University of Würzburg Medical Faculty Research Report 2008

University of Würzburg University of Würzburg Universitätsklinikum Würzburg Medical Faculty

Medical Faculty

Josef-Schneider-Str. 2 · 97080 Würzburg 2008 Report – Research University of Würzburg Medical Faculty http://www.uni-wuerzburg.de/ueber/fakultaeten/ Research Report 2008 medizin/startseite/ University of Würzburg Medical Faculty

Research Report 2008 Content

1 General Part 1.1 Preface 1.2 Medical Education ...... 6 1.3 Students’ Representatives ...... 9 1.4 The History of the Würzburg Medical Faculty ...... 10

2 Research Institutes 2.1 Institute of Anatomy and Cell Biology I ...... 12 2.2 Institute of Anatomy and Cell Biology II ...... 14 2.3 Institute of Physiology I ...... 16 2.4 Institute of Physiology II ...... 18 2.5 Biocenter Würzburg Chair of Physiological Chemistry I ...... 20 2.6 Biocenter Würzburg Chair of Physiological Chemistry II ...... 22 2.7 Institute for the History of Medicine ...... 24 2.8 Institute of Psychotherapy and Medical Psychology ...... 26 2.9 Institute for Hygiene and Microbiology ...... 28 2.10 Institute of Virology and Immunobiology, Chair of Virology ...... 30 2.11 Institute of Virology and Immunobiology, Chair of Immunology ...... 32 2.12 Institute for Molecular Infection Biology ...... 34 2.13 Institute of Pharmacology and Toxicology, Chair of Toxicology ...... 36 2.14 Institute of Pharmacology and Toxicology, Chair of Pharmacology ...... 38 2.15 Institute of Forensic Medicine ...... 40 2.16 Institute of Pathology ...... 42 2.17 Institute for Medical Radiation and Cell Research ...... 44 2.18 Institute of Human and Medical Genetics ...... 46 2.18.1 Division of Medical Genetics ...... 48

3 University Hospital 3.1 Introduction ...... 50 3.2 Department of Anaesthesia and Critical Care ...... 52 3.3 Department of Surgery I ...... 54 3.4 Department of Trauma, Hand, Plastic and Reconstructive Surgery ...... 56 3.5 Institute for Transfusion Medicine and Haemotherapy ...... 58 3.6 Department of Thoracic and Cardiovascular Surgery ...... 60 3.7 Department of Urology and Paediatric Urology ...... 62 3.8 Department of Orthopaedics ...... 64 3.9 Department of Obstetrics and Gynecology ...... 66 3.10 Department of Pediatrics ...... 68 3.11 Department of Internal Medicine I ...... 70 3.12 Department of Internal Medicine II ...... 73 3.12.1 Division of Molecular Internal Medicine ...... 76 3.13 Institute of Clinical Biochemistry and Pathobiochemistry – Central Laboratory (IKBZ) ...... 78 3.14 Department of Dermatology, Venereology and Allergology ...... 80 3.15 Institute of Radiology ...... 82 3.15.1 Division of Neuroradiology ...... 84 3.16 Department of Nuclear Medicine ...... 86 3.17 Department of Radiation Oncology ...... 88 3.18 Department of Oto-Rhino-Laryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery ...... 90 3.19 Department of Ophthalmology ...... 92 3.20 Department of Neurosurgery and Division of Pediatric Neurosurgery (until October 2007) ...... 94 3.21 Department of Neurology ...... 96 3.22 Institute for Clinical Neurobiology ...... 98 3.23 Department of Psychiatry, Psychosomatics and Psychotherapy with Division of Forensic Psychiatry ...... 100 3.24 Department for Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy ...... 102

4 Dental Hospital 4.1 Introduction ...... 105

2 4.2 Department of Orthodontics ...... 106 4.3 Department of Functional Materials in Medicine and Dentistry ...... 108 4.4 Department of Oral and Maxillofacial Plastic Surgery ...... 110 4.5 Department of Prosthodontics ...... 112 4.6 Department of Conservative Dentistry and Periodontology ...... 114 4.6.1. Division of Periodontology ...... 116

5 Additional Scientific Units 5.1 Collaborative Research Centers ...... 119 5.1.1 Collaborative Research Center 479, Variability of Pathogens and Host Reactions in Infectious Diseases ...... 119 5.1.2 Collaborative Research Center 487, Regulatory Membrane Proteins: From Molecular Recognition to Drug Targets ...... 120 5.1.3 Collaborative Research Center 567, Mechanisms of Interspecific Interactions of Organisms ...... 122 5.1.4 Collaborative Research Center 581, Molecular Models for Diseases of the Nervous system ...... 123 5.1.5 Collaborative Research Center 630, Recognition, Preparation and Functional Analysis of Agents against Infectious Diseases ...... 125 5.1.6 Collaborative Research Center 688, Mechanisms and Imaging of Cell-Cell Interactions in the Cardiovascular System ...... 127 5.1.7 Transregio-Collaborative Research Center 17, Ras-dependent Pathways in Human Cancer ...... 128 5.1.8 Transregio-Collaborative Research Center 34, Pathophysiology of Staphylococci in the Post-genomic Era ...... 130

5.2 Research Centers ...... 132 5.2.1 Rudolf Virchow Center / DFG Research Center for Experimental Biomedicine ...... 132 5.2.2 Interdisciplinary Center for Clinical Research (IZKF) ...... 135 5.2.3 Research Center for Infectious Diseases ...... 138 5.2.4 Interdisciplinary Cancer Center ...... 140 5.2.5 Interdisciplinary Centre for Addiction Research (ICAW) ...... 142 5.2.6 Interdisciplinary Center for Familial Breast and Ovarian Cancer ...... 144 5.2.7 Transplant Center (TPZ) ...... 146 5.2.8 Cardiovascular Center ...... 147 5.2.9 Center for Experimental and Molecular Medicine (ZEMM) ...... 149

5.3 Graduate Colleges ...... 151 5.3.1 Graduate College 520, Immunomodulation ...... 151 5.3.2 Graduate College 1048, Molecular Basis of Organ Development in Vertebrates ...... 152 5.3.3 Graduate College 1141, Signal Transduction: Where Cancer and Infection Converge ...... 153 5.3.4 Graduate College 1156, From Synaptic Plasticity to Behavioural Modulation in Genetic Model Organisms ...... 154 5.3.5 Graduate College 1253, Emotions ...... 155

5.4 MD/PhD-Program ...... 156

5.5 Research Units ...... 157 5.5.1 Clinical Research Unit 103, Osteogenic Stem ...... 157 Cell Differentiation and Therapy of Bone Loss ...... 157 5.5.2 Clinical Research Unit 124, The Tumor Microenvironment: Target Structure and Modulator of Immune Responses ...... 159 5.5.3 Clinical Research Unit 125, Attention-Deficit/Hyperactivity Disorder – Translational Research Focus on Molecular Pathogenesis and Treatment across the Life Cycle ...... 161

5.6 Research Alliances ...... 163 5.6.1 Rehabilitation Research Network of Bavaria ...... 163 5.6.2 BMBF-Network PathoGenoMik-Plus ...... 165 5.6.3 Network of Excellence EuroPathoGenomics ...... 166 5.6.4 Research Program of the BMBF: Effects and Mechanisms of Psychotherapy in the Treatment of Attention Deficit Hyperactivity Disorder (ADHD) in Children and Adults ...... 168

5.7. International Graduate School – Graduate School of Life Sciences ...... 170

6. The Medical Faculty: Basic Data ...... 171

3 1 General Part 1.1 Preface

After having issued the last research re- The mentioned core themes are becom- In this respect, the Faculty has perfectly port in 2002, the Faculty of Medicine is ing evident by interdisciplinary joint activi- achieved to substantiate the scientific fo- again presenting a report documenting the ties which are supported by external third- cus through new, respectively complimen- achievements and activities of the insti- party funds; these joint activities comprise tary teaching concepts. During the past tutes, clinics and research units and open- collaborative research centres, post grad- years, the Faculty of Medicine has coming this information to the public. uate programmes, DFG research groups, plemented the studies of Human Medicine the DFG Research Centre for Experimen- and Dentistry by innovative educational Both, the Faculty of Medicine’s scientific tal Biomedicine (Rudolf-Virchow-Centre) structures and two new courses of stud- foci and its strength particularly with re- and integrated projects funded by the ies. The course of studies Biomedicine, gard to the biomedical basic science, are BMBF and the EU. Members of the Fac- concluding with the Bachelor of Science decisively shaping the university of Würz- ulty of Medicine are taking an active part (B.Sc.) and being complemented by the burg. Targeted appointments and a very in all of the nine collaborative research masters programme (M. Sc.), is concen- close cooperation with the scientific fac- centres of the University of Würzburg from trating on the basic molecular and cellu- ulties were regarded as decisive premises which five are especially closely linked to lar principles of life. The curriculum, which for the development of the scientific pro- the Faculty of Medicine via their speakers. has been developed in cooperation with file and the development of productive re- Würzburg’s Faculty of Medicine is standing the Faculty of Biology, promotes the prac- search structures in the past. The foun- out for its reinforced support by third-party tical training in the laboratory. This course dation of the Biocentre (Biozentrum), the money for the joint projects. According to of studies aims at producing scientists for setup of the Research Center for Infectious DFG records, the University of Würzburg is the promising area of biomedical research Diseases (in which chairs of the Faculties unique in Germany for raising more funds at universities and in the industry. A train- of Biology, Physics, Chemistry and Phar- in medicine and biology for joint research ing programme for medicine students, macy besides diverse sections of the Fac- activities than for individual projects. The complimentary to the research foci, has ulty of Medicine are integrated), as well most recent DFG fund ranking proves that been developed by the implementation as the installation of the Rudolf-Virchow 80 % of the DFG allocations at the Univer- of the accompanying study course Exper- Centre for Experimental Biomedicine - one sity of Würzburg account for biology and imental Medicine. This course of studies of the first DFG-funded research centres medicine. A 60 % share of the third-party shall arouse the students’ interest for ba- – represent outstanding examples, not fund expenditures go on medical facilities sic research at a very early stage and thus only for the thematic breadth of the vari- at the University of Würzburg. This extraor- contribute to incrementing the number of ous biomedical disciplines represented in dinary position is also made evident by the junior researchers. The efforts for recruit- Würzburg, but also for the close coopera- statistics of the DFG fund ranking: Würz- ing and educating junior researchers have tion between the faculties and the interdis- burg’s Faculty of Medicine is holding the been followed up by the implementation ciplinarity of the research approaches. The 1st rank with € 50.9 mio. (Fig. 1), followed of the Graduate School of Life Sciences close cooperation between the theoreti- by LMU Munich (€ 36.9 mio.) and Tübin- (GSLS) in 2006 which is an important tool cal institutes and the clinical departments gen (€ 35.5 mio.). These figures show that for graduate training and which also gives is a further characteristic of the university the Faculty of Medicine is extremely pro- evidence of the excellent cooperation be- medicine in Würzburg. The Interdisciplinary ductive, making obvious that the Faculty of tween the Faculty of Medicine and the sci- Centre for Clinical Research (IZKF) high- Medicine essentially shapes the scientific entific faculties. lights this interaction between basic re- profile and underline it’s strategic impor- search and disease oriented research. Re- tance for the University of Würzburg. The further development of the Faculty of search institutes and departments which Medicine will depend on the creativity of its are closely linked to the clinics have been After having visited the Faculty of Medicine scientists and a purposeful appointment installed, measures which help to realize in 2005, the German Council of Science policy on the one hand. On the other hand, and structure the transformation of the and Humanities has released a statement it will essentially depend on the further im- biomedical and disease oriented basic rein 2006 about the faculty’s further develop- provement of the edificial substance. Mov- search into clinical research involving hu- ment. The document expressly acknowledg- ing into the Centre for Operational Med- man subjects. The Medical Faculty is fur- es the extraordinary level of performance as icine (ZOM) in 2004 as well as the im- ther promoting these processes and will a location of biomedical basic research. It minent completion of the Centre for Inter- set forward-looking impulses to the clini- also highly acknowledges the faculty’s renal Medicine (ZIM) are milestones for the cal and patient-oriented research and the search profile with the above mentioned development of the Faculty of Medicine, translational health research. A special five research priorities which have been de- rendering more attractive the location for emphasis in this context will be given to veloped within the past decade. This profile patients. These measures also contribute the further expansion of disease focussed has made Würzburg a biomedical research to develop and implement new concepts centres, following thus the examples of the area of supra-regional, in parts even of infor the training of medical students and to already established Cardiovascular Centre, ternational reputation, taking into special support the faculty’s efforts for further de- the Breast Centre and the Tumor Centre. account that apart from the university no veloping and strengthening the clinical re- other research institutions are present in search. The room situation for laboratories The Faculty of Medicine puts a special focus Würzburg. has partially improved when the Centre for on the following thematic fields: Experimental Molecular Medicine (ZEMM) • Infection and Immunity The statement of the German Council of was taken into operation in 2007/2008. • Cardiovascular system Science and Humanities also reconfirms The new facilities which will be gained for • Neuroscience the Faculty of Medicine’s concepts which the working groups of the Rudolf-Virchow- • Cancer, growth and differentiation are giving support to the development of Centre and the Institute for Molecular In- • Structure and function of proteins junior scientists. fection Biology by the move of the Surgical

4 Clinic into the ZOM will again decisively improve the working conditions for basic research and experimental clinical research. The mentioned building projects as a whole are forming part of a comprehensive concept bringing together all the institutes and clinics of the Faculty of Medicine on the medical campus within the next few years. I should like to use the opportunity in order to express my sincere thanks for the huge support for the realization of this concept which the Fac- ulty of Medicine is being given by the Bavarian State Gov- ernment and the Ba- varian Parliament. Fig. 1: Nationwide comparison of the DFG allocation 2002 – My special thanks 2004 (source: DFG). goes to MR (ret.) R. Külb from the Bavarian State Ministry for for the further development of our faculty. Sciences, Research and the Arts, his suc- Sincere thanks go further to the members cessor, MR H. Dierl, the member of the of the closer and wider Faculty Board and Budget Committee of the Bavarian Parlia- to the persons affiliated to the Faculty of ment, M. Ach (MdL) and Prof. Dr. W. Eyk- Medicine, who are notably contributing to mann (MdL), for their efficient support for the reputation and further development of the Faculty of Medicine. the faculty with their engagement and creativity. The fruits of the concerted efforts are Finally, I am very grateful for the numerous described in detail in the reports on the fol- suggestions which we have received from lowing pages. externs, the critical and constructive advice of our assessors of our research centres and research cooperation, who essentially contribute to the positive development of our faculty. I also thank the members of the Würzburg, January 2008 science council, who have given valuable Professor Dr. med. Matthias Frosch advice and impulse with their statements Dean

5 1.2 Medical Education

The requirements of the new Medical Li- censure Act (ÄAppO) were implemented in the clinical studies in the summer term of 2004. A thorough reorganization of the curriculum and study schedule was necessary for this purpose. The essential intention of the new Medical Licensure Act is to extend and improve the clinical practical education as well as to create interdisciplinary educational contents. For this purpose, 12 new interdisciplinary courses and required two-week clerkships in five clinical disciplines had to be integrated in the curriculum. Under the new regulations, the two written state exams formerly held during the clinical studies (1st and 2nd state exami- Fig. 1: Practicing with phantoms in the Skills Lab. nation) are not part of the curriculum any more. Therefore, a large part of the respon- special phantoms and models students ty (Juliusspital Würzburg, Missionsärztliche sibility for carrying out appropriate examina- learn and develop practical skills needed for Klinik Würzburg, Klinikum Aschaffenburg, tions had been transferred to the faculties. their profession. Since summer 2007, ski- Klinikum Coburg, Leopoldina-Krankenhaus For each discipline, for each interdisciplin- lls acquired during these courses are tested Schweinfurt) in 2005/2006. Comprehen- ary course and each new required clerkship with a standardized protocol (OSCE: Objec- sive evaluations have highlighted critical during the clinical studies a graded certifi- tive Structured Clinical Examination). The points and possibilities for improvement of cate of achievement had to be issued. The skills lab is open for medical students all the education during the internship, and three graded certificates of achievement for day long, so that all facilities are available have served as a basis for developing and the new interdisciplinary courses constitute for free training. implementing a structured internship cur- a special challenge. riculum in cooperation with the involved General Medicine hospitals. For this curriculum a so-called In conjunction with the curricular changes The new Medical Licensure Act is giving logbook has been devised, which serves as described, the Faculty of Medicine has is- more importance to the subject of general a guideline for the students’ training during sued regulations for studies and examina- medicine in medical studies. Medical stu- the internship. Anamneses, medical exam- tions conforming in every detail to the re- dents in Würzburg now have to complete inations, diagnostic and therapeutic mea- quirements of the new Medical Licensure a two week clerkship at a general practi- sures, etc. that have been performed by Act. tioner’s office, and they are offered “gen- the student are documented by the men- eral medicine” as an optional subject dur- toring doctor. The first evaluations which Students ing their internship. In addition to the exist- were made after the reorganization of the At present 1,923 students are enrolled at ing net of general practitioners’ offices, the curriculum show that the implemented the University of Würzburg for Human Medi- Medical Faculty has contracted numerous measures have helped to improve the in- cine, 625 for Dental Medicine, 76 for Bio- new general practitioners for this purpose. A ternship training considerably. medical Sciences (Bachelor) and 36 for part-time position for a physician has been the master course in Biomedical Sciences created to coordinate the students’ training Evaluation (status quo: winter term 2007/2008). 154 in general medicine. Students’ evaluations of courses and lec- medical students are first-year students; tures have been regularly performed since 23 of them were granted admission guar- New required clerkships 1999. More than 80 % of the students anteeing them a university place only until In addition to the clerkship in general med- regularly participate in the evaluation pro- the end of their preclinical studies including icine, the students have to complete two cess and thus provide extensive and sig- the first part of the State Medical Licensing week clerkships in surgery, internal medi- nificant data, which have led to different Examination (Physikum). 122 students are cine, paediatrics and gynaecology. In or- adjustments and improvements of the enrolled per term in the clinical study. der to improve the educational conditions educational program. For the respective for each student during this training, tuition teachers as well as for the clinics and in- Skills Lab fee-based financing has been used to em- stitutes the evaluation results offer an ex- The new Skills Lab, a practical clinical skills ploy teaching coordinators for surgery, inter- cellent basis for critically reviewing their teaching facility for Medical students, was nal medicine, paediatrics and gynaecology. own teaching quality. Extraordinary evalu- put into operation for the first time in the ation results are criteria considered in the summer term of 2004. The investment Electives assignment of the achievement-based fi- budget of 50,000 Euro permitted the pur- As the Free State of Bavaria has discon- nancial support (Leistungsorientierte Mit- chase of numerous models and other equip- tinued to grant financial support for hos- telverteilung, LOM). ment. Furthermore, 1,5 positions were cre- pitals involved in the education of Medi- ated and various tutors were contracted for cal students, the Faculty of Medicine has Examination performance the operation of the Skills Lab. Several re- concluded new agreements concerning In comparisons of results of the written quired courses are held in the Skills Lab and the medical students’ education during the examination included in the First Part of represent an essential element in the cur- last-year internship (Praktisches Jahr) with the State Medical Licensing Examination riculum. Through an intensive training with all hospitals associated with the Universi- (“Physikum”), the University of Würzburg

