The graduate program “Target Proteins” the International Graduate School (IGS) in of the Rudolf Virchow Center Professor Dr. med. Martin J. Lohse 2003. This section has not only built up new • The graduate program of the Research (Vice Dean) structures and developed key elements but Center for Infectious Diseases also served as a nucleus for the founda- • The MD/PhD-program of the Interdisci- Institut für Pharmakologie und Toxikologie, tion of the “Graduate School of Life Scienc- plinary Center for Clinical Research Lehrstuhl für Pharmakologie es” (GSLS). The last years, and in particular • Two DFG-funded graduate programs Versbacher Str.9 2006, have seen major steps towards this (GRK1048 “Molecular Basis of Organ 97078 Würzburg goal. The GSLS was successful in the “Ex- Development in Vertebrates” and the Tel.: 0931/201-48400 cellence Initiative of the Federal and State IEC of SFB-TR 17 “Ras-Dependent Can- E-mail: [email protected] Governments” and obtained funds to sup- cer”)) port fellowships and other activities within Dr. rer. nat. Gabriele Blum-Oehler (office) the GSLS. Separate graduate schools – The These programs came together to identify Tel.: 0931/31-81474 Graduate School of the Humanities (GSH) and develop common structures and cur- and the Graduate School of Science and ricula, to share activities and to set com- Technology (GSST) have been founded as mon standards (see box) for the graduate well. students. In 2006, the first graduate students received their PhD from this common program. Foundation of the International Gradu- ate School (2003-2005)

Discussions within the entire university on

University of Würzburg Graduate Schools (UWGS)

Fig. 1: Structure of the University of Würzburg Graduate School.

209 The growing Graduate School ertenkollegs”) and clinical research groups tors from all participating faculties. In 2009 (Klinische Forschergruppen), as well as also the number of doctoral students enrolled in Increases in size and scope resulting from other collaborative programs funded by the the doctoral study program “Life Sciences” the progressive integration of further pro- Federal Ministry of Education and Research rose to more than 230. Recently the video grams and the discussions in the context (BMBF), the European Union and other “The Secrets of Life” has been published by of the national “Excellence Initiative” called sources. The school is currently divided into the DFG video portal as part of the Excel- for a number of changes within the IGS in five separate Sections. In addition to the lence Initiative that describes the GSLS pro- 2006. These changes concerned both the Section “Biomedicine” and the MD/PhD gram in detail (http://www.excellence-initia- internal structure and the formal status. program, the Sections “Infection and Im- tive.com/wuerzburg-life-sciences). The IGS transformed into a holding struc- munity”, “Neuroscience” and “Integrative ture of the independent Graduate Schools Biology” were established. A section usual- by 2006 and was renamed as University of ly comprises different programs of about 15 Würzburg Graduate Schools (UWGS). These to 25 graduate students. These programs Graduate Schools now cater for the needs are the scientific as well as social “home” of different broad fields of science, unit- of the graduate students. ing research in the Life Sciences, the Hu- manities and Natural Sciences (see Fig. 1). A special fellowship program of the GSLS is Each of these schools independently han- the core element of funding by the Excel- dles their specific affairs. lence Initiative. The fourth round of international recruitment is currently underway. The holding, the UWGS, assures adherence To date more than 1000 standardized writ- to, and development along common rules. ten applications have been evaluated in a It also provides general services to the in- newly developed process in the recruitment dividual schools. In this context, graduation rounds, and interviews with more than 200 regulations (“Promotionsordnung”) were candidates were performed by the admis- developed and passed by the University sion board in Würzburg, by means of video Senate in 2006. These regulations contain conferencing and abroad. Nineteen of the a set of common articles along with spe- 34 fellows are from 10 different countries, cific regulations of the individual schools. underscoring the international character of The core principles laid down in the grad- the GSLS. uation regulations remain those that were originally established in the Section of Bio- Up to now, the number of formal members medicine, including a mentoring system of the GSLS rose to 180 principal investiga- as well as rules for admissions and formal standards (see box). A common charter for the UWGS and all the individual Graduate Key elements of training in the Graduate Schools schools was passed by the Senate in Au- gust 2007, regulating issues of member- • The traditional single advisor (“Doktorvater“) is replaced by a committee with three ship and operating procedures. The UWGS principal investigators (PIs). has also developed a standard regulation • A panel of training activities is offered, from which an individual program is tailored for doctoral study programs that is easi- to each graduate student. ly adaptable to the needs of the individu- • Graduate students actively participate in the program by offering and organizing al Graduate Schools. The Study programs courses and symposia. “Life Science” and “Humanities” were ap- • A set of requirements has to be met to warrant a common quality standard. proved by the Bavarian State Ministry of Sciences at the end of 2007. Mentoring System Each student has an individual supervisory committee, which meets with the doctoral student at regular intervals to monitor progress and adjust the research and training Recent developments in the Graduate activities. Additionally, the graduate students report the status of their project with- School of Life Sciences in the research groups and programs, to exchange ideas and obtain feedback within their peer-group. The Graduate School of Life Sciences (GSLS) is now the most advanced Gradu- Training activities ate School in Würzburg. The plans that were The training activities total a minimum of 150 hours per year and consist of laboratory set forth in the successful application within seminars, journal clubs, program-seminars, methods courses and transferable skills the Excellence Initiative have been put into workshops as well as retreats and international conferences. practice. Common Graduation Commission The GSLS now houses graduate students The participating faculties form a new common Graduation Commission within the of all collaborative research programs – Graduate School. The Commission is responsible for the conferral of all doctoral de- such as the DFG-funded collaborative re- grees within the Graduate School. This enforces common standards across disciplines search centers (“Sonderforschungsbe- and fosters interdisciplinary cooperation in graduate training. reiche”), research training groups (“Gradui-