6 scores top ranks among German medi- tion of students and professors. the employment of 5 scientists over a pe- cal schools. In spring 2006, 2007, Würz- In the beginning, equipment designed to im- riod of three years. Among the five Medi- burg medical students ranked first. More- prove practical training conditions was pur- cal faculties of Bavarian universities partici- over, medical students in Würzburg were chased such as modern microscopes, pho- pating in the Bavarian centre for medical very successful in the written examination tometers, cardiograms, phantoms, plasti- education, Würzburg represents the com- of the Second Part of the State Medical Li- nated body slices and anatomical models. petence centre for E-learning. The compe- censing Examination: in spring 2007 and Numerous student tutors were employed tence centres based at the other Medical autumn 2007 they ranked third among the for course mentoring and practical training. faculties are the centres for examinations 35 German faculties. Thus, the Würzburg Financial support is also granted to doctor- (LMU Munich), training during the intern- medical students were obviously very well al students to allow them to participate at ship (TU Munich), medical-didactic quali- prepared for this demanding final medical international congresses in order to pres- fications (Regensburg) and evaluation (Er- examination. ent the results of their thesis research. Fur- langen). ther means are used for the improvement of Albert-Koelliker teaching price childcare facilities for students’ children. Accompanying study course for Experi- Since winter term 2003, the Albert-Koel- mental Medicine liker teaching price endowed with 10,000 About half of the fees are used for the em- In order to offer medical students the possi- Euro is awarded for extraordinary teaching ployment of teaching coordinators, who or- bility of an intensive education in the field of achievements. A commission composed ganize and improve course curricula prefer- biomedical basic research, an “accompany- in equal parts of professors and students entially for the clinical education. Teaching ing study course for experimental medicine” chooses the laureate from the proposals. coordinators were granted for surgery, in- was launched in winter term 2005/2006. Laureates honoured to date are listed in ternal medicine, neurology, psychiatry, gy- This study course is mainly focussed on necology, pediatrics and for interdisciplinary research and imparts current scientific is- oncology. A further part-time position has sues in the biomedical field as well as basic been created for the promotion and coor- methods and experimental approaches at dination of international student exchange the interfaces of medicine, biology, chem- programs. For the future, the clinical-prac- istry and physics. The study programme is tical training shall be further expanded and based on an interdisciplinary cooperation improved. For this purpose, a skills clinic between the faculties of medicine, biology, (teaching clinic) shall be built up, into which chemistry and physics. the present skills lab will be integrated. The number of course participants per term is limited to 5, which permits an intensive Fig. 2: Awarding ceremony of the Koelliker E-learning – blended learning mentoring of the students. At present, 17 teaching price to doctors and tutors of the The virtual Bavarian University (Virtuelle students (5 of them female) are enrolled in Skills Lab by the Dean of Student Affairs, Hochschule Bayern – vhb) has been financ- this programme. Prof. D. Drenckhahn. Picture taken during ing numerous E-learning projects, for ex- the exam celebration in the Neubaukirche ample in dermatology, rheumatology and The study course programme is designed on 1st December 2007. internal medicine. At present, a university- to prepare the participating students for wide project of E-learning is being promot- their medical dissertation. The students paragraph 6 (“Essential Data of the Fac- ed, partially financed by tuition fees. The are expected to submit an experimental ulty”). The Albert-Koelliker teaching price is final goal is to integrate E-learning into all dissertation about a topic of the training awarded each term in June and in Decem- curricula (“blended learning”). In this proj- program. After completion of the whole ber in the course of the Medical Faculty’s ect, the Faculty of Medicine is cooperating programme including the medical disser- graduation ceremony in the Neubaukirche with other faculties, for example informa- tation all conditions are fulfilled to pre- of the University. tics, law, economics, philosophy and biol- pare a dissertation in natural sciences at ogy. The E-learning plat- Tuition fees form WueCampus which is Starting with the summer term of 2007, also partially financed by students studying in Bavaria have to pay tuition fees, facilitates ac- tuition fees of 500 Euros per term. Tuition cess and orientation for all fees have to be used exclusively for the im- students. provement of teaching and learning conditions, and it is important to clearly dis- E-learning in Würzburg tinguish this purpose from financing staff can rely on further finan- and basic equipment by the University`s cial support thanks to the budget provided by the state of Bavaria. installation of a “centre of Tuition fees amount to approx. 1 Mio Eu- competence in medical ed- ros per year, with 700,000 Euros available ucation in Bavaria” (“Kom- for educational purposes in preclinical and petenzzentrum Lehre in der clinical medicine including Biomedicine, Medizin in Bayern”) by the and 270,000 Euros for education in dental Bavarian State Ministry for medicine. Expenditure of the fees is decid- Science, Research and Art, Fig. 3: Example of an E-learning case in internal medicine ed by a commission with equal representa- which provides means for in WueCampus.

7 the Faculty of Biology of the University of The tuition fees allotted to the dental clinic es at the University of Würzburg. This in- Würzburg, and to finally receive the de- are mainly used for the financing of tutors terdisciplinary study course is also open for gree of “Dr. rer. nat” (PhD). This program and a part-time teaching coordinator as well postgraduate students of the faculties of thus complements the successful MD/ as for the financing of partly extremely ex- Biology, Medicine, Physics, Chemistry and PhD programme of the Faculties of Medi- pensive instruments and expendable items Mathematics. cine and Biology. for student courses. A part of the financial burden, which dental students have to bear Outlook for the future Dental medicine today, is thus taken off. The Faculty of Medicine aims at expand- At present, more than 600 dentistry stu- ing the international network by building up dents are enrolled at the University of Würz- In winter term 2007/2008, for the first new partnerships with foreign universities burg. About 260 of the students are in the time, a Committee and Dean of Student and by establishing a special study course preclinical, 350 in the clinical part of their Affairs and a Committee for Student Affairs programme for Human Medicine taught ex- education. The clinical studies are organized were appointed for the dental school. The clusively in English. Furthermore, a teach- according to the currently valid Medical Li- new Medical Licensure Act (ZAppO) for den- ing clinic as well as a mentoring programme censure Act for dentistry students, and all tistry which has been announced for a long for female students shall be implemented in required practical and theoretical courses time will apparently be issued soon and will the near future. Moreover, it is of great con- are offered. The recently refurbished dental require a significant effort for restructuring cern for the faculty to improve the child care clinic is located in the city centre. The den- the studies of dental medicine. conditions for students’ children. tal clinic’s location guarantees a high patient accessibility and an immediate prox- Biomedical Sciences imity to the local population. This becomes The first students of Biomedical Sciences Professor Dr. med. D. Drenckhahn, Dean of evident by the high patient influx: more than were enrolled in winter term 2000/2001. Student Affairs for Human Medicine 28,000 out-patients and more than 1,300 The curriculum comprises six terms with Professor Dr. med. Dr. med. dent. A. Kübler, in-patients were treated in 2007. courses and lectures in natural sciences Dean of Student Affairs for Dental Medicine and preclinical and theoretical clinical med- Dr. rer. nat. E. Lüneberg, Dean’s Office All departments are equipped according to icine and final graduation with the degree the newest technical standard. State-of- of “Bachelor of Science (B.Sc.)”. The un- the-art equipment necessary for a modern dergraduate study course is complemented dentist training is available. In most depart- by a postgraduate course, comprising three ments, interactive teaching concepts and terms during which participants acquire the problem-based learning integrated in the ”Master of Science (M.Sc.)” degree, and clinical training are now offered. Students can then go on in order to receive a PhD have access to an extensive library with nu- (Dr. rer. nat.). For PhD students, a special merous computer work stations with inter- class “Biomedical Sciences” is available net connection. within the Graduate School of Life Scienc-

Fig. 4: Students of dental medicine at the phantom course.

8 1.3 Students’ Representatives

Josef-Schneider-Str. 2 The group students` representatives are and for students in their fifth semester (i.e. 97078 Würzburg both elected as well as non-elected stu- beginning of “Klinik”). It informs students dents who are committed to work voluntari- about the faculty, lectures, courses, exams, Tel.: 0931 201-53859 ly for the interests of medical students at books, ongoing events and many more top- Fax: 0931 201-53858 the University of Wuerzburg Medical School. ics. We provide further information to all We have an office at our disposal which is students of the faculty on our homepage E-mail: [email protected] located in building No. D7 of the University or in the rooms of our office, where we also Hospital. have at our disposal specific learning material for most of the subjects. In addition, the Our work mainly consists of two parts: On local representatives of the exchange sec- the one hand we officially represent the tion of the German Medical Students’ Asso- medical students in various committees: ciation (bvmd-Germany), helping students the faculty and the student council and the in Wuerzburg to organize their internation- several appeal commissions of the faculty. al internships, and SEG-Med stand to the The second part includes several projects, students’ disposal in our faculty. SEG-Med such as working in our office, giving advice is a cooperation of numerous medical stu- to students, organizing different information dents throughout Germany that enables its events as well as contributing to students‘ members to purchase medical equipment social life at university by carrying through (stethoscopes e.g.) to a lower price. Once various parties or other meetings. a week our students’ council meeting takes place, which is supposed to enhance the The committees exchange of information between all members and to give room to discussions on The students´ representatives are entitled current topics. Additionally, students may to vote on many concerns of the faculty. contact us for advice with problems, con- Here, we opine the students’ point of view flicts or new ideas which concern the fac- on all topics being discussed. According ulty, the students’ council, lectures, cours- to the Bavarian university- law of October es, professors etc. At the beginning of every 2006, at least one student member is part semester we organize the so-called fresh- of every committee. Our representatives in mendays where freshmen at the university these committees are being elected by all get a chance to get to know the university, medical students. In this context, a topic their fellow students and the city of Wuerz- with exorbitant interest are the newly imple- burg. Furthermore, we contribute in the or- mented study fees. By constituting a com- ganization of several social events, such as mittee of equal numbers of students and film evenings, parties and opening days for professors, we set up a successful system students and pupils. On our permanent ef- of how to manage the allocation, review- fort to improve students’ curricula and the ing and evaluation process. In any case, system of education, we carried out an on- the study fees represent a new challenge line survey in December 2007, in order to for all persons concerned, especially within evaluate the structure of the schedule. All the context of a responsible and effective students from third year (fifth semester) on allocation. were asked to pronounce their opinion to furnish an overview on the broad interest of Projects students at our faculty.

During the past three years we have been publishing a guideline for medical students Susanne Keilig in their first semester (so called “Vorklinik”) Sophia Danhof

9 1.4 The History of the Würzburg Medical Faculty

The Medical Faculty of Würzburg ranks also a mathematician of international ac- Faculty’s state bluntly by asking: “Wherein among the four oldest medical faculties in claim, succeeded in establishing a flourish- lies the cause of the immense decline of the Germany. It was preceded only by Heidel- ing culture of medical dissertations and dis- Medical Faculty?” berg, Cologne and Erfurt, and thus has to- putations and promoted a number of medi- day a history of more than 600 years be- cal students to doctors. At the same time, It was due primarily to the incessant activi- hind it. Together with theology and law, conditions for clinical, practical training had ties of one man, Carl Caspar Siebold, that medicine had its place assigned among the markedly improved, thanks to the newly this rather desolate situation changed with- three higher faculties in 1402 already, at founded Julius-Spital. In contrast to many in a couple of decades and the Würzburg the original foundation of Würzburg Univer- other contemporary hospitals which cared Medical Faculty became one the foremost sity. It remains unclear to this day, howev- almost exclusively for the aged and invalid, institutions of its kind in Germany. Siebold, er, to what degree formal medical teaching the Julius-Spital was, from its very begin- since 1769 professor of anatomy, surgery was inaugurated at the time. Certainly, any ning, explicitly designated also as a hospi- and obstetrics, began a systematic drive regular teaching activities must have come tal “in aegrorum curationem”, i.e. for the to improve medical education, introduc- to an end with the rapid decline of the Uni- medical treatment of the curable sick. With ing new modern teaching methods. Since versity as a whole. Long before 1402 al- its many patients, the Julius-Spital thus of- 1766, medical students had been offered ready, Würzburg was held in high esteem fered a welcome opportunity to medical stu- regular clinical instruction again, in the Ju- as a center of medical learning, however. dents to observe manifold diseases and to lius-Spital. Towards the end of the 18th cen- Already in the late 13th century the abbot experience the effects of different curative tury, large scale reconstructions work creat- of the monastery of Aldersbach in Lower Ba- approaches. Such bedside teaching was ed space for about 200 curable patients varia undertook a journey of more than 300 very popular among contemporary medi- and thus markedly improved the conditions kilometers to consult the learned physicians cal students and was a major reason, why for practical bedside teaching. Siebold was in Würzburg about his failing health. About a number of medical students crossed the also a driving force behind the rebuilding of the same time, probably around 1280, one Alps and frequented one the Northern Ital- the Theatrum anatomicum and behind the of the most influential vernacular medical ian universities, where they were common- establishment, in 1805, of a modern oper- handbooks of the Middle Ages was written, ly allowed to accompany the professors on ation theatre in the Julius-Spital. Siebold’s the “Arzneibuch” of Ortolf von Baierland who the visits to the large municipal hospitals. sons were to follow their father’s footsteps called himself explicitly a “physician from and like him contributed to the moderniza- Würzburg”. Compiled “from all the Latin After van Roomen’s retirement and death tion of the hospital care and medical in- medical books I have ever read”, Ortolf’s and due to the recurring outbreaks of struction. Johann Barthel von Siebold who “Arzneibuch” offered of summa of medieval plague and the Thirty Years’ War the Würz- worked primarily as an anatomist and sur- medical learning. From the mid-14th centu- burg Medical University lost much of its in- geon lectured about pathological anatomy ry, an topographical illustration of the brain ternational renown, however. Only very few for the first time. Adam Elias von Siebold by the Würzburg canon Berthold von Blu- medical students continued to find their way continued his father’s efforts to improve ob- mentrost has come down to us, which at- to Würzburg and even fewer were promoted stetrical training for medical students and tributed the major rational faculties – imagi- to doctors of medicine. From the late 17th midwives. In 1805, he opened the first ob- nation, cogitation and memory – to the vari- century, the government tried to counteract stetrical hospital in Würzburg in a building ous cerebral ventricles. This made perfect this trend and initiated important reforms. which formerly housed epileptics. sense within the ruling Galenic paradim, The number of medical chairs was raised to which associated the rational faculites with five in 1709; originally there were only two The rapid ascent of the Medical Faculty un- very subtle and mobile animal spirits in the or three. Following the example of leading der Siebold and his sons was ultimately cru- ventricles rather than with the cerebral sub- protestant universities such as Leiden and cial for the survival of the University as a stance itself. Halle a botanical garden was set up; bo- whole. When Würzburg came under Bavar- tanical gardens were then considered im- ian rule in 1803, it was the university in In the 16th century, various learned physi- portant teaching tools which helped med- Bamberg rather than the one in Würzburg cians of renown were active in Würzburg, ical students get familiar with the various which was closed. In the process, the Würz- Burckhard von Horneck, for instance, and plants used as medicinal drugs. An anatom- burg Medical Faculty even saw its fame fur- Johannes Posthius. Only with the second ical theater was built in the garden pavilion ther promoted by leading professors from foundation of the University in 1582, how- of the Julius-Spital and the famous Parisian the former Bamberg institution. One of Ger- ever, formal academic medical teaching surgeon Louis Sievert was brought in to im- many’s foremost anatomists, physiologists was put into place again. Again, medicine prove anatomical teaching. The professor of and embryologists, Ignaz Döllinger, joined ranked among the University’s three high- anatomy was instructed to dissect a corpse its ranks. Like Döllinger, Wilhelm von Hoven, er faculties from the start, though it took at least every four weeks in the winter time, a former school mate of Friedrich Schiller, several years until the Medical Faculty truly in the presence of the other professors. came from Bamberg to Würzburg. Later he came to life. In 1587, the faculty’s statutes Academic disputations and dissertations became a major medical figure in Nurem- were approved. By 1593, finally, the profes- were encouraged. Yet these efforts bore lit- berg, and was, by all appearances, the driv- sors had been appointed and began teach- tle fruit, at first. The Faculty lacked profes- ing force behind the first double-blind trial in ing. Würzburg had come to offer exception- sors whose fame could attract medical stu- history, which was organized in Nuremberg ally good conditions for a sound medical ed- dents from further away, and the teaching 1835 in an attempt to disprove the efficacy ucation. Adrian van Roomen, also known methods remained rather old-fashioned. In of homeopathic drugs. The strongest attrac- as Adrianus Romanus, had been appointed 1739, the professors still had to be explic- tion on German medical students was ex- to the first and most prestigious professor- itly forbidden to dictate their lectures were erted, for a couple of years, by the Philoso- ship, the chair for medical theory. Within by word. In 1758, Karl Philipp von Greiffen- pher Schelling who sought to put medicine a couple of years, van Roomen, who was klau began his request for a survey of the on new, philosophical foundations. At the

10 height of his fame in Würzburg, 270 stu- The National Socialist period left deep marks jor role in the new Graduate School for Life dents wrote their names into the matricles on the Würzburg Medical Faculty. The Insti- Science. Würzburg also has come to house in one year. Soon, growing disillusionment tut für Vererbungswissenschaft und Rasse- a center for research on infectious diseas- set in, however, and his audience shrank forschung (Institute of Genetics and Racial es and a center for interdisciplinary clini- rapidly. Research) conducted large scale genetic cal research. In addition, since 1971, a fair surveys of the population in the area around number of so-called “Sonderforschungs- Over the following decades, Würzburg in- Würzburg. The Werner Heyse, who was ap- bereiche” (special research areas) have creasingly turned into a center of empiri- pointed professor of psychiatry in Würzburg been active, financed by large grants from cal-observational and, finally, laboratory- in 1939 in disregard of the Faculty’s prefer- the Deutsche Forschungsgemeinschaft. based, experimental approaches. Clinical ences, played a leading role in the so-called The trend towards interdisciplinary research instruction was further thanks to a massive „Aktion T4”, the organized mass murder of and medical care gained further momen- expansion of policlinical care. Thousands of 10.000s of psychiatric and handicapped tum over the last years, with plans for the out-patients provided medical students with men, women and children between 1939 creation of a “Zentrum Operative Medizin” unique possibilities to visit and observe the und 1941. Based on the „Gesetz zur Ver- (Center for Operative Medicine), opened in patients in their homes and to take respon- hütung erbkranken Nachwuchses“ (1933) 2004, a “Zentrum Experimentelle Moleku- sibility for their care, guided by a more expe- forced sterilizations and abortions were per- lare Medizin” (Center for Experimental Mo- rienced physician. Johann Lukas Schönlein, formed in the Maternity Hospital under Carl lecular Medicine) and a “Zentrum Innere the foremost representative of the so-called Gauß. George Schaltenbrand, professor of Medizin” (Center for Internal Medicine). “natural history school” in medicine, intro- neurology and later widely acknowledged as duced scores of students to his approach. one of the leading researchers on multiple He focused on a detailed and unprejudiced sclerosis in the world, vaccinated inmates Professor Dr. med. Dr. phil. M. Stolberg observation of signs and symptoms as the of the psychiatric hospital in Werneck with Institute for the History of Medicine basis of a new, empirically founded nosol- the cerebral fluid of monkeys who, he be- ogy. Thanks to his method Schönlein de- lieved, suffered from multiple sclerosis, in scribed various diseases for the first time order to prove the contagious nature of the and some like the Schoenlein-Henoch pur- disease. Most of the other hospitals and in- pura (Vasculitis allergica) carry his name to stitutes were also in some way or other im- this day. Nikolaus Anton Friedreich gave an plicated in National Socialist medicine and account of facial nerve paralysis. Johann almost all professors lost their chairs after Georg Pickel and Johann Joseph von Scher- 1945. er helped lay the groundwork for a modern science of pharmaceutics and medical The massive air raid in the spring of 1945 chemistry respectively. Around the middle also damaged or destroyed large parts of of the 19th century, Franz von Rinecker was the university and the hospitals. Already a the Faculty’s dominant figure. He made im- couple of days after the raid, the first oper- portant contributions to pediatrics, psychi- ations were performed again, however, and atry and dermatology alike and thanks to out-patient care as well as work on the wards his efforts Würzburg can boast one the first was resumed. Only ten years after the end pediatric hospitals at any university in the of the war, the Faculty counted three of the world. Under Rinecker’s leadership, Rudolf big names in contemporary Western medi- Virchow and Albert Kölliker were appointed cine among its members, the surgeon Wer- professors, who helped turn anatomy and ner Wachsmuth, the internist Ernst Woll- pathology into modern laboratory sciences heim and the otorhinolaryngologist Horst and, in the case of Virchow’s cellular pa- Wullstein. Wullstein not only acquired inter- thology, provided contemporary medicine national fame with his new method of tym- as a whole with a new theoretical basis. panoplasty and his operation microscope. Outstanding contributions came from re- As the driving force behind the foundation searchers outside of the Medical Faculty, of a “head clinic” he also set the path for a from the biologists Julius Sachs and The- development towards the establishment of odor Boveri, for example, and, above all, interdisciplinary centers which increasingly from the physicist Wilhelm Conrad Röntgen came to shape the Faculty and which act- who discovered the x-rays. ed as crucial catalysts for cutting edge biomedical research. In 1992, a new center By 1900, the Julius-Spital – in 1800 still to for biomedical research was opened on the a large degree a last resort for poor, single Hubland, which today brings together mem- patients and invalids – and the various uni- bers of ten different institutions, from the versity hospitals had become the most im- faculties of medicine, chemistry and phar- portant providers of medical care in Würz- macy as well as biology., In 2002, the Vir- burg. In the 1920s, the close and fruitful, chow Zentrum was established as a nation- though sometimes conflict-ridden ties be- al research center for experimental biomed- tween the Juliusspital and the Medical Fac- icine, endowed with a number of research ulty were somewhat loosened when the new professorships and research groups head- Luitpold-Hospital was built in Grombühl. ed by junior researchers, which plays a ma-

11 2 Research Institutes 2.1 Institute of Anatomy and Cell Biology I

Mission anions, and the zwitterion carnitine. Us- Professor Dr. med. Hermann Koepsell (Head) and Structure ing site directed mutagenesis we identified seven amino acids in OCT1 that are criti- Koellikerstr. 6 The research at Chair I is dedicated to the cal for the binding of substrates and inhibi- 97070 Würzburg structure, function, distribution and regulators. Computer modeling of the OCT1 ter- Tel.: 09 31 / 31-2700 tion of membrane proteins, in particular to tiary structure in analogy to the elucidat- Fax: 09 31 / 31-2087 transporters of sugars and drugs. Further- ed structure of a bacterial transporter (lac- more, the function of an intracellular regu- tose permease) revealed a large binding E-mail: [email protected] latory protein for plasma membrane trans- pocket in which the critical seven amino www.uni-wuerzburg.de/anatomie porters is investigated. This regulatory pro- acids are directed to the aqueous phase. tein represents a novel target for the modu- Using fluorescent labeling of single amino

CONTACT DETAILS CONTACT lation of transport processes. The methods acids of OCT1 we could demonstrate mo- used in this research include molecular bition of the 11th transmembrane domain ology, cell biological and biochemical inves- during transport of organic cations. A de- tigations, transport measurements, electri- tailed analysis of the currents induced by cal measurements on Xenopus laevis oo- translocation of organic cations in wildtype cytes, and breeding and characterisation of OCT1 and rOCT1 mutants suggests a trans- transgenic mice. port mechanism according to the “alternat- ing access” model. In a first step substrate Members of chair I are: the department binds to the outward-facing substrate bind- head, four assistant professors, three tech- ing pocket. Thereafter the binding pocket nicians and MD-students. Two Post-Docs, undergoes a conformational change after two PhD-students funded by the Collabora- which the subtrate binding pocket is acces- tive Research Centre (SFB 487) are also sible from the intracellular side (inward-fac- included. ing conformation). This allows release of the substrate to the cytosol. We have successful expressed members of the SLC22-fam- Major Research ily in insect cells and in a cell free expres- Interests sion system. Furthermore, we purified and reconstituted active transporters in proteo- The main focus is the elucidation of the mo- liposomes. In collaboration with another re- lecular mechanisms of function and regu- search group attempts will be undertaken to lation of physiologicaly important transport crystallize expressed and purified transport- proteins in the plasma membrane. One proj- ers and to determine tertiary structures by ect deals with polyspecific cation transport- X-ray diffraction. ers of the SLC22-family, which are involved in the absorption of drugs in small intestine as well as in excretion of drugs and drug Function and regulation of the sodium metabolites in kidney and liver. Further- D-glucose cotransporter SGLT1 more, these transporters are essential for the distribution of neurotransmitters in the We generated SGLT1-specific antibodies, brain. The first member of this family (OCT1, which are used to investigate the function SLC22A1) of polyspecific drug transporters and localization of SGLT1 in intestine, kid- was cloned in 1994 in this department. An- ney, liver, lung, and different glands. Fur- other project deals with the sodium-depen- thermore, we generated mice with a SGLT1 dent D-glucose transporter SGLT1. SGLT1 (SLC5A1 gene) knock out, which survive on absorbs dietary D-glucose in the small in- a D-glucose and D-galactose free diet. A testine and reabsorbs D-glucose from the couple of years ago we cloned the intracel- primary urine in the proximal tubule of the lular regulator protein RS1, which is encod- kidney. A key element in this project is the ed by the intronless gene RSC1A1. RS1 is investigation of the regulator protein RS1 localized at the trans-golgi network, where (RSC1A1), which was cloned in 1992 in it inhibits the budding of SGLT1-contain- this group. RS1 regulates the trafficking of ing vesicles. During mitosis or in less dif- SGLT1 to the plasma membrane and modu- ferentiated cells, RS1 is localized in the lates SGLT1 transcription in the nucleus. nucleus, where it inhibits SGLT1-transcription. In mice with a RS1 (RSC1A1 gene) knock out, absorption of D-glucose in the Substrate recognition and transport small intestine was increased; furthermore, mechanism of the polyspecific trans- these mice developed adipositas. We iden- porters of the SLC22-family tified two RS1 domains, which are responsible for the post-transcriptional inhibition of The SLC22-family of transporters includes SGLT1. Tripeptides derived from these do- transporters for organic cations, organic mains inhibited SGLT1 function at nanomo-

12 Fig. 1: Model of the inward-facing substrate binding pocket of the organic cation transporter rOCT1. The 4th transmembrane α-helix (TMH) is coloured in green, TMH10 is coloured in red. For the indicated amino acids a contribution to substrate binding has been shown experimentally. lar intracellular concentrations. The inhibiting tripeptides are taken up by enterocytes via a peptide transporter and are, therefore, potential drugs for the treatment of adipositas.

Popp C, Gorboulev V, Müller TD, Gorbunov D, Shatskaya N, Koepsell H (2005) Ami- Teaching no acids critical for substrate affinity of rat organic cation transporter 1 line the sub- Education of medical and dental medical strate binding region in a model derived students in microscopical and macroscopi- from the tertiary structure of lactose permease. Mol. Pharmacol. 67, 1600-1611. cal anatomy and in cell biology. Education of PhD and MD students. Classes in trans- Schmitt BM, Koepsell H (2005) Alkali cat- porters and channels. ion binding and permeation in the rat organic cation transporter rOCT2. J. Biol. Chem. 280, 24481-24490.

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.

SELECTED PUBLICATIONS Pharmacol. 73, 50-61.

Osswald C, Baumgarten K, Stümpel F, Gorboulev V, Akimjanova M, Knobeloch K- P, Horak I, Kluge R, Joost H-G, Koepsell H (2005) Mice without the regulator gene Rsc1A1 exhibit increased Na+-D-glucose cotransport in small intestine and develop obesity. Mol. Cell. Biol. 25, 78-87.

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 affin- 13 ity. J. Biol. Chem. 282, 28501-28513. 2.2 Institute of Anatomy and Cell Biology II

Professor Dr. med. Detlev Drenckhahn (Head) Mission soprotective steroid hormones, glucocor- and Structure ticoids (GC) and estrogen which improve Koellikerstr. 6 permeability properties of the BBB. Re- 97070 Würzburg Research in the department is focused on search projects concentrate on elucidat- Tel.: 09 31 / 31-2702 two main areas of interest. The research ing the molecular basis how GCs and es- Fax: 09 31 / 31-2712 group on cell biology (head scientist: Prof. trogen regulate BBB permeability. Effects E-mail: [email protected] Dr. D. Drenckhahn) analyses structural, mo- of GCs and estrogen are known to be me- http://www.uni-wuerzburg.de lecular and functional properties of the cy- diated by their cognate steroid hormone /ueber/fakultaeten/medizin/institute/institut_ toskeleton and the regulation of endothe- receptors, the GC and estrogen receptor, fuer_anatomie_und_zellbiologie/startseite/ lial barrier. so that a special emphasis is laid on their function acting as ligand-dependent tran-

CONTACT DETAILS CONTACT Professor Dr. med. Peter Kugler The research group on neurobiology (head scriptional regulators. Tel.: 09 31 / 31-2704 scientist: Prof. Dr. P. Kugler, Prof. Dr. E. Asan) studies the transport and metabolism of neurotransmitter glutamate and investi- Pemphigus pathogenesis gates the organization and ultrastructure of (D. Drenckhahn, J. Waschke, A Hübner) various CNS regions (e.g. amygdala). The life-threatening blistering skin disease Research in the department is carried out pemphigus is primarily caused by antibod- by 11 postdoctoral scientists, 18 Ph.D.- ies against cell adhesion molecules (desmo- students, and 12 technical assistants. cadherins). We investigate whether these autoantibodies directly interfere with bind- Two existing experimental systems to mea- ing of these adhesion molecules or whether sure forces between molecules and cells cell signalling pathways are responsible for (atomic-force-microscopy, laser-tweezers) skin blistering. were further improved. In the years 2004- 2006 a new technique to measure vascular permeability in rats in vivo (single- Proteins of the nucleus microvessel perfusion technique) was es- (S. Hübner) tablished. The nucleus represents the “control center” of eukaryotic cells with many proteins Major Research playing an important role in maintaining Interests its structural and functional integrity. We focus on such proteins (i.e. lamins and Endothel barrier regulation in vivo and kanadaptin) and perform investigations in vitro in the context of fundamental and patho- (D. Drenckhahn, J. Waschke, N. Schlegel, physiological aspects (i.e. lamino-pa- A Hübner) thies).

The endothelium lines the inner surface of the vascular wall. We investigate how in- Glutamate transporters in the brain flammatory mediators induce the formation (P. Kugler) of gaps between endothelial cells which allow the leakage of plasma into the sur- Glutamate is used as an excitatory neuro- rounding tissue and thereby may lead to se- transmitter by numerous neuronal sys- vere edema. We focus on the regulation of tems in the brain. Synaptically released cell adhesion molecules (cadherins, clau- glutamate has to be eliminated rapidly dins, integrins) and of the cytoskeleton. from the extracellular space via glutamate transporters (EAAT1-5), since otherwise it would overexcite and damage neighboring Molecular mechanisms of steroid-in- neurons. We try to obtain insights into the duced regulation of permeability in the subcellular localization and translocation haematoencephalic barrier of glutamate transporters in glutamater- (C. Förster) gic neurons.

The integrity of the blood brain barrier (BBB) is compromised in many disorders Emotions of the human CNS leading amongst oth- (E. Asan) ers to increased vascular permeability and reduced expression of tight junction and The corpus amygdaloideum (amygdala) is adherens junction proteins. Therapeutical of decisive importance for emotional pro- strategies include treatment with the va- cesses. Malfunctions in interconnections of

14 Asan E, Yilmazer-Hanke DM, Eliava M, Hantsch M, Lesch K-P, Schmitt A (2005) The corticotropin-releasing factor (CRF)- system and monoaminergic afferents in the central amygdala: investigations in dif- Fig. 1: Cytoskeleton and adhesion molecules (cadherins) control the barrier between ferent mouse strains and comparison with the rat. Neuroscience, 131:953-967. blood and tissue (endothelial layer). How inflammatory stimuli modify the barrier is one aspect investigated by the group. Förster C, Silwedel C, Golenhofen N, Bu- rek M, Kietz S, Mankertz J, Drenckhahn D this brain area may contribute to neuropsy- rying out such investigations, we support (2005) Occludin as direct target for glu- cocorticoid-induced improvement of blood chiatric, especially affective disorders. We studies in numerous clinical and basic sci- brain-barrier properties in a murine in vitro analyze the structure of amygdaloid network ence projects dedicated to elucidate mo- system. J. Physiol. 565:475-486. and investigate which factors could be re- lecular mechanisms of nervous system dis- sponsible for normal function and patholog- orders. Hübner S, Eam JE, Hübner A, Jans DA ic changes. (2006) Laminopathy-inducing lamin A mutants can induce redistribution of lamin binding proteins into nuclear aggregates. Ultrastructure of tissues and cells of Exp. Cell Res. 312:171-183.

the nervous system Teaching SELECTED PUBLICATIONS (E. Asan) Kugler P, Schleyer V (2004) Developmen- tal expression of glutamate transporters Courses in microscopic and macroscopic and glutamate dehydrogenase in astro- Morphological investigations, especially on anatomy, neuroanatomy and cell biology cytes of the postnatal rat hippocampus. an electron microscopy level, deliver impor- are held for medical and dentistry students Hippocampus 14:975-985. tant contributions to the analysis of chang- (a total of 430 students per year). The de- es in the nervous system which may be the partment hosts a yearly meeting of the Ana- Waschke J, Spindler V, Bruggeman P, Zillik- ens D, Schmidt G, Drenckhahn D (2006) cause of neuropsychiatric disorders. By car- tomical Society (last week of September). Inhibition of Rho A activity causes pemphigus skin blistering. J. Cell Biol. 175:721- 15 727. 2.3 Institute of Physiology I

Professor Dr. med. Michaela Kuhn (Head) Mission ciency, the cardiac synthesis and release and Structure of ANP is markedly enhanced, but the car- Röntgenring 9 diovascular effects are clearly diminished, 97070 Würzburg Our research activities are in the field of indicating a receptor or postreceptor de- Tel.: 09 31 / 31-2721 cardiovascular physiology and pathophys- fect of GC-A. Biochemical studies in trans- Fax: 09 31 / 31-2741 iology. Our investigation has focused on fected GC-A–overexpressing cells showed E-mail: [email protected] understanding the molecular mechanisms that phosphorylation of GC-A within the in- wuerzburg.de associated with specific forms of arterial tracellular domain is essential for its ac- www.physiologie.uni-wuerzburg.de/ hypertension and cardiac hypertrophic re- tivation process. In turn, desensitization physiologieI/ modeling. Another major point of interest and/or inactivation of GC-A probably in- is the function of SPRED proteins in cel- volves ANP-dependent dephosphorylation

CONTACT DETAILS CONTACT Professor Dr. rer. nat. Kai Schuh lular proliferation and differentiation. In of GC-A. Notably, the responsiveness of Tel.: 09 31 / 31-2740 particular, by application of gene targeting GC-A to ANP is also reduced by exposure technology in mice, we obtained new in- to growth hormones such as Angiotensin II sights into the diverse physiological func- and endothelin and in vitro this correlates tions of natriuretic peptides, nitric oxide with receptor dephosphorylation. In col- (NO) and their guanylyl cyclase (GC) recep- laboration with Professor Albert Sickmann tors as well as of SPRED proteins. These (Protein Mass Spectrometry, Rudolf-Vir- different projects are supported by the DFG chow-Center) our project in the SFB 487 (SFB 688 and 487, besides personal fund- attempts to identify (in)activating modifi- ings) and the IZKF Würzburg. cations of GC-A and the mediating regulatory proteins. Major Research Interests Cardiac effects of ANP (M. Kuhn, K. Völker, S. Krautblatter, M. Endothelial effects of the cardiac hor- Klaiber) mone atrial natriuretic peptide (ANP) (M. Kuhn, B. Gaßner, B. Schreier) Cardiac hypertrophy is a common and often lethal complication of arterial hypertension. The cardiac hormone atrial natriuretic pep- Cardiac myocytes have signaling pathways tide (ANP), via its vasodilating and diuretic that agonize and antagonize hypertrophic effects, has an important physiological role growth. In chronic hemodynamic overload, in the maintenance of arterial blood pres- there is a significant increase in ANP expres- sure and volume. Its guanylyl cyclase-A (GC- sion in the cardiac ventricles. Our studies A) receptor is highly expressed in vascular in cultured myocytes and genetically engi- endothelium, but the functional relevance neered mice showed that in this situation the of this is controversial. To dissect the en- ANP / GC-A pathway exerts not only endo- dothelium-mediated actions of ANP in vivo, crine but also local antihypertrophic actions we inactivated the GC-A gene selectively (Figure 1). The molecular mechanism(s) by in endothelial cells. Mice with endothelium- which ANP and GC-A inhibit cardiac hyper- restricted GC-A deletion exhibited reduced trophy is not definitively known. Our observa- vascular permeability to plasma protein, re- tions suggest that ANP modulates myocyte sulting in chronically increased plasma vol- intracellular pH and Ca2+ homeostasis and ume, arterial hypertension and cardiac hy- counter-regulates calcium-dependent hyper- pertrophy. Renal excretion and vasodilation trophic signaling pathways such as CaMKII did not account for these changes. Thus and calcineurin. ANP-induced increases in endothelial permeability may be critical to the ability of ANP to lower arterial blood pressure. Our Interaction of Ca2+- and NO-dependent current studies supported by the SFB 688 Pathways in the Cardiovascular System are directed to dissect the cellular pathways (K. Schuh, D. Fetting, T. Fischer, R. Freud- mediating these effects. inger)

Aim of this project is the generation of Posttranslational modifications of the transgenic mouse models to investigate ANP receptor the interactions of Ca2+- and NO/cGMP- (M. Kuhn, M. Hartmann, J. Schröter, A. dependent signaling pathways in com- Gazinski) ponents of the cardiovascular system. To do so, we combine the tetracycline-reg- In some forms of arterial hypertension and ulated Tet-Off system with corresponding as one of the earliest and pathognomonic transgenes under control of tetracycline events in cardiac hypertrophy and insuffi- responsive elements. As a result, expres-

16 Fig. 1: The guanylyl cyclase A ( GC-A) receptor mediates the endocrine effects of atrial natriuretic peptide (ANP) regulating arterial blood pressure and volume homeostasis and also local antihypertrophic actions in the heart. sion of various proteins can be induced tissue-specifically e.g. in vascular smooth Teaching muscle cells (SM22 alpha promoter) or in cardiac myocytes (alpha MHC promoter). Physiology and pathophysiology (together Subsequently, the effects of transgenic with Chair II) for the students of medicine, overexpression on our model systems will dentistry, pharmacy, psychology, and infor- be investigated. matics (lectures, seminars, integrated seminars, and practical courses as well as examinations). In vivo Relevance of the MAPK Pathway Inhibitor SPRED (K. Schuh, M. Ullrich, P. Benz)

Spreds form a new protein family with an N-terminal Enabled/VASP homology 1 do- Sabrane K, Kruse MN, Fabritz L, Zwiener M, main, a central c-Kit binding domain, and Zetsche B, Skryabin BV, Baba HA, Yanagi- a C-terminal Sprouty-related domain. They sawa M, Kuhn M (2005) Vascular endothe- are able to inhibit the Ras/ERK signaling lium is critically involved in the hypotensive pathway after various mitogenic stimula- and hypovolemic actions of atrial natriuretic tions. They inhibit cellular proliferation and peptide. J Clin Invest. 115: 1666-1674. differentiation and have a high potential as Kilic A, Velic A, De Windt L,J, Fabritz L, tumor markers and suppressors of carcino- Voß M, Mitko D, Zwiener M, Baba HA, van genesis. One aim of this project is getting Eickels M, Schlatter E, Kuhn M (2005) + a deeper insight into the physiological func- Enhanced activity of the myocardial Na / H+ exchanger NHE-1 contributes to cardi- tions of SPRED proteins in an entire organ- ac remodeling in ANP – receptor deficient ism. In order to achieve this, we used a gene mice. Circulation 112: 2307-2317. trap model, which results in an ablation of the spred2 gene and in the replacement of Yurukova S, Kilic A, Völker K, Leinewe- the endogenous gene by a reporter gene, ber K, Dybkova N, Maier LS, Brodde O- E, Kuhn M (2007) CamKII – mediated allowing expression profiling of spred2. Fur- increased lusitropic responses to ß-adr- thermore, we are interested in the inhibitory enoreceptor stimulation in ANP – recep-

function of SPREDs in cellular systems, i.e. SELECTED PUBLICATIONS tor deficient mice. Cardiovasc Res 73: which are the interacting partners neces- 678-688. sary to exert the inhibitory role. Based on Kilic A, Bubikat, A, Gaßner B, Baba H.A., this integrated approach, we hope to gain Kuhn M (2007) Local actions of atrial na- detailed insights into the molecular mecha- triuretic peptide counteract angiotensin II nisms as well as into the in vivo functions stimulated cardiac remodeling. Endocrinol- of SPRED proteins. ogy 148: 4162-4169. Bundschu K, Walter U, Schuh K (20007) Getting a first clue about SPRED func- 17 tions. BioEssays 29: 897–907. 2.4 Institute of Physiology II