210 211 6. The Medical Faculty: Basic Data

1. Collaborative Research Centers, Research Training Groups, Clinical Research Units

Collaborative Research Centers: Research Training Groups: Clinical Research Units:

Collaborative Research Center 479, Varia- Research Training Group 520, Immunomo- Clinical Research Unit 103, Osteogenic bility of Pathogens and Host Reactions in dulation Stem Cell Differentiation and Therapy of Infectious Diseases Bone Loss Research Training Group 1048, Molecular Collaborative Research Center 487, Regu- Basis of Organ Development in Vertebrates Clinical Research Unit 124, The Tumor Mic- latory Membrane Proteins: From Molecular roenvironment: Target Structure and Modu- Recognition to Drug Targets Research Training Group 1141, Signal lator of Immune Responses Transduction: Where Cancer and Infection Collaborative Research Center 567, Me- Converge Clinical Research Unit 125, Attention-De- chanisms of Interspecific Interactions of ficit/Hyperactivity Disorder - Translational Organisms Research Training Group 1156, From Syn- Research Focus on Molecular Pathogene- aptic Plasticity to Behavioural Modulation in sis and Treatment across the Life Cycle Collaborative Research Center 581, Mole- Genetic Model Organisms cular Models for Diseases of the Nervous Clinical Research Unit 216, Characterizati- System Research Training Group 1253, Emotions on of the Oncogenic Signaling-Network in Multiple Myeloma: Development of Targe- Collaborative Research Center 630, Recog- Research Training Group 1522, HIV/AIDS ted Therapies nition, Preparation and Functional Analysis and Associated Infectious Diseases in of Agents against Infectious Diseases Southern Africa

Collaborative Research Center 688, Me- chanisms and Imaging of Cell-Cell Interac- tions in the Cardiovascular System

Transregio-Collaborative Research Center 17, Ras-Dependent Pathways in Human Cancer

Transregio-Collaborative Research Center 34, Pathophysiology of Staphylococci in the Post-genomic Era

Transregio-Collaborative Research Center 52, Transcriptional Programming of Indivi- dual T-Cell Subsets