Professor Dr. rer. nat. Andreas Karschin Mission ty. Tandem-pore potassium channels car- (Head) and Structure ry these currents and can be inactivated by neurotransmitters such as serotonin. Röntgenring 9 The research activities of the department We could show that these channels sig- 97070 Würzburg focus on the molecular, biochemical and nificantly regulate the excitability of the Tel.: 09 31 / 31-2730 pharmacological/functional characteriza- neurons in the PnC as well as in the amyg- Fax: 09 31 / 31-2741 tion of two different classes of ion chan- dala. E-mail: [email protected] nels: tandem-pore potassium channels http://www.physiologie.uni-wuerzburg.de/ and acid-sensing ion channels. Another physiologieII/ focus of our research is the analysis of the Tandem-pore potassium channels as molecular gating mechanism of mechani- therapeutical targets of antidepres-

CONTACT DETAILS CONTACT Professor Dr. rer. nat. Stefan Gründer cally activated ion channels, in particular sants (acting Head in 2007) the transduction channel of sensory hair (E. Wischmeyer) Tel.: 09 31 / 31-6046 cells. Tandem-pore potassium channels are the Professor Dr. rer. nat. Erhard Wischmeyer In addition to the chairman, the staff in- molecular correlate of background potas- (acting Head since 1. 1. 2008) cludes two associate professors, four re- sium currents. They control the excitability Tel.: 09 31 / 31-2623 search associates, four technical assistants of neurons in the central nervous system and several academic co-workers that are and are expressed e.g. in the limbic sys- financed through third-party funds. tem of the brain and in the heart. Patho- logical changes in the limbic system may cause symptoms from mood disorders to Major Research depressions. Antidepressants are the main Interests pharmacological tools for therapy. Howev- er, their use is limited by unwanted cardi- Molecular understanding of the proton ac side effects, which might be caused by gating of ASICs an interaction with the same target protein (S. Gründer, X. Chen) in heart cells. So far, one member of the tandem-pore potassium channel family has Protons are the simplest transmitter; they been identified to be sensitive to several participate in the synaptic transmission in antidepressants. This potassium channel is the CNS as well as in the excitation of no- also expressed in cardiac cells, suggesting ciceptors in the PNS. One of the most im- that it causes the cardiac side effects of an- portant class of neuronal receptors for pro- tidepressants. tons are acid-sensing ion channels (ASICs). Activation of ASICs contributes to neuronal death associated with stroke. Our aim is it Molecular characterisation of a me- to elucidate the activation mechanism of chanically gated ion channel ASICs by protons. This will also increase (S. Gründer, D. Wiemuth, I. Kadurin) our understanding of the role of these receptors in situations such as stroke, isch- Mechanically activated ion channels are emia, and metabolic acidosis for example arguably the least characterised ion chan- during exercise. nels, and this in spite of the fact that they serve many physiological functions. We have cloned a new ion channel that is a Regulation of neuronal excitability and good candidate for a mechanosensitive synaptic transmission by potassium ion channel from sensory hair cells. We channels want to identify proteins that are associ- (M. Weber) ated with this channel and that are important for its mechanical gating. We use The efficacy of synaptic transmission de- this system as a model to define the mo- pends on pre- and postsynaptic ion cur- lecular organisation of a mechanosensi- rents. Synaptic transmission in a pontine tive complex. brain stem nucleus (PnC) plays a crucial role during processing of the startle response. This nucleus integrates a num- Cellular excitability modulates the ex- ber of different synaptic inputs, e.g. in- pression of potassium channel genes puts from the amygdala in fear and anxi- (F. Döring) ety. However, the detailed characteristics and regulation of the synapses remain to The excitability of neurons crucially depends be clarified. Possibly, background potas- on the resting potassium conductance. This sium currents play an important role be- conductance is predominantly mediated cause they modulate neuronal excitabili- by inwardly rectifying potassium channels

18 Fig. 1: The figure shows a preliminary model for the activation of an acid-sensitive ion channel (ASIC) by protons (From: Paukert et al. (2008) J. Biol. Chem.).

(Kir) and tandem-pore potassium channels robiology (lectures, seminars and practical (K2P). Studies using in vitro models of neu- courses as well as examinations). Together ronal cell cultures have shown that gene ex- with colleagues from the university hospi- pression of potassium channels is modu- tal, the institute offers seminars that deep- lated by changes in the resting membrane en the understanding of the clinical aspects potential. Our investigations on K2P chan- of physiology. nel knockout mice demonstrated that the loss of individual potassium channels, accompanied by a reduction of neuronal potassium conductance, is compensated by increased expression of related potassium channels. We want to identify i) the individual potassium channel genes that are regulated by changes in the membrane potential and ii) the signalling pathways that couple gene expression of ion channels to cellular excitability.

Chen X, Kalbacher H, Gründer S (2005) Molecular characterisation of peptide- The tarantula toxin Psalmotoxin 1 inhibits gated ion channels Acid Sensing Ion Channel (ASIC) 1a by in- (S. Gründer, A. Golubovic) creasing its apparent H+ affinity. J. Gen. Physiol. 126: 71-79. It is textbook knowledge that neuropeptides Shin, J-B, Adams D, Paukert M, Siba M, activate exclusively G-protein-coupled-re- Sidi S, Levin M, Gillespie PG, Gründer S ceptors that mediate slow neurotransmis- (2005) Xenopus TRPN1 (NOMPC) local- sion. We have cloned form the freshwater izes to microtubule-based cilia in epithelial polyp Hydra an ion channel that is directly cells, including inner ear hair cells. Proc. Natl. Acad. Sci. USA 102: 12572-12577. gated by a neuropeptide. This result shows that simple nervous systems use neuropep- Döring F, H. Scholz H, Kühnlein R, tides also for fast neurotransmission. The Karschin A and Wischmeyer E (2006). human genome contains ionotropic recep- Novel Drosophila two-pore domain K+ tors that are related to the peptide-gated channels: rescue of channel function by heteromeric assembly. Eur. J. Neurosci 24: channel of Hydra. We are currently investi- 2264-2274. gating whether these human channels are

also directly gated by neuropeptides. SELECTED PUBLICATIONS Golubovic A, Kuhn A, Williamson M, Kal- bacher H, Holstein TW, Grimmelikhuijzen CJ, Gründer S (2007) A peptide-gated ion channel form the freshwater polyp Hydra. J. Biol. Chem. 282: 35098-35103. Teaching Dobler T, Springauf A, Tovornik S, Weber The department teaches physiology and M, Schmitt A, Sedlmeier R, Wischmeyer E, Döring F (2007). TRESK two-pore do- pathophysiology to students of medicine, main K+ channels constitute a significant dentistry, pharmacy, psychology and neu- component of background potassium currents in murine dorsal root ganglion neu- 19 rones. J. Physiol. 585: 867-879. 2.5 Biocenter Würzburg Chair of Physiological Chemistry I

Professor Dr. rer. nat. Dr. h.c. Mission still unsolved question whether nevi are a Manfred Schartl (Head) and Structure benign, precancerous state of the malignant melanoma. Biozentrum Complying to the perspectives of research Am Hubland at the Biocenter, extending from function- 97074 Würzburg al molecular biology to the development of Functional analysis of Hey genes Tel.: 09 31 / 888-4149 the total organs and its interactions with the (M. Gessler) Fax: 09 31 / 888-4150 environment, all individual research groups E-mail: [email protected] of our chair contribute to research in ba- Hey genes are essential transducers of Del- http://pch1.biozentrum.uni-wuerzburg.de sic biochemistry as well as cell biology. The ta/Notch signals and they control embryon- multi-faceted approach is well reflected in ic development of the cardiovascular sys-

CONTACT DETAILS CONTACT Professor Dr. rer. nat. Stefan Gaubatz the fact that the scientists of the institute tem. Hey1, Hey2 and HeyL are needed for Tel.: 09 31 / 888-4138 are biologists, chemists and physicians and epithelial to mesenchymal transformation that the head of the institute is a member of (EMT) of the endocardium in the developing Professor Dr. med. Manfred Gessler the Medical as well as the Biological Faculty heart, a prerequisite for the formation of the Tel.: 09 31 / 888-4159 of the University. septum and valves. Furthermore, Hey1 und Hey2 participate in the positioning of the The research interests of the individual atrioventricular canal as an organizing cen- groups range from functional molecular and ter. These findings were supported by high cellular biology to questions concerning the resolution magnetic resonance imaging of development of entire organs and their in- knockout embryos (Figure). Hey genes are teractions with the environment, in line with induced by hypoxia and they mediate arte- the mission of research at the Biocenter. rialization of endothelial cells. They repress The multi-faceted approach is well reflected expression of the venous regulator Coup- in the fact that the scientists of the institute TFII and thereby control angiogenesis. A are biologists, chemists and physicians and lack of Hey1 and Hey2 leads to a lethal an- that the head of the institute is a member of giogenesis defect. the Medical as well as the Biological Faculty Our work on the fjx1 ligand as part of the of the University. planar cell polarity (PCP) pathway showed that fjx1 regulates dendrite growth in the CNS and it seems to participate in additional PCP processes in other organs. Major Research Interests Analysis of Wilms tumors Molecular analysis of melanoma forma- (M. Gessler) tion (M. Schartl) Within the framework of the German Wilms Tumor Study our tumor bank has been ex- Due to the enormous complexity and vari- panded and we could identify several new ety of human cancerous diseases, animal genes whose expression correlates with tu- models are especially suited to analyse ba- mor prognosis. A parallel re-evaluation of all sic mechanisms of tumour development previously known candidate genes in a large and progression on the genetic and mo- cohort of more than 200 Wilms tumors re- lecular level. Small laboratory model fish vealed that significant associations could species, the Medaka and Xiphophorus are be substantiated in only a fraction of cases. used to study melanoma formation in-vivo Further validation and functional analyses in a comparative approach with mouse and of these genes are currently under way. human melanoma cell lines. This led to a better understanding of the intracellular processes, which are responsible for the The role of the pRB/E2F pathway in gene transformation of normal, healthy pigment expression and cell cycle progression cells to tumour cells. Through proteome (S. Gaubatz) and microarray analyses interesting, novel melanoma molecules were identified. The Research focuses on E2F transcription fac- usefulness of these as tumour markers or tors, the retinoblastoma protein and relat- therapeutic targets is currently evaluated. ed pocket proteins. These proteins play key Of special importance was the finding that roles in the regulation of cellular prolifera- a high signalling output of the melanoma tion, differentiation and apoptosis and they inducing growth factor receptor Xmrk leads have been implicated in tumorigenesis. We to senescence of melanocytes and a ne- have recently identified LINC, a novel E2F/ vus cell-like appearance. This contributes pocket protein complex in human cells that a new aspect to the clinical important, but is related to similar complexes in inverte-

20 Fig. 1: Ventricular septum defect of a Hey2 knockout embryo. Failure to close the interventricular septum (IVS) leads to an open connection (double arrow) between the right and left cardiac chamber (RV, LV). (Picture: Lang and Gessler). brates. LINC regulates the expression of mitotic genes and is essential for cell cycle progression through the G2 phase and for entry into mitosis. Inactivation of the LIN9 subunit of LINC 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 knockdown of LIN9 promotes tumorigenesis by weakening the mitotic spindle checkpoint and increasing genomic instability.

Fischer A., Schumacher N., Maier M., Teaching Sendtner M., and Gessler M. (2004). The Notch target genes Hey1 and Hey2 are The chairs of Physiological Chemistry offer required for embryonic vascular develop- a broad spectrum of lectures, seminars and ment. Genes & Development 18: 901- practical courses. A focus is on the theo- 911. retical and practical training of more than Osterloh L., von Eyss B., Schmit F., Rein 400 students of Medicine and Dentistry in L., Hubner D., Samans B., Hauser S. and their curricular subjects Biochemistry and Gaubatz S. (2007) The human synMuv- Molecular Biology. In addition, 24 students like protein LIN-9 is required for transcription of G2/M genes and for entry into mi- of Biomedicine (B.Sc./M.Sc.) are taught in- tosis. EMBO J, 26: 144-157 tensively in Biochemistry, Molecular Biolo- gy and Developmental Biology. For Biolo- Schmit F., Korenjak M., Mannefeld M., gy students advanced courses are offered Franke C., von Eyss B., Gagrica S., Hae- as minor subject in Physiological Chemis- nel F., Brehm A., Gaubatz S. (2007) LINC, a human complex that is related to pRB- try and in conjunction with the Institute for containing complexes in invertebrates reg- Biochemistry as major subject Biochemis- ulates expression of G2/M genes. Cell Cy-

try. Additional training courses for PhD stu- SELECTED PUBLICATIONS cle, 6: 1903-13 dents are offered within the framework of Wellbrock C., Froschauer C., Hassel, J., the Institute-based research training groups Fischer P., Becker J., Vetter C.S., Beh- 639 and 1048 (Graduiertenkollegs) and the rmann I., Kortylewski M., Heinrich P. C., Graduate School of Life Sciences (GSLS). Schartl M. (2005) STAT5 contributes to interferon resistance of melanoma cells. Curr. Biol., 15: 1629-1639

Schäfer M., Rembold M., Wittbrodt J., Schartl M. and Winkler C. (2005) Medial floor plate formation in zebrafish consists of two phases and requires trunk-derived 21 Midkine-a, Genes Dev, 19: 897-902 2.6 Biocenter Würzburg Chair of Physiological Chemistry II

Professor Dr. med. Manfred Gessler Mission Ongoing projects concern: (acting Head) and Structure • Molecular recognition and primary activation steps in BMP/GDF-receptor Biozentrum The department of Physiological Chemistry complexes (W. Sebald). Am Hubland II (PCII) is part of the „Biozentrum“ founded • Osteogenic stem cell-differentiation 97074 Würzburg in 1990, where 10 institutions from the fac- and therapies of bone loss (W. Se- Tel.: 09 31 / 888-4159 ulties of Biology, Chemistry and Medicine bald). Fax: 09 31 / 888-7038 cooperate in teaching and research. PCII • Structure and specificity of VWC do- E-mail: [email protected]. teaches biochemistry for large numbers of mains from crossveinless-2 (T. Müller, www.pch2.biozentrum.uni-wuerzburg.de preclinical students in Medicine and Den- W. Sebald). tistry. Research at PCII is organized across • BMP heterodimers.

CONTACT DETAILS CONTACT Professor Dr. rer. nat. Ernst Conzelmann traditional borders of disciplines and facul- • L51P BMP-2 as Nogginblocker. Tel.: 09 31 / 888-4120 ties. The aim of PCII is to contribute to ther- • Large scale production of rekombinant apy and diagnosis of several human disor- proteins. Professor Dr. rer. nat. Jürgen Hoppe ders (asthma, allergies, cancer, organ and • Interleukin-4 antagonists. Tel.: 09 31 / 888-4130 tissue regeneration, cardiac hypertrophy, fatty acid metabolism) by the establishment Professor Dr. rer. nat. Walter Sebald of biological model systems and the set up Metabolic pathways in peroxisomes: al- (Emeritus) of chemical/biochemical methodology. pha-methylacyl-CoA-racemase Tel.: 09 31 / 888-4111 (E. Conzelmann)

• Elucidation of structure and mechanism of the enzyme Major Research • Significance of the enzyme in the me- Interests tabolism of cholesterol and of branched- chain fatty acids, i.a. by analysis of a Strukture, mechanism and cellular mouse knock-out model functions of growth and differentiaton • Simultaneous targeting of the same factors enzyme to different cellular compart- (W. Sebald) ments • Role as marker for tumours of the pros- We are focussing on Interleukins involved tate and of other organs in generation and maintenance of allergic diseases and asthma, as well as on BMP´s/ TGF-b´s, which regulate the development Role of the murine Caspase-12 and regeneration of tissues and organs. (J. Hoppe)

Fig. 1: The bone morphogenetic protein BMP-2 signals into target cells by assembling two types of receptor kinases in the cell membrane. We have elucidated the structure of the ternary complex consisting of the dimeric BMP-2 and two ectodomais of each BMP receptor IA and Activin receptor IIB.

22 Fig. 2: The activity of BMP-2 in the organism is regulated by the binding of proteins containing VWC domains. We have solved the structure of the complex between dimeric BMP-2 and two VWC domains of the BMP modulator protein crossveinless-2.

Caspase-12 was originally described as initiator caspase, which is avtivated in a [Ca2+] i dependent manner after ER-Stress. Our results do not support this model. In contrast caspase-12 was found to be cleaved after asp-94 by caspase-3 independently of ER-stress. By using cleavages site specific antibodies we could exclude a further processing of caspase-12 in the intersub- Issa, J. P., do Nascimento, C., Bentley, M. unit regions. Our model locates caspase-12 V., Del Bel, E. A., Iyomasa, M. M., Sebald, downstream of caspase-3, questioning its W., and de Albuquerque, R. F., Jr. (2008): proposed role as initiator caspase. Bone repair in rat mandible by rhBMP-2 associated with two carriers. Micron 39: 17-24.

Kotzsch, A., Nickel, J., Seher, A., Hei- Teaching necke, K., van Geersdaele, L., Herrmann, T., Sebald, W., and Mueller, T. D. (2008): The chair of Physiological Chemistry II in Structure analysis of BMP-2 type I receptor complexes reveals a mechanism of re- conjunction with the Chair of Physiologi- ceptor inactivation in juvenile polyposis cal Chemistry I is in charge of all teaching syndrome. J Biol Chem. 283: 5876-5887. in Biochemistry and Molecular Biology for more than 400 students of Medicine and Saremba, S., Nickel, J., Seher, A., Dentistry per year as well as 24 annual stu- Kotzsch, A., Sebald, W., and Mueller, T. D. (2007): Type I receptor binding of bone dents of Biomedicine (B.Sc./M.Sc.). morphogenetic protein 6 is dependent on N-glycosylation of the ligand. Febs J 275:

SELECTED PUBLICATIONS 172-183.

Weber, D., Kotzsch, A., Nickel, J., Harth, S., Seher, A., Mueller, U., Sebald, W., and Mueller, T. D. (2007): A silent H-bond can be mutationally activated for high-affinity interaction of BMP-2 and Activin type IIB receptor. BMC Struct Biol 7: 6.

Zhang, J. L., Huang, Y., Qiu, L. Y., Nickel, J., and Sebald, W. (2007): von Willebrand factor type C domain-containing proteins regulate bone morphogenetic protein signaling through different recognition mechanisms. J Biol Chem 282: 20002-20014. 23 2.7 Institute for the History of Medicine

Mission changing roles and patterns of interaction Professor Dr. med. Dr. phil. Michael Stolberg and Structure among patients, relatives, physicians, nurs- (Head) es and priests. The Institute for the History of Medicine is Oberer Neubergweg 10a the only institution of the Medical Faculty 97074 Würzburg which approaches medical issues primar- Physicians and the Physician’s Author- Tel.: 09 31 / 888-3093 ily from the perspective of the humanities. ity in the Early Modern Period Fax: 09 31 / 888-3099 During the last years, the relatively small (M. Stolberg, D. Groß, J. Steinmetzer, T. E-mail: [email protected] scientific staff (head of department and two Walter) www.medizingeschichte.uni-wuerzburg.de collaborators) was complemented by about twice that number of scientists employed In this project, we have followed the careers

CONTACT DETAILS CONTACT through outside funding (Deutsche Forsc- and typical career patterns of early modern hungsgemeinschaft, Fritz-Thyssen-Stiftung, learned physician and analyzed the various KAAD, private sponsoring). About a dozen strategies they used to achieve and secure more scientists support the teaching activi- professional status and personal authority, ties. Large parts of the Institute are housed at a time when their curative skills were, in in a former ONT-clinic donated for the pur- hindsight, not superior to those of their nu- pose by the former Würzburg Professor merous less learned competitors. Horst Wullstein and his wife Sabina. Further rooms are in the former Zoology building in the city center. The Institute’s library com- Out-Patient Medical Care 1600-1850 prises about 60.000 volumes and ranks (M. Stolberg, K. Nolte) among the largest of its kind in the German speaking area. Little is known, so far, about the history of ordinary physicians’ medical practice, neither about the structure and social extrac- Major Research tion of ordinary physicians’ clientele nor Interests about the ways in which they applied the medical theories which they had acquired Research at the Institute focuses on pre- during their studies to their daily diagnos- modern medicine (ca. 1400-1850). More tic and therapeutic practice. Using physi- recently, the history of medical ethics from cians’ case books kept by ordinary physi- the Middle Ages until today has emerged as cians as well as journals from the newly es- a second area of special interest. A number tablished policlinics in Würzburg and Göt- of research projects are currently undertak- tingen around 1800 we are embarking on en at the Institute or are just about to be an international cooperative research proj- concluded. ect designed to approach these issues in a comparative perspective.

Medical Ethics in Ordinary Medical Practice Research Group Monastic Medicine (M. Stolberg, K. Nolte) (J. G. Mayer, R. Windhaber)

While a fair amount of research has been This interdisciplinary research group was done on the historical development of the formed at the Institute several years ago theological und philosophical debates about bringing together medical historians and spe- euthanasia and other major ethical issues, cialists of pharmacology. The group works on we know very little, so far, about the way or- the history of Western monastic healing and dinary physicians, nurses, relatives and pa- more generally on the history of medicinal tients dealt with these issues on a day-to- plants in the medieval and early modern pe- day basis. Our research has thus shown, riod. One of its major aims is also to preserve for example, that various means to achieve this historical knowledge and make it acces- active euthanasia were widely accepted sible to modern medical practitioners. among the population across Europe in the early modern period and we have been able to identify physicians who already around History of Palliative Medicine 1800, publicly endorsed active euthanasia (M. Stolberg, H. Langrieger, K. Max) on dying patients, a century earlier than had hitherto been assumed. Analysing the at- The long pre-history of modern palliative titudes towards truth-telling in the case of medicine is virtually unknown. In this proj- fatal progrnosis and towards informed con- ect we pursue for a period spanning from sent to painful and risky operations we have the 16th to the 20th centuries how physi- been able to show the crucial importance of cians and nurses dealt with incurable and

24 Fig. 1: Doctor’s visit (Egbert van Heem- skerk III, ca. 1725). dying patients and analyse the role which hospitals, poor-houses and similar institutions played in taking care of such patients over the centuries.

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

Based on printed and manuscript medical writing, on court records and on let- ters and autobiographies written by physicians and patients and 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.

Teaching Groß, D.; Steinmetzer, J. (2006) Volcher Coiter (1534-1576) und die Konstituier- The Institute offers 16 compulsory courses ung ärztlicher Autorität in der Vormoderne. in Medical Terminology and Professional Ori- Aachen. entation every term, for students of medicine and of dentistry. It is also responsible Nolte, K. (2007) Vom Umgang mit unhei- lbar Kranken und Sterbenden in „Krank- for the course in “History, Theory and Ethics” en-Besuchs-Anstalten“ zu Beginn des 19. which all medical students have to do in their Jahrhunderts. In: Würzburger medizinhisto- third year. In addition, a wide variety of elec- rische Mitteilungen 26: 28-52. tive courses and seminars is offered, ranging Nolte, K. (2006) Wege zu einer „Patien- from „Medical English“ and courses in bibli- tengeschichte des Sterbens“ 19. Jahr- ography and palaeography to seminars deal- hundert, in: BIOS 19, Heft 1: 36-51. ing with specific topics of medico-historical interest. The Institute is also responsible for Stolberg, M. (2007) Active euthanasia in the teaching of medical history and medical early modern society. Learned debates and popular practices. In: Social history of theory at the University of Regensburg. Indi- medicine 20: 205-221. vidual staff members and collaborators have

also assumed teaching responsibilities at the SELECTED PUBLICATIONS Stolberg, M. (2007) „Cura palliativa“. Historical Faculty in Würzburg and at the Uni- Begriff und Diskussion der palliativen Krankheitsbehandlung in der vormodernen versities of Ulm and St. Gallen. Medizin (ca. 1500-1850). In: Medizinhis- torisches Journal 42: 7-29. 25 2.8 Institute of Psychotherapy and Medical Psychology

Mission Psychooncology Professor Dr. med. Dr. phil. Hermann Faller and Structure (H. Faller) (acting Head) The Institute of Psychotherapy and Medi- As an extension of various projects on cop- Klinikstr. 3 cal Psychology was founded in 1958 as the ing with illness in cancer patients and its 97070 Würzburg first of its kind in Germany. Its focus areas prognostic significance, the following ques- Tel.: 09 31 / 31-2713 include research, education, and patient tions are examined in an ongoing multi-cen- Fax: 09 31 / 31-6080 care. The interdisciplinary research topics ter study: What is the prevalence of psycho- E-mail: [email protected] comprise methodological and clinical psy- logical distress and psychological disorders www.psychotherapie.uni-wuerzburg.de chotherapy research as well as research of among cancer patients? What are cancer the processes involved in coping with illness patients’ needs for psychosocial support?

CONTACT DETAILS CONTACT and rehabilitation. In the area of medical In this study, patients with various cancer education, the institute is responsible for types, from various treatments stages (acute the following subjects: Medical Psychology care, rehabilitation) and settings (in-patient and Sociology in the first study section, Psy- and out-patient care) are included. chotherapy and Psychosomatic Medicine as well as Rehabilitation Sciences in the second. For patient care, psychotherapeutic Psychonephrology out-patient department and consultation- (S. Neuderth) liaison services for the University Hospital are provided. In transplantation medicine, living do- nor kidney transplantation is becoming in- Currently, 8 researchers are financed by creasingly important. In cooperation with the institute’s budget and another 13 by the Department of Internal Medicine I (Ne- third-party payer. Several close clinical and phrology), both donors and recipients who research co-operations with the University had been psychologically evaluated before Hospital exist. The institute is a member the kidney transplantation are followed up. of the Comprehensive Cancer Center, the The various aspects of the transplantation Breast Center and the Center of Cardiovas- process, such as decision making, risk-per- cular Disorders of the University Hospital. ception and information status as well as Its section of Rehabilitation Sciences co- health-related quality of life, psychological ordinates the Rehabilitation Research Net- distress, sense of self-worth, and benefit work of Bavaria (RFB; see Ch. 5.6 Research finding, are evaluated. Networks).

Obesity Treatment (M. Schowalter) In cooperation with the Obesity Center of the University Hospital of Würzburg, a com- Major Research prehensive evaluation of pre- and post-op- Interests erative psychological factors in patients with morbid obesity undergoing bariatric surgery Psychocardiology is performed. Furthermore, behavioral cri- (H. Faller) teria of decision making before surgery and a post-surgical after-care program are de- The prevalence of depression in patients with chronic heart failure is high. In our research, which is performed in cooperation with the Department of Internal Medi- cine I (Prof. Angermann, Prof. Ertl), we examine the factors that put patients at risk for depression and whether depression itself is a risk factor for heightened mortality in chronic heart failure (Fig. 1). Moreover, we evaluate an intervention for optimizing disease management programs, including telephone-based patient education, in re- gards to mortality, morbidity, re-hospitalisation, and quality of life (INH Study). In a future study, the efficacy of pharmacother- apy of depression in reference to mortal- Fig. 1: Depression and survival rate of pa- ity in chronic heart failure will be examined tients with chronic heart failure according (MOOD-HF Study). to degree of depression.

26 veloped. We evaluate both the success of this after-care program and the short and long-term psychosocial outcomes of the surgical treatment.

Patient Education (H. Faller, H. Vogel, A. Reusch)

Patient education is a central feature of medical rehabilitation in chronic diseases. Several research projects aim to advance the concepts of patient education, to enhance patient orientation, to perform a survey on the present state of education practice, to develop an education database, and to evaluate the effectiveness of educational programs in various disorders (e.g. chronic low back pain). Specific strategies are implemented to increase the sustainability of education effects and to transfer newly learned skills to every-day life situations. Examples include behavioral planning and Fig. 2 Impact of depression on disease-specific quality of life in chronic heart failure after-care using modern media (telephone- (Kansas City Cardiomyopathy Questionnaire). based after-care, live-online after-care via the internet) (see also RFB, Ch. 5.6 Re- search Networks). Quality of Life Measurement Courses, and Integrated Seminars/Semi- (H. Faller) nars with Clinical Aspects. An optional seminar on Research Methods and Evalua- Occupational Rehabilitation A final research focus of the Institute is the tion (Evidence-Based Medicine) is also of- (H. Vogel, S. Neuderth) development and psychometric evaluation fered. Moreover, the Institute takes part in of self-assessment instruments for health- the Integrated Lecture and Integrated Prac- To increase the rehabilitants’ chance of re- related quality of life. In collaboration with tical Courses of Psychiatry, Psychosomat- turning to work, early identification of pa- the Department of Internal Medicine I (Prof. ics, and Psychotherapy. (Teachings within tients with occupational impediments and Angermann, Prof. Ertl), an innovative tool for the cross-sectional subjects are presented corresponding occupational treatments are the assessment of disease-specific quality under RFB, Ch. 5.6 Research Networks). necessary. Thus, several projects aim at of life in chronic heart failure has been psy- developing screening instruments for oc- chometrically evaluated (Kansas City Car- cupational impediments, creating a survey diomyopathy Questionnaire; Fig. 2). In co- of the present state of work-related treat- operation with the Orthopedic University ments in rehabilitation and fostering shared Hospital (Prof. König), the German version decision making regarding treatment selec- of the Short Musculoskeletal Function As- tion (see also RFB, Ch. 5.6 Research Net- sessment Questionnaire, has been devel- works). oped and evaluated. In a large multi-center study, several quality of life questionnaires, Faller H, Schmidt M (2004) Prognostic which are frequently used in medical reha- value of depressive coping and depression Quality Management bilitation (SF-36, IRES, SCL-90-R), have in survival of lung cancer patients. Psycho- Oncology 13:359-363. (H. Vogel, S. Neuderth) been examined regarding their sensitivity to change. In an ongoing multi-center study, Faller H, Störk S, Schowalter M, Stein- Quality management programs have been the Health Education Impact Questionnaire büchel T, Wollner V, Ertl G, Angermann CE developed for a large number of institu- (heiQ) is being translated and psychomet- (2007) Depression and survival in chronic heart failure: Does gender play a role? Eur tions. These include a concept for quality rically evaluated in collaboration with the J Heart Fail 9:1018-1023. management in medical rehabilitation car- Medical University of Hannover and the Uni- ried out by the statutory accident insurance versity of Melbourne, Australia. Faller H, Störk S, Schowalter M, Stein- and a quality management concept for pre- büchel T, Wollner V, Ertl G, Angermann CE vention and rehabilitation in mother-child- (2007) Is patients’ health-related quality of life an independent predictor of survival clinics. Another method of quality assur- in chronic heart failure? J Psychosom Res ance is the development of guidelines for 63:533-538. the rehabilitation process. In the context of Teaching the guideline program of the German Statu- Schowalter M, Benecke A, Lager C, Heim- bucher J, Bueter M, Thalheimer A, Fein tory Pension Insurance, the institute is re- Within the subjects of Medical Psychology

SELECTED PUBLICATIONS M, Richard M, Faller H (2008) Changes in sponsible for the field of rehabilitation for and Medical Sociology, the following com- depression following gastric banding op- children and youth. pulsory classes are provided: Lectures, eration: a 5 to 7-year prospective study. Obesity Surgery 18:314-320. 27 2.9 Institute for Hygiene and Microbiology

Professor Dr. med. Matthias Frosch (Head) patient care also includes the development molecular mechanisms effective during as- of strategies for the prevention of hospital ymptomatic colonization of the nasophar- Josef-Schneider-Str. 2 / E1 infections and the monitoring of hospital hy- ynx, a biofilm model is applied. Further- Tel.: 09 31 / 201-46160 giene. Annually approximately 85.000 mi- more, the group works on the impact of the Fax: 09 31 / 201-46445 crobiological analyses are performed. capsular polysaccharide and its biochemi- Email: [email protected] The research activity of the institute mainly cal modifications, since this surface struc- http://www. hygiene.uni-wuerzburg.de focuses on the elucidation of the molecular ture is believed not only to support invasive http://www.meningococcus.de mechanisms in the pathogenesis of infec- disease, but also to have a pivotal role in http://www.echinococcus.de tious diseases. Using tools from molecular host-to-host transmission. genetics, cell biology, immunology and ge- Professor Dr. rer. nat. Klaus Brehm nome research the pathogenicity of bacte- CONTACT DETAILS CONTACT Tel.: 09 31 / 201-46168 ria, fungi and parasites is investigated and Genome research on pathogenic bac- novel strategies for the diagnosis, therapy teria Professor Dr. med. Dr. rer. nat. Bhanu Sinha and prevention of infectious diseases are (C. Schoen, M. Frosch) Tel.: 09 31 / 201-46949 developed. Genomics of pathogenic bacteria is one Professor Dr. med. Ulrich Vogel At the institute the “Bundesministerium für main research focus at the institute encom- Tel.: 09 31 / 201-46802 Gesundheit” established the national refer- passing different pathogenic species. The ence centre for meningococci (NRZM). The comparison of the genomes from patho- activities of the NRZM include the identifi- genic as well as non-pathogenic species cation as well as the serological and mo- provides insight into the genetic basis of lecular typing of meningococci, an advisory the observed differences in the pathogen- service in case management and the coun- ic phenotypes and the evolution of patho- selling of public health departments in the gens. Whole-genome sequences are also epidemiological monitoring of putative out- required for the construction of DNA micro- breaks of meningococci diseases. The insti- arrays which allow for a genome-wide anal- tute is part of the pan-European network of ysis of gene regulation and genome varia- reference centres the “European Monitor- tion. This work has been performed in the ing Group on Meningococci”. Moreover, on frame of the BMBF funded competence behalf of the Robert-Koch Institute the insti- network „Genomforschung an pathogenen tute also functions as consiliary laboratory Bakterien (PathoGenoMik)“. A microar- for Haemophilus influenzae and echinococ- ray facility was established at the institute cosis, employing special diagnostic tests which allows the fabrication of microarrays and providing advice on diagnosis, therapy, and the conduction of experiments not only prevention and epidemiology. for all pathogens for which the genome sequence is available but also for eukaryotic genes with known sequences (e. g. from Major Research human or mouse). Interests

Infection biology of meningococcal disease (O. Kurzai, A. Schubert-Unkmeir, M. Frosch)

Meningococci, an important cause of sep- Mission ticemia and meningitis in infants and ado- and Structure lescents, are in the focus of research on infection biology and population genetics. The main tasks of the Institute for Hygiene The molecular basis of transmission across and Microbiology are the laboratory diagno- the blood-brain barrier and the interaction sis of infectious diseases caused by bacte- of meningococci with the complement sys- ria, fungi and parasites, the advice of cli- tem and dendritic cells as central effectors nicians with respect to diagnosis, therapy of the human innate immune system are and prevention of infectious diseases, the major points of interest in our research. Fig. 1: Bacterial biofilm formed by two research on infectious diseases and their variants of Neisseria meningitidis. The causative agents, hospital hygiene as well strains are expressing different fluores- the education of students in medicine, den- Population biology and biofilm forma- cent proteins to allow the visualization tistry and related subjects. tion of meningococci of their growth in a dynamic “Flussmo- (U. Vogel, H. Claus) dell”. The biofilm model is used for the In addition to the comprehensive range of analysis of DNA exchange between me- routinely used diagnostic tools the institute The population biology of N. meningitidis ningococci, which is of fundamental im- also provides special molecular and sero- and its spread among human hosts is an- portance for the genetic diversity of the logical test systems. Our commitment to alyzed by bacterial finetyping. To study the bacteria.

28 Fig. 2: Human brain microvascular endothelial cells incubated with MitoTracker Red CMXRos to label the mitochondria. After fixation and permeabilization, the cells were stained with Alexa Fluor 488 phalloidin to label the filamentous actin (F-actin) and finally counterstained with DAPI to label the nucleus.

Staphylococcus aureus Fox-tapeworm and alveolar echinococ- Elias, J., Harmsen, D., Claus, H., Hel- (B. Sinha) cosis lenbrand, W., Frosch, M., and Vogel, U. (K. Brehm) (2006). Spatio-temporal analysis of me- Staphylococcus aureus is one of the most ningococcal disease in Germany. Emerg. common causes of bacterial infection in hu- Alveolar echinococcosis is a life-threatening Infect. Dis. 12:1689-1695. mans. Despite this, a high proportion of the parasitosis in humans causing destruction Schoen, C., Blom, B., Claus, H., Sch- healthy population is colonized without suf- of liver tissue by the tapeworm larva. We ramm-Glück, A., Brandt, P., Müller, T., fering from infection. To understand this in- have shown that cells of this parasite make Goesmann, A., Joseph, B., Konietzny, S., teraction we characterize the interplay be- use of hormone based communication sys- Kurzai, O., Schmitt, C., Friedrich, T., Linke, tween S. aureus and host cells. We have tems which are closely related to cell-cell B., Vogel, U., Frosch, M. (2008). Whole genome comparison of disease and car- shown that S. aureus is able to invade host communication systems of the host. The riage strains provides insights into viru- cells and persist intracellularly during infec- possibility of cross-communication between lence evolution in Neisseria meningitidis. tion. Invasion of host cells involves a phago- the parasite and the host, which could be Proc. Natl. Acad. Sci. U.S.A., 105: 3473- cytosis related process. The maturation of one reason for the long persistence of tape- 34788. S. aureus containing phagosomes and a worm infections and their modulation of Spiliotis, M., Konrad, C., Gelmedin, V., possible correlation between invasive po- human immune responses is in the focus Tappe, D., Brückner, S., Mösch, H.U., tential and virulence are in the focus of cur- of current research. In genome- and pro- Brehm, K. (2006) Characterisation of

rent research. Beside these experiments, teome-based approaches parasite specific SELECTED PUBLICATIONS EmMPK1, an ERK-like MAP kinase from the response of S. aureus to contact with factors suited as targets for anti-infective Echinococcus multilocularis which is activated in response to human epidermal biocides is analyzed. therapy are identified. growth factor. Int. J. Parasitol. 36:1079- 1112.