Transregio-Collaborative Research Center 58, Fear, Anxiety, Anxiety Disorders

2. Honorary doctorates awarded by the medical faculty

1948 Dr. Albert Knoll 1991 Prof. Dr. Arno G. Motulsky 2005 Prof. Dr. Volkmar Braun Ludwigshafen Seattle, USA Tübingen 1952 Prof. Dr. Georg Hohmann 1995 Prof. Dr. Peter Vogt 2007 Prof. Dr. G. Fritz Melchers München La Jolla, USA Basel/Berlin 1956 Dr. G. Wahl 1995 Prof. Alan E.H. Emery 2008 Prof. Dr. Harald zur Hausen* Würzburg Budleigh Salterton, England Heidelberg 1961 Prof. Dr. Ernst Freudenberger 1997 Prof. Dr. Hans Thoenen Basel, Schweiz München 1982 Dr. Johannes von Elmenau 2000 Prof. Dr. Hermann Bujard München Heidelberg 1982 Prof. Dr. Wilhelm Feldberg 2001 Prof. Dr. Hermann Wagner (*Nobel laureate) London, England München

212 3. Rinecker- medals awarded by the medical faculty

1890 Prof. Dr. Robert Koch* 1917 Prof. Dr. Heinrich Albers-Schönberg 1973 Prof. Dr. Dr. Viktor Emil Freiherr v. Berlin Hamburg Gebsattel 1891 Prof. Dr. Camillo Golgi* 1922 Prof. Dr. Franz Hofmeister Würzburg/Bamberg Pavia, Italien Würzburg 1977 Prof. Dr. Georges Schaltenbrand 1994 Prof. Dr. Emil von Behring* 1929 Prof. Dr. Ludolf von Krehl Würzburg Marburg Heidelberg 1982 Prof. Dr. Loris Premuda 1897 Prof. Dr. Johannes von Kries 1936 Prof. Dr. Adolf Butenandt* Padua, Italien Freiburg i. B. Danzig 1986 Prof. Dr. Shaul G. Massry 1900 Prof. Dr. Karl Schleich 1943 Prof. Dr. Bernhard Bavink Los Angeles, USA Charlottenburg Bielefeld 1993 Prof. Dr. Miklos Palkovits 1903 Dr. Ernst Overton 1950 Prof. Dr. Georg Sticker Budapest, Ungarn Würzburg Zell a. Main 1995 Prof. Dr. Ernst J.M. Helmreich 1909 Prof. Dr. Clemens von Pirquet 1956 Prof. Dr. Erich Grafe Würzburg Breslau Garmisch-Partenkirchen 2009 Prof. Dr. Volker ter Meulen 1912 Geheimrat Dr. Max Rubner 1965 Prof. Dr. Hans Rietschel Würzburg Berlin Würzburg (*Nobel laureates)

4. Carl Caspar von Siebold-medals awarded by the medical faculty

2009 Prof. Dr. Walter Eykmann 2009 Manfred Ach Würzburg Margetshöchheim

5. Virchow-Lectures

1997 Prof. Dr. Melitta Schachner 2000 Prof. Dr. Rudolf Jänisch 2005 Prof. Dr. Hartmut Michel* Hamburg Cambridge, USA Frankfurt 1997 Prof. Dr. Donald Metcalf 2001 Prof. Dr. Manfred Eigen* 2005 Prof. Dr. Svante Pääbo Melbourne, Australien Göttingen Leipzig 1997 Prof. Dr. Carlo Croce 2002 Prof. Dr. Axel Ullrich 2006 Prof. Dr. Günter Blobel* Philadelphia, USA Martinsried New York, USA 1997 Prof. Dr. Ralph Steinmann 2002 Prof. Dr. Alfred Wittinghofer 2007 Prof. Dr. Oliver Smithies* New York, USA Dortmund Chapel Hill, USA 1998 Prof. Dr. Salvador Moncada 2002 Prof. Dr. Dieter Gallwitz 2007 Prof. Dr. Klaus Rajewsky London, England Göttingen Boston, USA 1998 Prof. Dr. Max Perutz* 2003 Prof. Dr. Peter Gruss 2008 Prof. Dr. Hans C. Clevers Maryland, USA München Utrecht, Niederlande 1999 Prof. Dr. Heiner Westphal 2004 Prof. Dr. Kai Simons Cambridge, USA Dresden 2000 Prof. Dr. Harald zur Hausen 2004 Prof. Dr. Peter Walter Heidelberg San Francisco, USA (*Nobel laureates)