Immune-response against fungal patho- Werbick C, Becker K, Mellmann A, Juu- gens Teaching ti KM, von Eiff C, Peters G, Kuusela PI, Friedrich A, Sinha B. (2007) Staphylococ- (O. Kurzai) cal Cassette Chromosome mec type I, spa Student’s courses are organised for stu- type, and expression of Pls are determi- Fungal infections are an increasing threat dents of medicine, dentistry, biomedicine, nants of reduced cellular invasiveness of for immunocompromised patients. By char- pharmacy and food chemistry. Scientists at methicillin-resistant Staphylococcus aureus isolates. J. Infect. Dis., 195:1678- acterizing the molecular basis of interaction the institutes participated in the organiza- 1685. between Candida albicans and Aspergillus tion of several scientific and medical meet- fumigatus and the innate immune system ings. Wozniok, I., Hornbach, A., Schmitt, C., we try to identify correlates of protective im- Frosch, M., Einsele, H., Löffler, J., Kurzai, munity and possible ways for adjuvant im- O. (2008) Induction of ERK kinase signalling triggers morphotype specific killing of mune therapy. Candida albicans filaments by human neu- trophils. Cell Microbiol. 10: 807-20. 29 2.10 Institute of Virology and Immunobiology, Chair of Virology

Professor Dr. med. Axel Rethwilm (Head) Mission sistant isoform of the host encoded cellu- and Structure lar prion protein (PrPC) accumulates within Versbacher Str. 7 infected tissues. After infection prions ac- 97078 Würzburg Research within the Chair of Virology is fo- cumulate in a first step within the lympho- Tel.: 09 31 / 201-49554 cussed on the analysis of the regulation of reticular system before degeneration of the Fax: 09 31 / 201-49553 viral replication and gene expression, com- nervous system occurs. The mechanisms of E-mail: [email protected] plex investigations of the pathogenesis of neuroinvasion into the brain, the role and Internet: http://www.virologie.uni-wuerzburg.de/ viruses, research into the sensitivity to an- function of PrPC, and the molecular aspects tivirals and the development of viral vectors of prion-induced neurodegeneration are an- Professor Dr. med. Michael Klein towards gene therapy. The Chair of Virology alyzed within various projects. Furthermore Tel.: 09 31 / 201-49164 is also responsible for the provision of vi- immunotherapeutic concepts are currently

CONTACT DETAILS CONTACT rus diagnostics to the University Hospital. explored to develop a vaccination strategy Professor Dr. med. Volker ter Meulen We host approx. 65 scientists and work in against the disease. (Emeritus, President of the Leopoldina) close cooperation with the Chair of Immu- Tel.: 09 31 / 201-49971 nology at our Institute as well as the Centre For Infectious Diseases, a number of Ba- Pathogenesis of Pneumoviruses sic Research Programmes (SFBs), Gradu- (C. Krempl) ate Schools and the Interdisciplinary Centre for Clinical Research. Respiratory Syncytial virus (RSV) is major viral cause of serious lower respiratory tract disease in the pediatric world, in the elder- Major Research ly and in severely immunocompromized pa- Interests tients. However, an effective antiviral therapy or a licensed vaccine is lacking, pos- Molecular mechanism of Measles virus sibly due to a fragmentary understanding induced immunosuppression of pathogenicity mechanisms and lack of a (S. Schneider-Schaulies) permissive animal model. Infection of mice with the closely related pneumonia virus of Measles virus (MV) infections cause a gen- mice (PVM) causes symptoms that are sim- eralised immunosuppression which almost ilar to those induced by RSV-infection of hu- exclusively accounts for their high morbidity mans. Thus, the group is using PVM-infec- rates. Typically, peripheral blood T lympho- tions as surrogate model. By using reverse cytes, fail to expand in response to poly- genetics that permits introduction of de- clonal stimulation ex vivo, indicating they fined mutations into the PVM genome, the received anergising signals. The MV glyco- group is identifying and characterizing viral protein complex, identified as effector struc- and host factors involved in pathogenicity. ture in this process, targets activation of the The results of these studies will contribute phosphatidyl-inositol-3-kinase via contact to a better understanding of the mechanism with an unknown receptor which is currently of RSV-induced disease and might help to being identified. Most likely, dendritic cells optimize the rational design of a live-attenu- (DCs) are central to MV-induced immuno- ated RSV vaccine. suppression. DCs take up MV by specific receptors (CD150 and DC-SIGN), mature, yet fail to promote expansion of cocultured al- Modellsysteme für Virusaufnahme und logenic T cells in mixed leukocyte reactions. Mechanismen der Virusausbreitung This is because they do not support forma- (J. Schneider-Schaulies) tion of stable conjugates with T cells as required for their activation. Amongst other The group investigates mechanisms of vi- proteins, the MV glycoprotein complex pres- rus spread in various model systems. In the ent at the DC/T cell interface contributes to focus of interest are uptake and spread of synapse destabilisation. measles virus, which is accompanied by a transient immunosuppression and may persist in the central nervous system. Recently, Neuroimmunology and Neurodegenera- the group has established a model of per- tion of Prion Diseases sistent CNS infection in immunocompetent (M. Klein) mice using a recombinant neurotropic measles virus to find new posibilities of therapy. Prion diseases or transmissible spongiform The role of cytotoxic and regulatory T cells, encephalopathies (TSE) belong to a group as well as application of possibly therapeu- of infectious, fatal, neurodegenerative dis- tically usable antiviral short interfering RNA eases, which affect both animals and hu- (siRNA) against measles are investigated. mans. During disease, PrPSc, an abnormal, An effective inhibition of virus replication detergent-insoluble, relatively protease-re- was achieved with siRNAs directed against

30 transcripts of the components of the viral research group, the pathogenesis of these replicative complex. Similar test systems to disease entities are studied using SIV-in- Teaching identify inhibitors of virus uptake and spread fected rhesus macaques in a cooperation are being developed for canine distemper, with the German Primate Center and HIV- In addition to lectures, colloquia for stu- Nipah- and Dengueviruses. infected patients in a clinical study including dents of biology, biomedicine and medicine 3 clinical and 2 theoretical institutes. The we offer practical courses for interested stu- studies include the role of the NMDA recep- dents. Molecular Biology of Foamy Viruses tors on the progression of neurodegenera- (J. Bodem, A. Rethwilm) tion as well as their relation to the excitatory amino acid transporters which are respon- The foamy virus mechanisms of replication sible for the removal of glutamate from the are distinct from all other retroviruses (or- extrasynaptic space and thereby the pro- thoretroviruses). In particular, they show an tection of neurons from excitotoxic death. extremely high degree of genome conserva- The plastic adaptations at the glutamater- tion, have developed own mechanisms of gic synapse are correlated to the presynap- transcriptional and posttranscriptional regu- tic regulation of the dopaminergic pathways lation of gene expression, and show distinct in order to gain insight on the primary and features of particle assembly and matura- secondary pathogenetic cascades following tion. We are elucidating these phenomena initiation of inflammative processes in HIV/ using various techniques in molecular virol- SIV dementia. ogy.

Clinical Virology Development of Foamy Virus Vectors for (B. Weißbrich, J. Schubert, U. Herre) Gene Therapy (C. Scheller, A. Rethwilm) 30-35 thousand clinical samples are processed each year. Furthermore, a variety The benign character of natural foamy vi- of clinical virological questions are being rus infections and a variety of other favour- addressed. In a cooperation with the chil- able features has led to the development of dren’s hospital of the university clinic, new foamy virus vectors for somatic gene thera- respiratory viruses are being studied. The py. Such vectors for the efficient transduc- human bocavirus (first described in 2005) tion of mesenchymal and haematopoietic has been detected in 11 % of nasopha- Yun SW, Ertmer A, Flechsig E, Gilch S, Rie- stem cells are under development. ryngeal samples from children who were derer P, Gerlach M, Schätzl HM, Klein MA hospitalised for acute respiratory diseas- (2007) The tyrosine kinase inhibitor ima- es. Strikingly, we detected a high number tinib mesylate delays prion neuroinvasion CNS Gene Transfer of coinfections with other respiratory virus- by inhibiting prion propagation in the pe- (E. Koutsilieri, C. Scheller, M. Klein, A. Reth- es among the children who were positive riphery. J. Neurovirol. 13, 328-337. wilm) for bocavirus DNA. Further studies includ- Müller N, Avota E, Schneider-Schaulies J, ing antibody determinations are currently Harms H, Krohne G, Schneider-Schaulies We investigate the application of foamy vi- ongoing in order to elucidate if bocavirus S (2006) Measles virus contact impedes ral vectors in the transduction of haemato- is a “real pathogen” or just an “innocent cytoskeletal remodeling associated with T cell adhesion, spreading and CD3 cluster- poietic stem cells as a tool for a novel gene bystander”. ing in the immunological synapse. Traffic therapeutic approach to generate transgen- 7, 849-858. ic microglia for the treatment of Parkinson’s disease in a mouse animal model. Moreover, Cooperations with Mwanza/Tanzania Neske F, Blessing K, Tollmann F, Schubert we use Adeno-Associated Viral Vectors for and Cape Town/South Africa J, Rethwilm A, Kreth HW, Weissbrich B (2007) Real-time PCR for diagnosis of hu- intracerebral delivery of allele-specific amy- (C. Scheller, J. Bodem, E. Koutsilieri, A. man bocavirus infections and phylogenet- loid precursor protein (APP)-shRNA for the Rethwilm) ic analysis. J. Clin. Microbiol. 45, 2116-

treatment of hereditary Alzheimer’s disease SELECTED PUBLICATIONS 2122. in an APP-transgenic mouse model. We are enforcing the collaborations with Meisner F, Neuen-Jacob E, Sopper S, African countries to characterize African Schmidt M, Schlammes S, Scheller C, HIV isolates and to improve anti-retrovi- Vosswinkel D, Ter Meulen V, Riederer P, Pathogenesis of SIV/HIV dementia ral therapy. We are in particular interested Koutsilieri E (2008) Disruption of excitato- (E. Koutsilieri, C. Scheller) to determine the resistance profile of Afri- ry amino acid transporters in brains of SIV- can HIVs. The HIV pandemia strikes Africa infected rhesus macaques is associated with microglia activation. J. Neurochem. HIV/SIV dementia is probably a result of an most and has considerable medical and 104, 202-209. initial microglial activation in CNS, produc- social economical consequences. Here we tion of inflammatory mediators with subse- want to offer our virological and research Sopper S, Nierwetberg D, Halbach A, Sau- quent direct cytocidal effect on non-infect- expertise that should be embedded in a er U, Scheller C, Stahl-Hennig C, Mätz- Rensing K, Schäfer F, Schneider T, ter ed neural cells or indirect actions on the higher order collaborative effort between Meulen V, Müller JG (2002) Impact of sim- regulation of the functional elements of Wuerzburg University and African hospitals/ ian immunodeficiency virus (SIV) infection synapses and neurodegeneration. In this universities. on lymphocyte numbers and T-cell turn- over in different organs of rhesus mon- 31 keys. Blood 101, 1213-1219. 2.11 Institute of Virology and Immunobiology, Chair of Immunology

Professor Dr. rer. nat. Thomas Hünig (Head) Mission T cell activation by non-conventional an- and Structure tigens Versbacherstr. 7 (T. Herrmann) 97078 Wuerzburg The research groups of this chair are par- Secretary: ticularly interested in the differentiation, Most T cells recognize complexes of pep- Tel.: 09 31 / 201-49951 activation and mutual interactions of T and tide antigens bound to MHC molecules. Fax: 09 31 / 201-49243 B lymphocytes, as well as NKT cells, my- Moreover there are non-conventional anti- www.uni-wuerzburg.de/virologie eloid suppressor cells and dendritic cells. gens such as glycolipids and „Phosphoan- The approaches in basic research will al- tigens“. The group of T. Herrmann investi- Professor Dr. rer. nat. Thomas Herrmann low a better understanding of the immune gates the activation of T-cells with specific- Tel.: 09 31 / 201-49955 system and immunologically mediated ity for such non-conventional antigens (rat

CONTACT DETAILS CONTACT diseases which lead to new experimental NKT cells and human Vγ9Vδ2 T cells). Fur- Professor Dr. rer. nat. Manfred Lutz therapies against allergies, autoimmune thermore the function of a „new“ non-poly- Tel.: 09 31 / 201-49957 diseases, transplant rejection and graft- morphic rat MHC class II molecule (RT1D2) versus-host-disease. There exist multiple is investigated. interactions with other groups of our Uni- versity but also within Germany and internationally. Research is complemented by Tolerance induction by dendritic cells the laboratory of immunodiagnostics which (M. Lutz) analyses autoantibodies from patient samples (head Dr. T. Kerkau). Dendritic cells are key mediators of immune responses but they are also essential to maintain tolerance. Tolerogen- ic functions are mediateted through “im- mature” or “semi-mature” activation stag- Major Research es while “mature” or “licensed” dendritic Interests cells induce immunity. We are investigating physiological T cell tolerance mecha- Function of the costimulatory receptor nisms induced by dendritic cells in antigen- CD28 transgenic K5-mOVA mice such as anergy, (T. Hünig) immune deviation and regulatory T cells. We also use in vitro generated tolerogen- Using newly developed monoclonal antibod- ic dendritic cells to modulate immune re- ies with specificity for the mouse CD28 mol- sponses in mouse models of allergy, auto- ecule, we are studying the effects of block- immunity and transplantation. ade versus stimulation of this receptor on the composition and function of the murine immune system. Immunosuppression by myeloid suppressor cells (M. Lutz) Regulatory T-cells in mice and rats (T. Hünig) Myeloid suppressor cells in mice and humans represent early differentiation stages Besides the search for novel, functionally of the myeloid lineage. At a certain level important cell surface receptors on regu- of their development they can be activated latory T-cells, we are particularly interest- to produce nitric oxide and suppress over- ed in the mechanisms by which stimulato- shooting CD4 and CD8 T cell responses. ry CD28-specific monoclonal antibodies in- This is however also exploited by tumors crease the number and enhance the func- and microbial pathogens such as Myco- tion of regulatory T-cells in vivo. bacteria. The knowledge about the induction of myeloid suppressor cells will help to improve immune responses against tumors CD8 T-cell-mediated autoimmunity in and lead to new strategies for vaccine de- mouse model of Multiple Sclerosis velopment. (T. Hünig)

Through transgenic expression of a cyto- Regulation of maturation and differen- solic model antigen in oligodendrocytes tiation of B cells which form the myelin sheath around the (I. Berberich, M. Herold) axons, CD8 “killer” T-cells, but not CD4 “helper” T-cells, specific for the model an- B cells mature in the bone marrow and tigen can induce MS-like lesions in the finally differentiate in spleen and lymph CNS of mice. nodes after contact with their cognate an-

32 Fig. 1: Attack of cytotoxic T-lymphocytes on the brain´s white matter. The section through the cerebellum of a mouse shows the ac- cumulation of cytotoxic T-lymphocytes (green) in the central region, the so-called white matter, where oligodendrocytes (red) form the myelin sheaths around the axons which transmit neuronal impulses. The section was taken from transgenic mice expressing the model-antigen ovalbumin (OVA) in oligodendrocytes and killer cells specific for OVA. Similar accumulations of cytotoxic cells are seen in lesions of human Multiple Sclerosis. tigen. During all these steps, survival of B cells depends on the fact that the cell is potentially beneficial for the organism, i.e. can recognize foreign antigen, and does not attack the own body. In the latter case, such autoreactive cells have to be deleted. This decision about life and death among other things depends on the integrity of the cell’s mitochondria assured by so-called anti-apoptotic proteins of the Bcl-2 family. Research focuses on the analysis of the regulation and functionality of A1/Bfl1, a member of this pro- Beyersdorf, N., S. Gaupp, K. Balbach, J. tein family. Schmidt, K.V. Toyka, C.H. Lin, T. Hanke, T. Hünig, T. Kerkau, and R. Gold. (2005) Se- lective targeting of regulatory T cells with Regulation of misguided immune reac- CD28 superagonists allows effective thera- tions py of experimental autoimmune encephalomyelitis. J Exp Med 202:445-455. (T. Kerkau, N. Beyersdorf) Cao Y, C. Toben, S.Y. Na, K. Stark, L. The team is working on the significance Nitschke, A. Peterson, R. Gold, A. Schim- and therapeutic manipulation of regulato- pl, and T. Hünig (2006) Induction of experimental autoimmune encephalomyeli- ry T cells in the context of pathological im- tis in transgenic mice expressing ovalbu- mune reactions. Here, in addition to an- min in oligodendrocytes. Eur. J. Immunol. imal models of multiple slerosis, we are 36:207-15. particularly interested in the study of Graft- versus-host-disease, a major complication Herold, M.J., J. Zeitz, C. Pelzer, C. Kraus, A. Peters, G. Wohlleben, and I. Berber- after allogeneic bone marrow transplanta- ich (2006) The Stability and Anti-apoptotic tion. Function of A1 Are Controlled by Its C Ter-

SELECTED PUBLICATIONS minus. J. Biol. Chem. 281:13663-13671.

Pyz, E., O. Naidenko, S. Miyake, T. Yama- mura, I. Berberich, S. Cardell, M. Kronen- berg, T. Herrmann (2006) The comple- Teaching mentarity determining region 2 of BV8S2 (V beta 8.2) contributes to antigen recog- Basic lecture for students of medicine, nition by rat invariant NKT cell TCR. J. Im- munol. 176:7447-55. biomedicine and biology are offered. These are complemented by a series of Rößner, S., C. Voigtländer, C. Wiethe, J. seminars for advanced students togeth- Hänig, C. Seifarth, and M.B. Lutz (2005) er with practical courses of 8 weeks per Myeloid dendritic cell precursors generated from bone marrow suppress T cell year. responses via cell contact and nitric oxide production in vitro. Eur. J. Immunol. 33 35:3533-3544. 2.12 Institute for Molecular Infection Biology

Professor Dr. rer. nat. Dr. h.c. mult. Mission Enterobacterial adhesins/ invasins and Jörg Hacker (Head) and Structure countermeasures (T. Ölschläger) Röntgenring 11 The Institute for Molecular Infection Bi- 97070 Würzburg ology was founded 1993 as an interdis- Special attention is paid to the analysis of Tel.: 09 31 / 3-2575 ciplinary institution at the Medical Fac- invasion and adherence of pathogenic en- Fax: 09 31 / 31-2578 ulty of the University of Würzburg and is terobacteria. The research group aims at E-mail: [email protected] a part of the „Research Center for Infec- the specific interference of adhesion-me- http://www.uni-wuerzburg.de/infektionsbiologie tious Diseases“. As the chairman is also diated host-pathogen interaction. Besides a member of the Faculty of Biology, the mechanisms of molecular pathogenicity, Professor Dr. rer. nat. Dr. med. habil. institute represents a link between these the use of probiotics in order to counteract CONTACT DETAILS CONTACT Heidrun Moll two faculties. The institute is closely asso- bacterial infection is investigated using pro- Tel.: 09 31 / 31-2627 ciated with the young investigator groups biotic E. coli strain Nissle 1917 as a model of the Research Center for Infectious Dis- organism. Professor Dr. rer. nat. Joachim Morschhäuser eases. The research of the institute aims Tel.: 09 31 / 31-2152 to elucidate fundamental aspects of infection processes. The research groups Immunological and cell biological stud- at the institute study several molecular ies on the pathogenicity of Leishmania aspects of infections caused by bacteria, parasites parasites and fungi. Additionally, the in- (H. Moll, K. Remer) teractions between parasitic pathogens and the host immune system are inves- Leishmania cause different clinical pic- tigated in detail. tures, whose expression depends on the immune response of the infected host. This model allows to study the immunological mechanisms of defense against infectious pathogens. The group investigates the role of chemokines and dendritic cells in host resistance against Leish- Major Research mania and works on the identification and Interests characterization of leishmanicidal compounds. The main interest of the working groups of the institute is the analysis of the mechanisms that allow pathogens to trigger in- Biology and Pathogenicity of Candida fections. Furthermore, the reactions of albicans the host cells in response to contact with (J. Morschhäuser) pathogens is studied. In addition to microbiological, molecular and cell biologi- The group aims at the characterization of cal methods, genomic (genome analysis) molecular mechanisms of infection by Can- and proteomic (protein expression analy- dida albicans and of the nature of antifun- sis) approaches are applied within the fol- gal resistance. For this purpose, the signals lowing projects: and signal transmission routes that control morphogenesis, virulence gene expression and antifungal drug resistance in C. albi- Virulence mechanisms and genome di- cans are studied. versity of enterobacteria (U. Dobrindt) Molecular and cellular studies of Legio- Pathogenic enterobacteria possess, in con- nella pneumophila trast to many of their non-pathogenic com- (K. Heuner) mensal relatives, additional DNA regions, i.e. the so-called Pathogenicity- or Genom- The causative agent of Legionnaires’ dis- ic Islands. The group characterizes process- ease, Legionella pneumophila, is able to es involved in genetic diversity and genome invade and destroy human lung macro- optimization of pathogenic and commensal phages. The natural niche of these patho- enterobacteria. The structure, function and gens are protozoa in the environment. The distribution of virulence-associated genes group studies the interaction of these proto- as well as the regulation of gene expres- zoa with Legionella pneumophila and focus- sion are studied. Furthermore, we aim at es on the investigation of the host-patho- the functional characterization of novel vir- gen interaction as well as the function and ulence-associated genes of pathogenic en- regulation of various specific virulence fac- terobacteria. tors of this pathogen.

34 Fig. 1: Impact of genome plasticity on the evolution of pathogenic bacteria due to genome rearrangements, gene loss and the acquisition pathogenicity islands, phages and plasmids.

Virulence- and resistance mechanisms Nougayrède, J.-P., Homburg, S., Taieb, F., of pathogenic staphylococci Teaching Boury, M., Brzuszkiewicz, E., Gottschalk, (W. Ziebuhr, K. Ohlsen) G., Buchrieser, C., Hacker, J., Dobrindt, A considerable part of the teaching activi- U., and Oswald, E. (2006) Escherichia coli Staphylococci are among the most impor- ties contribute to the training of biologists induces DNA double strand breaks in eu- tant nosocomical pathogens. The ability of in the Department of Microbiology. These karyotic cells. Science 313:848-851. these pathogens to form biofilms and to activities include lectures in general micro- Brzuszkiewicz, E., Brüggemann, H., Liese- develop antibiotic resistance is intensively biology, on issues of pathogenicity and im- gang, H., Emmerth, M., Ölschläger, T., studied in this group. The gene expression munology, as well as seminars on current Nagy, G., Albermann, K., Wagner, C., Bu- of these pathogens is studied under con- topics of Infection Biology and courses and chrieser, C., Em�dy, L., Gottschalk, G., Hacker, J., and Dobrindt, U. (2006) Com- ditions that mimic the host by the use of internships. Some of these events are also parative genomic analysis of extraintestinal in vivo-infection models. These studies also part of the curriculum of the Biomedical pathogenic Escherichia coli strains reveals include methods of functional and compar- Education. The institute organizes lectures, how to become an uropathogen. Proc. ative genomics and proteomics. courses, seminars and summer schools for Natl. Acad. Sci. USA 103:12879-12884. the members of the Graduate College “In- Reuß, O., and Morschhäuser, J. (2006) A fectiology” in association with the Interna- family of oligopeptide transporters is re- Molecular characterisation of pathogen- tional Graduate School “Life Sciences” at quired for growth of Candida albicans on

ic reactions of Entamoeba histolytica the University of Würzburg. SELECTED PUBLICATIONS proteins. Mol. Microbiol. 60:795-812. (H. Bruhn) Moll, H. (2006) Dendritic cells in leish- maniasis: regulators of immunity and tools Entamoeba histolytica causes human am- for new immune intervention strategies. oebiasis, the second leading cause of death In: Handbook of Dendritic Cells – Biolo- due to parasitic infections worldwide. The gy, Diseases and Therapies (M.B. Lutz, A. amoeba lives as a commensal in the hu- Steinkasserer, and N. Romani, eds.) Wiley- VCH, Weinheim, Germany, pp. 669-691. man intestine and can occasionally pene- trate into the surrounding tissue thereby ex- Hauck, C.R., and Ohlsen, K. (2006) Sticky citing severe tissue destruction which most- connections: extracellular matrix protein ly results in severe liver abscesses. The fac- recognition and integrin-mediated cellular invasion by Staphylococcus aureus. Curr. tors involved in the destruction of the host Opin. Microbiol. 9:1-7. cells by the amoeba are characterized at the molecular level.

35 2.13 Institute of Pharmacology and Toxicology, Chair of Toxicology

Professor Dr. sc. techn. Werner K. Lutz Mission the course of events leading to mutations. (Head) and Structure Epigenetic mechanisms include hormonal effects, changes in the cell cycle and dis- Versbacher Str. 9 The departments of Pharmacology (chaired turbance of cell differentiation. 97078 Würzburg by Prof.Dr. Martin J. Lohse), and Toxicolo- Tel.: 09 31 / 201-48402 gy constitute the Institute of Pharmacolo- Fax: 09 31 / 201-48446 gy and Toxicology. The building accommo- Biomarkers E-mail: [email protected] dates the research laboratories and offices, http://www.toxikologie.uni-wuerzburg.de a lecture hall seating 300 students, course A second research focus is biomarkers in laboratories, a seminar room, and a library both animals and humans. Biomarkers of Professor Dr. rer. nat. Helga Stopper for pharmacology and toxicology. Facilities exposure are based mainly on the analy- CONTACT DETAILS CONTACT Tel.: 09 31 / 201-48427 for animal husbandry, work with high levels sis of metabolites in urine, including met- of radioactive isotopes, a repair shop, and abolic profiling of major classes of conju- Professor Dr. med. Gilbert Schönfelder computer facilities for medical students are gates. Analysis of biofluids is also used for Tel.: 09 31 / 201-48777 also available. metabonomics, in an attempt to find treatment- or disease-related changes. Early The workforce of the department of Tox- cytological alterations are investigated in icology comprises between 50 and 60 the search of early biomarkers of toxici- members. Six research groups are led ty and carcinogenicity in kidney and liver, by the University Professors Dr. Werner including idiosyncratic reactions. Biomark- K. Lutz (Head since 1994), Dr. Helga ers of genotoxicity include investigation of Stopper, Dr. Gilbert Schönfelder, the As- genomic damage in blood cells. Oxidative sociate Professors Dr. Erwin Eder and Dr. stress and advanced glycation end prod- Wolfgang Dekant, and the Research Asso- ucts should also be mentioned. Biomark- ciate Dr. Angela Mally. Postdocs and on av- ers of individual susceptibility are studied erage 15 Ph.D. students with degrees in in connection with side effects of radiochemistry, food chemistry, biology, phar- therapy and differences in metabolism due macy, and medicine accomplish the exper- to genetic polymorphisms or inhibition of imental work, supported by about an equal enzymes involved in resorption, metabo- number of technicians. lism and excretion.

Risk Assessment Major Research Interests Knowledge on the mode of toxic action is a prerequisite for biologically based extra- Most of our research is funded by grants. polation from cells in culture or laboratory We rank first among the Chairs of Toxicol- animals to humans, from high dose to low ogy of the Bavarian Universities in this re- dose, and from the reproducible situation spect. This is also reflected by the number of experimental systems to the heterogene- of publications in refereed Journals reach- ity of a human population. Efforts on dose- ing 20 per year on average over the last response relationships and mixture effects 12 years. are based on experimental data but include elaborate statistical analysis as well as ki- netic modeling. Chemical Carcinogenesis

Our research focuses on elucidating the Investigated Compounds first-line interactions of mutagenic and carcinogenic chemicals with biological tar- The list of investigated compounds com- get, with the aim of a mechanistically sup- prises a variety of chemical classes and ported risk characterization of chemically sources. Exposure at the work place and induced cancer in humans. We investigate in the environment include aromatic hy- the kinetics and metabolism of chemicals drocarbons and substituted derivatives, as in vitro, in cells, animals and humans, pay- well as chlorinated and fluorinated chemi- ing special attention to the metabolic ac- cals. Dietary exposure includes mycotox- tivation to chemically reactive intermedi- ins (ochratoxin A), heat-derived products ates, their interaction with biological mac- (acrylamide, furan), migrants from poly- romolecules such as DNA and protein, and mers, phytoestrogens, as well as differ- their detoxification. Numerous assays have ent types of fat and their (per)oxidation been developed to study the genotoxicity products. For drugs, we focus on agents by covalent DNA binding, induction of oth- for which the probability of side effects er types of DNA damage (see Figures) and is modulated by pharmacogenetic differ-

36 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.

sale. Prof. Lutz is Chairman of the Study Committee for the Curriculum in Biomedi- cine and chairs the admission committee for the respective M.Sc. Program. Prof. Stopper is Coordinator of the Graduate Program „Target Proteins“. All professors teach in the postgraduate courses organized by the Society of Toxicology of the DGPT to register as DGPT and EUROTOX- certified Toxicologist. Editing and reviewing for scientific journals, membership in national and international scientific committees and consulting of political and govern- mental bodies is another part of our activities in the field. For the chemical and Fig. 2: “The Micronucleus Test”: Chromo- pharmaceutical industry, we offer both the- some damage is indicated by the presence oretical and experimental expertise for co- of a DNA-containing fragment in the cyto- operations. plasm of the bi-nucleated cell in the middle of the three cells. Lutz, W. K., Lutz, R. W. and Andersen, M. E. (2006) Dose-incidence relationships derived from superposition of distributions ences and/or enzyme inhibition. Com- of individual susceptibility on mechanism- pounds with estrogenic and antiestrogen- based dose responses for biological ef- ic activity are used primarily in connection fects. Toxicol. Sci. 90, 33-38. with the investigation of epigenetic effects. Menendez, D., Krysiak, O., Inga, A., Geh- Endogenous and unavoidable DNA-dam- randt, B., Resnick, M.A. and Schönfelder, aging agents and processes that contrib- G. (2006) A SNP in the flt-1 promoter in- ute to “spontaneous” tumor formation are tegrates the VEGF system into the p53 transcriptional network. Proc. Natl. Acad. also of interest. Oxidative stress is consid- Sci. USA 103, 1406–1411. ered a major factor in this respect. Brink, A., Schulz, B., Stopper, H. and Lutz, W. K. (2007) Biological significance of DNA adducts investigated by simultaneous analysis of different endpoints of genotoxicity in L5178Y mouse lymphoma cells Teaching treated with methyl methanesulfonate.

SELECTED PUBLICATIONS Mutat. Res. 625, 94-101. Our staff covers all aspects of toxicology Walitza, S., Werner, B., Romanos, M., and shares the responsibility with the Phar- Warnke, A., Gerlach, M. and Stopper, H. macology Department for teaching gener- (2007) Does methylphenidate cause a cy- al and systematic pharmacology for stu- togenetic effect in children with attention dents of medicine and biomedicine, phar- deficit hyperactivity disorder? macy, dentistry, and biology. For chemis- Environ. Health Perspect. 115, 936-940. try students, a special course meets the Rached, E., Hard, G.C., Blumbach, K., legal requirements according to the “Ge- Weber, K., Draheim, R., Lutz, W.K., Ozden, fahrstoffverordnung” to allow graduates to S., Steger, U., Dekant, W., and Mally, A. do business in chemical manufacture and (2007) Ochratoxin A: 13-week oral toxicity and cell proliferation in male F344/N rats. Toxicol. Sci. 97, 288-98. 37 2.14 Institute of Pharmacology and Toxicology, Chair of Pharmacology

Professor Dr. med. Martin J. Lohse (Head) cal functions and their potential to serve as We investigate their function and regulation drug targets. In addition to standard bio- in various model systems, most importantly Versbacher St. 9 chemical and molecular biology equipment receptors for adrenaline and noradrenaline 97078 Würzburg the chair has a SPF unit for the genera- and for parathyroid hormone. We are also Tel.: 09 31 / 201-48400 tion of transgenic mouse models as well as studying the mechanisms that lead to de- Fax: 09 31 / 201-48539 equipment for rapid microscopic imaging, sensitization of receptors, i.e. their habitua- E-mail: [email protected] for confocal, 2-photon and TIRF microscopy tion to prolonged stimuli, which may be the www.pharmakologie.uni-wuerzburg.de and for electrophysiology. basis of tolerance against drugs. In the past few years we have developed a variety of Professor Dr. med. Dr. rer. nat. Stefan The chair also provides a drug information techniques to visualize receptor activation Engelhardt service for the university hospital and medi- and inactivation with the aid of new sensors CONTACT DETAILS CONTACT Tel.: 09 31 / 201-48710 cal faculty as well as outside physicians and and fluorescence microscopy methods. This pharmacists. permits the direct study of receptors and Professor Dr. med. Dr. rer. nat. Stefan Schulz signaling mechanisms „at work“, and the Tel.: 09 31 / 201-48984 analysis of the speed and localization of cel- Major Research lular signals. Interests

Research in pharmacology is primarily con- G-Proteins und Regulation of Ion Chan- cerned with cell surface receptors for the nels stress hormones adrenaline and noradren- (M. Bünemann) aline, and with related receptors that bin, for example, opiates, somatostatin and ad- Many ion channels are regulated by recep- enosine. These receptors are being inves- tors and G-proteins. We investigate the mo- tigated with a large array of methods and lecular mechanism of this control, and use questions that range from the structures fluorescence methods to visualize an entire of receptors and ligands to transgenic dis- signaling chain from the receptor to the ac- Mission ease models and studies on patient sam- tivation of the ion channel. and Structure ples. Our research is funded by grants from the DFG, in particular the SFB487 and 688, The Institute of Pharmacology and Toxicol- the EU, the BMBF (Federal Ministry of Re- Somatostatin and Opiate Receptors ogy comprises Chairs for Pharmacology search), the Bavarian research Foundation (S. Schulz) (Prof. Lohse) and for Toxicology (Prof. Lutz). and others. Presently, the institute also houses several Opiate receptors are the targets for mor- research groups of the Rudolf Virchow Cen- phine and heroin and play a central role in ter that was funded in 2002 and that is Mechanisms und Function of G-Protein- pain perception; somatostatin receptors chaired by Prof. Lohse. coupled Receptors regulate cell growth and appear to be im- (M. Lohse, C. Hoffmann, V.O. Nikolaev) portant in several types of cancer. Both re- The chair comprises a total of 75 people, ceptor families belong to the G-protein-cou- 40 of whom are paid from grants. All re- Communication between receptors occurs pled receptors. We investigate their regu- search groups are devoted to the investi- via hormones and neurotransmitters that lation and cellular trafficking, with the aim gation of molecular mechanisms of cellu- are recognized by specific receptors, which of identifying ligands for improved pain and lar communication, their role for physiologi- constitute the primary class of drug targets. tumor therapy.

Fig. 1: A newly developed fluorescence sensor shows an increase (red color) of the second messenger cGMP in primary mesangial cells of the kidney.

38 Adenosine Receptors and their Ligands (K.-N. Klotz)

Adenosine is a ubiquitous mediator that acts on cells via four different receptors. In collaboration with chemists we develop selective ligands for these receptors and investigate the principles of their specific recognition.

Mechanisms of Heart Failure and Car- diac Signaling (S. Engelhardt, K. Lorenz)

Chronic heart failure is one of the main health problems of old age. Based on a mouse model of slowly developing heart failure we are searching for genes and mechanisms that contribute to heart failure and dilatation and may offer new therapeutic avenues. Several such candidates have been identified in recent years: the sodium/proton exchanger NHE1, the interleukin converting enzyme ICE, the transcriptional regulator NAB1, and the protein kinase inhibitor RKIP. More recently, we have begun to elucidate the role of newly discovered micro RNAs in heart failure.

Fig. 2: Cardiac gene expression – many of the 20.000 investigated genes are less Receptor-Antiodies in Heart Failure (green) or more (red) active in failing compared to healthy heart. (R. Jahns, in collaboration with the Depart- ment of Medicine)

Over many years we have demonstrated the presence of antibodies against β1-adrenergic receptors in about a third of patients with chronic heart failure. These auto-an- Behr B, Hoffmann C, Ottolina G, Klotz tibodies reduce the chance of survival of KN (2006) Novel mutants of the human these patients by 50%. We have now gener- beta1-adrenergic receptor reveal amino ated a corresponding animal model by im- acids relevant for receptor activation. J munizing rats with receptor epitopes. In a Biol Chem. 281, 18120-18125. project funded by the BMBF GoBio program Buitrago M, Lorenz K, Maass AH, Ober- we now want to try to develop a therapeutic dorf-Maass S, Keller U, Schmitteckert EM, strategy based on cyclic peptides. Ivashchenko Y, Lohse MJ, Engelhardt S (2005) The transcriptional repressor Nab1 is a specific regulator of pathological cardiac hypertrophy. Nature Medicine 11, Teaching 837-844. Hoffmann C, Gaietta G, Bünemann M, The Institute is responsible for teaching Adams S, Oberdorff-Maass S, Behr B, pharmacology and toxicology to students Vilardaga JP, Tsien RY, Ellisman MH, Lohse MJ (2005) A FlAsH-based FRET approach in medicine, dentistry, biology and biomedi- to determine G-protein coupled receptor cine. The focus is on general and clinical activation in living cells. Nature Methods

pharmacology for medical students (5th, SELECTED PUBLICATIONS 2, 171-176. 6th and 8th term) and pharmacy students Lorenz K, Lohse MJ, Quitterer U (2003) (5th-8th term). We also play a key role in Protein kinase C switches the Raf kinase the conception of the new research orient- inhibitor from Raf-1 to GRK-2. Nature ed BSc/MSc curriculum in Biomedicine and 426, 574-579. participate in the curriculum in Experimen- tal Medicine. We also offer the full curricu- Vilardaga JP, Nikolaev VO, Lorenz K, Fer- lum for the medical specialties of pharma- randon S, Zhuang Z, Lohse MJ (2008) Conformational crosstalk between �2-ad- cology and clinical pharmacology. renergic and µ-opioid receptors controls cell signaling. Nature Chemical Biology 4, 39 126-131. 2.15 Institute of Forensic Medicine

Professor Dr. med. Dieter Patzelt (Head) Mission quately determined: a forensic approach and Structure to appraising the age of the respective in- Versbacher Str. 3 dividuals has been presented using pro- 97078 Würzburg The Institute of Forensic Medicine at the cedures of mRNA analysis or detection of Tel.: 09 31 / 201-47020 University of Würzburg has an academic 4977 base pair deletions in the mitochon- Fax: 09 31 / 201-47000 staffing plan which comprises the head of drial genome. E-mail: [email protected] the institute and four physicians, two toxi- www.uni-wuerzburg.de/rechtsmedizin cologists and a molecular biologist. The ex- Molecular biological species diagnostics isting staff situation reflects the specialist were conducted and DNA was analyzed in requirements in respect of research, teach- hair and stored skeletal material, in some ing and the forensic medical equivalent of cases by doctoral students. Finally, it has

CONTACT DETAILS CONTACT medical care. become feasible to make an individual identification on the basis of semen from Forensic medical care encompasses prac- vasectomized men. tical medicolegal work in Lower Franco- nia and adjacent areas of Upper Franconia Transplantation surgery, prenatal medicine and Baden-Württemberg that is conduct- and stem cell research have raised ethical ed at the request of courts, state attorneys questions on the borderline zones of human and police. The main task is to investigate life. Our institute has presented a distinc- deaths from unnatural causes, to appraise tion between the anthropological category physical injuries to live persons that are rel- human and the biological category human evant in penal law terms, and forensics as life that has led to a more objective dis- a service to resolve capital crimes, to clar- cussion. ify contentious paternity and forensic toxicological analysis to establish the cause of death as well as to clear up road traffic of- fences. Teaching

Medical students are instructed in foren- Major Research sic medicine in the main lecture course, Interests by means of practicals and seminars. In the main lecture course, chiefly the correct Forensic medical research is oriented to the procedure for a medical autopsy is taught. special needs of legal practice. According- This requires comprehensive knowledge of ly, it has forensic pathological, forensic mo- forensic traumatology and toxicology and is lecular biological and forensic toxicological consolidated in an obligatory autopsy prac- aspects. Forensic medicine in Würzburg fo- tical in small groups. Teaching consists of cuses on natural science. Legal and foren- thanatology, forensic traumatology, forensic sic psychiatric matters are therefore no lon- serology/molecular genetics, forensic toxi- ger dealt with. cology and questions of medical law. The latter is gaining importance since medicine In clarifying the cases of death from unnat- is increasingly subject to legal consider- ural causes, establishment of the time of death within the 24-hour period is entirely feasible; after this time, it is largely impos- sible. The RNA analysis introduced by our institute has opened up a novel avenue to resolve this problem: by measuring the stability of the mRNA using real-time PCR, the range of changes in the body that are associated with the time of death can be extended.