213 6. of the Albert Koelliker-Award for excellent teaching

Semester Winners Autumn 2003 Doctors of the Department for Anaesthesiology and students of the AGN (Arbeitsgemeinschaft Notfallmedizin): PD Dr. F. Kehl, Dr. A. Schoefinius, cand. med. T. Plappert, cand. med. U. Rohsbach

Spring 2004 Professor Dr. K. Wilms, Head of the Medical Policlinic

Autumn 2004 Professor Dr. D. Patzelt, Head of the Institute of Forensic Medicine

Spring 2005 Professor Dr. A. Warnke, Head of the Department for Child and Adolescent Psychiatry

Autumn 2005 University lecturers of the Institute for Anatomy and cell Biology: Prof. Dr. D. Drenckhahn, Prof. Dr. E. Asan, Prof. Dr. P. Kugler, Dr. J. Waschke

Spring 2006 Professor Dr. M. Gekle, Physiological Institute

Autumn 2006 Professor Dr. M. Frosch, Head of the Institute for Hygiene and Microbiology

Spring 2007 Professor Dr. M. Böck, Head of the Institute for Clinical Transfusion Medicine and Haemotherapy

Autumn 2007 University lecturers and tutors of the Skills Lab: Professor Dr. W. Voelker (Med. Clinic I), Professor Dr. M. Schmidt (Med. Clinic I), PD Dr. R. Jahns (Med. Clinic I), Dr. J. Schönberger (Med. Clinic I), Dr. W. Burghardt (Med. Clinik II), PD Dr. Dr. U. Dietz (Surgery), PD Dr. T. Meyer (Surgery), PD Dr. E. Gerharz (Urology), S. Böning (Urology), cand. med. S. Beck, cand. med. J. Filser, cand. med. J. Jahn, cand. med. P. Jahn, cand. med. S. Koerdt

Spring 2008 Professor Dr. H. Hebestreit, Department of Pediatrics

Autumn 2008 University Lecturers for General Medicine: Dr. M. Ertel, Dr. P. Rost und Dr. W. Heppner representative for more than fifty contracted physician‘s offices

Spring 2009 Professor Dr. H. Klinker, Department of Internal Medicine II Professor Dr. A. Renk, Department of Prosthodontics

Autumn 2009 Professor Dr. C.-T. Germer, Head of the Department of General, Visceral, Vascular and Pediatric Surgery

214 7. Habilitations 2008 2009 Clinical Clinical Dr. med. Christoph Kleinschnitz Neurology Dr. rer. nat. Siebke Stieler-Melfsen Clinical Child- and Dr. med. Heinz-Theo Pelzer Internal Medicine Adolescent Dr. med. Andreas Schäfer Internal Medicine Psychology Dr. med. Ralf Melcher Internal Medicine Dr. med. Claudia Kauczok Dermatology Ph.D. Edna Grünblatt Clinical and Venerology Neurochemistry Dr. rer. nat. Jörg Wischhusen Tumorimmunology Dr. med. Jörn Maroske Surgery Dr. med. J örg Engel Obstetrics and Dr. med. Martin Lauer Psychiatry and Gynecology Psychotherapy Dr. med. Christian Jacob Psychiatry and Dr. med. Jan Kuhlencordt Internal Medicine Psychotherapy Dr. med. Klaus Steger Surgery Dr. med. Andreas Reif Psychiatry and Dr. med. Peter Dahlem Pediatrics Psychotherapy Dr. med. Gernot Stuhler Internal Medicine Dr. med. Giles Vince Neurosurgery Dr. med. Carsten Wessig Neurology Dr. med. Günther Schlunck Ophthalmology Dr. med. Ralf Muellenbach Anaesthesiology Preclinical Dr. med. Thomas Wurmb Anaesthesiology Dr. med. Ralf Kurzai Medical Dr. med. Frank Schuster Anaesthesiology Microbiology Dr. med. Dr. rer. nat. Antje Kroner-Milsch Experimental Dr. rer. nat. Fred Lühder Immunbiology Neurology Dr. rer, nat. Angela Mally Toxikology and Dr. med. Ralph Kickuth Radiology Pharmacology Dr. med. Christoph Schimmer Cardiovascular Dr. rer. nat. Frank Döring Physiology Surgery Dr. rer. nat. Christopher Volk Anatomy and Dr. med. Markus Lange Anaesthesiology Cell Biology Dr. med. Stephan Mielke Internal Medicine Dr. med. Thomas Kerkau Immunology Dr. med. Dr. med. dent. Urs Müller-Richter Dental-, Oral- and Dr. rer. nat. Thomas Müller Physiological Maxillofacial Chemistry Medicine, especially Oral and Maxillofacial Surgery Dr. med. Thomas Thum Internal Medicine Dr. med. Robert Mlynski Otorhinolaryngology

Preclinical Dr. med. Tiemo Katzenberger Pathology and Pathological Anatomy Dr. med. Olaf Rolf Orthopaedics Dr. med. Alexandra Schubert-Unkmeir Medical Microbiology Dr. rer. nat. Heike Claus Medical Microbiology

215 8. Statistics

Registration numbers

Year human medicine / dentistry / biomedicinr Bc. / biomedicine ma. / thereof female thereof female thereof female thereof female

WS 2007/08 154 / 83 60 / 40 34 / 27 12 / 6

SS 2008 153 / 72 59 / 39 - -

WS 2008/09 149 / 86 58 / 36 31 / 23 15 / 14

SS 2009 149 / 77 60 / 30 - -

WS 2009/10 151 / 92 62 / 40. 31 / 25 7 / 7

Graduations (Abschlüsse)

Year human medicine / dentistry / biomedicine Bc. / biomedicine Ma. / thereof female thereof female thereof female thereof female

Autumn 2007 96 / 64 40 / n. s. 21 / 12 14 / 11

Spring 2008 118 / 72 42 / n. s. - 6 / 3

Autumn 2008 116 / 65 64 / n. s. 22 / 17 15 / 11

Spring 2009 150 / 99 30 / n. s. - 3 / 1

Autumn 2009 123 / 73 61 / n. s. 13 / 13 9 / 4

Doctorates (without doctorates in natural sciences)

Year preclinical clinical total

2008 39 172 211

2009 47 178 225

Habilitations

Year preclinical clinical total

2008 7 11 18

2009 4 20 24

216 Imprint:

Publisher: Medical Faculty, University of Würzburg Josef-Schneider-Str. 2 97080 Würzburg, Germany http://www.uni-wuerzburg.de/ueber/fakultaeten/medizin/startseite/

Editorial Staff: Michael Kuhn Matthias Frosch

Image sources: Cover: Medical Faculty / Institutes and University Hospital Page 6: W. Dürr, N. Schmelz, Building Authority Würzburg Page 7: W. Dürr, University Hospital, Building Authority Würzburg Page 8: Department of Neurology Page 9: Department of Neurology

Layout: Schimmel Satz & Graphik GmbH Im Kreuz 9 97076 Würzburg, Germany

The present Research Report can be downloaded in German and English at: http://www.uni-wuerzburg.de/ueber/fakultaeten/medizin/dekant/ University of Würzburg University of Würzburg Universitätsklinikum Würzburg Medical Faculty

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