Before we presented our own molecular genetic research results, the origin of blood, Fig. 1: Age estimation on the basis of mi- e.g. menstrual blood or blood deriving from tochondrial sequence analysis (age-de- injuries, could not be determined. Interna- pendent raised incidence of the 4977 bp tionally, this was feasible for the first time deletion): The mean value and the stan- only subsequent to our research on recep- dard deviation for the respective tissue in tor-specific endometrial mRNA. the three age groups ≤ 30 years (blue), ≤ 70 year (red) and ≤ 90 years (green) is The age of bloodstains and the age of per- shown. The number of samples investigat- sons who have left stains cannot be ade- ed is also specified.

40 ations. Future physicians are trained to take the legal background into account in their work in such a way that they cannot be ac- cused of not meeting their obligations. One focus of forensic traumatology is detecting signs of domestic violence. In the interdisciplinary subjects, Prevention and Treatment of Addiction is dealt with under the ban- ner title of preventive medicine and a seminar Ethics in Medicine is conducted as one of the selectable compulsory subject which can be chosen.

Forensic Medicine for Lawyers is a well- attended lecture course for law students. Moreover, legal interns are instructed on the effects of alcohol and drugs in road traffic in conjunction with a scientifically supervised drinking experiment.

Bauer M, Patzelt D (2002) Evaluation of mRNA markers for the identification of menstrual blood. J Forensic Sci 47: 1278 – 1283.

Bauer M, Polzin S, Patzelt D (2003) Quantification of RNA degradation by semi-quantitative duplex and competitive RT-PCR: a possible indicator of the age of bloodstains? Forensic Sci Int 138: 94 – 103.

Bauer M, Patzelt D (2003) A method for simultaneous RNA und DNA isolation from dried blood and semen stains. Forensic Sci Int 136: 76 – 78.

Bauer M, Gramlich I, Polzin S, Patzelt D (2003) Quantification of mRNA degradation as possible indicator of postmortem

SELECTED PUBLICATIONS interval - a pilot study. Legal Med (Tokyo) 5: 220 – 227.

Patzelt D (2004) Grenzbereiche menschli- chen Lebens. Rechtsmedizin 14: 247 41 – 250. 2.16 Institute of Pathology

Professor Dr. med. Dr. h.c. Mission ly early stages of lymphoma development Hans Konrad Müller-Hermelink (Head) and Structure were investigated. Ongoing research projects include the association of infectious Josef-Schneider-Str. 2 The Institute of Pathology of Wuerzburg agents with and the analysis of chromo- D-97080 Würzburg University is a medical facilty with a staff somal imbalances in MALT-type lympho- Tel.: 09 31 / 201-47776 of over 100, including 6 professors and ma. Fax: 09 31 / 201-47440 about 15 pathologists, with a dual func- E-mail: [email protected] tion in clinical support and research. Its The consultation center for lymph node pa- www.pathologie.uni-wuerzburg.de main clinical tasks include histologic and thology coordinates histologic evaluation cytologic diagnosis of biopsies and other of patients enrolled in one of several clini- Professor Dr. med. Stefan Gattenlöhner materials, and autopsies. Specialized de- cal therapeutic trials of the “German study CONTACT DETAILS CONTACT Tel.: 09 31 / 201-47420 partments for Applied Cytology and Tumor group for high-malignant non-Hodgkin Lym- Genetics, Neuropathology, and Molecu- phoma” (DSHNHL), and the european mul- Professor Dr. med. Wolfgang Roggendorf lar Pathology concentrate on specific di- ticentric study of peripheral T-cell lympho- Tel.: 09 31 / 201-47429 agnostic topics. The institute has estab- mas. lished itself as a successful scientific facil- Professor Dr. rer. nat. Dr. sc. nat. Edgar Serfling ity with broad research interests, with an Tel.: 09 31 / 201-47431 emphasis on hematopathology (especially Molecular Pathogenesis of Malignant B- lymph node pathology). With its large con- cell-Lymphomas sultation service for other pathology insti- (A. Rosenwald) tutes with respect to diagnostically difficult neoplastic alterations of bone marrow and The research group is focused on the mo- lymph nodes, the institute acts as a na- lecular characterization of malignant lym- tional diagnostic reference center for all phomas. By using gene expression pro- german multicentric clinical therapeutic filing (Affymetrix technolgy) and corre- trials of malignant lymphomas. lating global transcriptional profiles with morphologic, cytogenetic und molecular features, it is working towards a molecular classification of lymphomas, a goal recently accomplished in the case of Burkitt´s lymphoma in collaboration with Major Research 2 scientifc consortia. Furthermore the re- Interests search group acts on a global level as one of seven FDA-approved centers for the de- Hematopathology Research and Con- velopment of a diagnostic microarray for sultation Center for Lymph Node Pa- lymphomas. thology (H. K. Müller-Hermelink) Therapeutic Relevance of CD56 Depen- Several research groups operate with- dant Signalling Pathways in Ischemic in the national consultation center for Cardiomyopathy and Malignant Hema- lymph node pathology. (1) The group of topoietic Neoplasias Dr. E. Haralambieva analyses the biologic (S. Gattenloehner) heterogeneity of multiple myeloma after succeeding in developing reliable fluores- Preliminary work demonstrated that the cence in situ hybridization (FISH) proto- specific overexpression of the cell adhe- cols that enable the detection of various sion molecule CD56 (NCAM) in the myo- chromosomal translocations in routinely cardium from patients with ischemic car- fixed paraffin embedded tissue samples. diomyopathy is regulated by novel iso- (2) Within the Peripheral T-cell Lymphoma forms of the transcription factor RUNXI. Research Group, Dr. E. Geissinger dem- Tansfection assays proved that murine onstrated that anaplastic large cell lym- cardiomyocytes with stable overexpres- phomas (ALCL) lack the expression of a sion of CD56 have a strong induction of T-cell receptor (TCR) and associated sig- apoptosis and decreased calcium influx, nalling molecules. Priv.Doz Dr. A. Zettl es- resulting in cardiomyocyte loss and re- tablished the genetic differences among duced contractility, representing the hall- peripheral T-cell lymphomas and showed marks of heart failure. By contrast in ma- two genetically and clinically different lignant hematopoietic neoplasias such as variants of enteropathy-type intestinal T- acute myeloid leukemia or multiple my- cell lymphoma.. The group of Dr. P. Adam eloma, CD56 induced nuclear transloca- focuses on indolent B-cell non-Hodgkin tion of NF-kappaB and increased bcl2L12 lymphomas (MALT-type lymphoma / fol- expression blocked by the NF-kappaB we- licular lymphoma). In the past especial- delolactone. Since the overexpression of

42 DC56 and its dependant downstream cas- tors controlling NFATc1 expression in vivo, cades has impact on progression of isch- and to analyze interaction of NFATc fac- Teaching emic cardiomyopathy and malignant he- tors with other transcription factors such matopoietic neoplasias, the inhibition or as GATA-3, STAT6 and Foxp3. To this aim, The institute of pathology is responsible for regulation of such pathways might open the research group cooperates with the teaching pathology within the medical cur- new aspects in the therapy of these dis- proteomics facility at the Rudolf-Virchow- riculum of Wuerzburg medical school. Five eases with mostly fatal course. Center of experimental biomedicine and professors and about 10-15 lectures share with the department of molecular plant in the teaching, its major element being a physiology and biophysics of Wuerzburg concentrated course of pathology compris- Immunotherapy for Rhabdomyosarcoma university. ing lectures, seminars, practical classes and Rhabdoid Differentiated Tumors (histology) and macropathologic case dem- (S. Gattenloehner) onstrations (autopsies). Additional courses Human Immunity to Cancer for graduate students cover a wide range Rhabdomyosarcoma (RMS) is the lead- (H.P. Vollmers) of specific subjects, techniques, and skills. ing malignant soft tissue tumor in chil- Pathology lecturers also participate in inter- dren with high mortality rates in spite of The experimental work of this research disciplinary teaching projects (e.g. interdis- modern multimodality tratments. Since group is focused on human immunity to ciplinary oncology) and clinico-pathologic strong expression of the gamma-subunit cancer in which antibodies play an im- conferences for several hospitals and de- of the acetylcholine receptor (AChR) de- portant role. To investigate their nature, partments. fining the fetal AChR isoform is specific function, and targets, the group screened for rhabdomyoblasts, the question arose thousands of human monoclonal an- whether RMS cells could be killed by an tibodies. All tumor-specific antibodies anti-fetal AChR-directed immunotherapy. proved to be natural antibodies, mostly of Based on a fully human Fab-fragment with IgM isotype, coded by distinct germ line anti-fetal AChR specificity, the research genes, their targets being post-transcrip- group generated a chimeric T-cell recep- tionally modified carbohydrate epitopes tor (TCR) harbouring the fAChR specific on cell surface receptors like CD55, CFR- antibody fragment (single chain Fv scFv) 1 or GRP78. Furthermore, all tested an- attached to the zeta chain of the TCR and tibodies remove malignant cells in vitro a Pseudomonas exotoxin A based immu- and in vivo by inducing apoptosis. In col- notoxin that both kill human embryonal laboration with Australian and US pharma and alveolar RMS cell lines in vitro and companies, several antibodies are in pre- delay RMS development in a transplan- clinical development. The ongoing scien- tation model in mice. Since the fAChR is tific work is concentrated on the charac- also expressed on rhabdoid differentiated terisation of the antibody targets and the tumors other than RMS such as malig- apoptotic pathways. nant melanomas and is induced by con- Gattenlöhner S, Bröcker EB, Müller-Her- ventional chemotherapy on RMS cells in melink HK. (2008) Malignant melano- vivo, anti-faChR scFv based immunother- Neurooncology and Neurodegeneration ma with metastatic rhabdomyosarcoma- apies might be a promising alternative (W. Roggendorf) toid transdifferentiation. N Engl J Med. therapeutic strategy for such aggressive 358:649-50. and high-malignant tumors. Ependymomas are primary tumors of the Leich E, Hartmann EM, Burek C, Ott G, central nervous systems occurring rela- Rosenwald A. (2007) Diagnostic and prog- tively often in childhood. The pathogene- nostic significance of gene expression pro- Transcriptional Control of Lymphokine sis of these tumors is poorly understood, filing in lymphomas. APMIS. 115:1135- Genes in T-Lymphocytes and prognostic assessment based on his- 46. (E. Serfling) tologic features is difficult. With the goal Vollmers HP, Brändlein S. (2007) Natu- to analyse ependymomas on a molecular ral antibodies and cancer. J Autoimmun. The experimental work of the department level, the research group detected dele- 29:295-302. of molecular pathology within the institute tions to occur especially on chromosomes of pathology of Wuerzburg university is de- 6, 9, and 22, and used cDNA microarrays Serfling E, Chuvpilo S, Liu J, Höfer T, Pal- metshofer A. (2006) NFATc1 autoregula- voted to the transcriptional control of lym- and RT-PCR to examine gene expression. tion: a crucial step for cell-fate determina- phokine genes in T lymphocytes, in par- These results were correlated with clinical tion. Trends Immunol. 27:461-9.

ticular to that of IL-2, IL-4 and IL-5 genes. parameters yielding prognostic factors in- SELECTED PUBLICATIONS This work lead to a detailed analysis of fluencing survival. – Another project about Gattenlöhner S, Chuvpilo S, Langebrake C, Reinhardt D, Müller-Hermelink HK, Ser- NFAT transcription factors whose induc- neurodegeneration investigates the role of fling E, Vincent A, Marx A. (2007) Nov- tion – by elevated Ca++ levels and cal- impaired microcirculation in the pathogen- el RUNX1 isoforms determine the fate of cineurin-mediated signals – appears to esis of M. Alzheimer. In cooperation with acute myeloid leukemia cells by controlling be unique for the activation of lympho- other european tissue banks, the group CD56 expression. Blood. 110:2027-33. cytes. In the future the research group participates in developing standardizied Lukashova I, Kneitz S, Monoranu C, Rut- plans to study expression and function of operation procedures (SOP) for further re- kowski S, Hinkes B, Vince GH, Huang B, individual NFATc isoforms, to characterize search on tissue of the central nervous Roggendorf W. (2007) Ependymoma gene DNA sequence elements and tissue fac- system of humans. expression profiles associated with histological subtype, proliferation, and patient 43 survival. Acta Neuropathol. 113:325-37. 2.17 Institute for Medical Radiation and Cell Research

Professor Dr. med. Ulf R. Rapp (Head) Mission but also provide a powerful system for the and Structure pre-clinical evaluation of novel therapeutic Versbacher Straße 5 modalities. We have generated a mouse 97078 Würzburg The Institut für Medizinische Strahlenkunde model for non-small cell lung cancer. These Tel.: 09 31 / 201-45141 und Zellforschung (MSZ) was founded in mice express in specific cells of the lung an Fax: 09 31 / 201-45835 1993 and adjusted to modern safety stan- oncogenic form of the RAF kinase, called E-mail: [email protected] dards by extensive remedial actions, which C-RAF BXB, and develop lung tumors with- www.uni-wuerzburg.de/strahlenkunde were completed in 2006. The MSZ is the in two weeks after birth. No progression of Bavarian Center for Experimental Cancer these adenomas towards metastasis has Professor Dr. rer. nat. Albrecht Müller Research of the University of Würzburg and ever been observed. However, when cell- Tel.: 09 31 / 201-45848 is endowed with one full, two associate and cell adhesion was compromised by interfer-

CONTACT DETAILS CONTACT six assistant professorships. In addition, in ence with the function of E-cadherin, the Professor Dr. rer. nat. Thomas Raabe 2007 an independent junior group of the lung adenomas progressed to highly inva- Tel.: 09 31 / 201-45841 Bavarian Genome Research Network Bay- sive and aggressive adenocarcinomas (Ce- Gene (Eugen Kerkhoff) and a DFG Emmy- teci et al, 2007). There was a massive for- Noether group (Krishnaraj Rajalingam) were mation of intratumoral vessels and vascu- settled at the MSZ. The objective of the ap- larized tumors gave rise to metastases. In proximately 70 employees is to better un- ongoing studies the molecular details of the derstand cancer in order to develop novel progression from benign to malignant lung therapeutic approaches. Special empha- tumors are further investigated. This should sis is on the analysis of signaling pathways, lead to the identification of novel molecular which are disrupted in tumors. In addition, targets for cancer therapy. in cooperation with pharmaceutical companies the MSZ is involved in the development of small molecule inhibitors and therapeutic Neurobiology vaccines for cancer. Because of the intimate (U. R. Rapp, R. Götz) relationship between cancer and regenerative stem cells a group is also devoted to the The RAF kinase family encompasses three biology of stem and tumor stem cells (Prof. family members, A-RAF, B-RAF and C-RAF. Albrecht Müller). This work is supported by The neurobiology group is using genetic ap- experiments with model organisms includ- proaches in mice to dissect the individual ing the fruit fly Drosophila (Prof. Thomas and common functions of these three iso- Raabe). The MSZ is working together close- forms. In the past the group neurobiology ly with several institutes of the faculties of was able to show that specific cell popula- medicine, biology and chemistry. tions in the developing embryo require either C-RAF or B-RAF for their survival. In order to further evaluate the function of RAF in the suppression of cell death, the role of Bag1, Major Research a co-chaperone for the heat shock protein Interests Hsp70, which interacts with RAF and other proteins, was examined. By targeted gene Investigations on the mechanisms of cell disruption in mice, we showed that Bag1 growth, differentiation and survival are plays an essential role in survival of differen- the main research areas at the MSZ. Dis- tiating neurons and hematopoietic cells and ruption of these processes is directly as- identified the mechanism of action (Götz et sociated with the development of a vari- al, 2005). In order to delineate the func- ety of disorders such as cancer. Current tion of B-RAF in the brain, mice with condi- methods of modern molecular biology, tional inactivation of B-RAF and B-RAFKIN/ biochemistry, cell biology, genetics and KIN mice lacking B-RAF and expressing A- structural analysis are utilized. Some of RAF under the control of the B-RAF locus the research groups are mentioned in de- were created. Our data revealed distinct, tail below: non-redundant functions for B-RAF and A- RAF during brain development and demonstrate that B-RAF is an important mediator Tumor Genetics of neuronal survival, migration and dendrite (U. R. Rapp, R. Götz) formation (Camarero et al, 2006).

Lung cancer is the most prevalent neoplasm in the industrialized world with 1.2 million Tumor Therapy annual deaths. Mouse models of lung can- (U. R. Rapp, B. Bergmann) cer offer not only the opportunity to study the impact of oncogenes and other genetic Immunotherapy is a promising approach for factors on tumor initiation and progression the treatment of cancer. The idea is to en-

44 wolf et al, 2005). Also, we are analysing the developmental potential of mesenchymal and uniparental embryonic stem cells. Albrecht Müller is speaker of the national DFG priority program 1356: Pluripotency and cellular reprogramming and member of the bioethics committee of the Bavar- ian state government.

Molecular Genetics Fig. 1: The MSZ building. (T. Raabe)

One of the central challenges in neurobio- gage the immune system of a tumor pa- logical research is the elucidation of cel- tient in a way that it is able to detect and to lular and molecular mechanisms of brain destroy the tumor. Due to the limited effi- development. Despite major anatomical ciency of current approaches, new methods differences between vertebrate and inver- have to be developed. It has been shown tebrate nervous systems, the astounding recently that immune therapies are particu- similarity in their molecular mechanisms larly successful when different parts of the of development is becoming increasingly immune system work together in the fight clear. Therefore, Drosophila melanogaster against the tumor. In the group tumor thera- offers the opportunity to develop a gen- py modified intracellular bacteria strains are eral understanding of brain development used as carriers for tumor proteins. These through the use of genetic, molecular and infectious bacteria do not harm humans functional studies. The group is focusing but increase the specific immune response on signaling pathways regulating neuronal against the tumor. The greatest progress has stem cell proliferation, specification and been made so far with a salmonella-based differentiation. vaccine, which is expressing a RAF oncogene. In a lung tumor mouse model it was shown that after the administration of this vaccine tumor mass was reduced and the life span of mice was increased (Gentschev Teaching et al, 2005). In partnership with the company Æterna Zentaris the MSZ is in prepara- Prof. Rapp is speaker of the German- Götz R, Wiese S, Takayama S, Camarero tion for clinical trials of a salmonella-based French Research Training Group “Signal GC, Rossoll W, Schweizer U, Troppmair J, vaccine against prostate cancer. If success- Transduction: Where cancer and infec- Jablonka S, Holtmann B, Reed JC, Rapp ful, this approach will be adapted to other tion converge” (http://www.gcwn.de) and UR, Sendtner M (2005) Bag1 is essential tumor types. deputy speaker of the BioMedTec Interna- for differentiation and survival of hemato- tional Graduate School of Sciences “Lead poietic and neuronal cells. Nat Neurosci 8:1169-78. Structures of Cell Function” (Elitenetwork Stem Cell Biology Bavaria; http://www.bigss.de). At the MSZ Camarero GC, Tyrsin OY, Xiang C, Pfeiffer (A. Müller) more than 30 students are currently do- V, Pleiser S, S Wiese, Götz R, Rapp UR ing research for their diploma, MD or PhD (2005) Cortical migration defects in mice expressing A-RAF from the B-RAF locus. Stem cells are rare but essential cell types theses. Lectures, seminars and practical Mol Cell Biol. 26:7103-15. for development and tissue regeneration. courses are offered for medicine, biology Research on stem cell biology and cellu- and biomedicine students with focus on ra- Ceteci F, S Ceteci, Karreman C, Kramer lar pluripotency is one of the most prom- diology, neurobiology, cell biology and ge- BW, Asan E, Götz R, Rapp UR (2007) Dis- ising research fields in human medicine. netics. ruption of tumor cell adhesion promotes angiogenic switch and progression to mi- The possibility to reprogram cells into any crometastasis in RAF-driven murine lung type of adult stem cells for the purpose of cancer. Cancer Cell 12:145-59.

cell replacement holds tremendous thera- SELECTED PUBLICATIONS peutic promise and may circumvent ethi- Gentschev I, Fensterle J, Schmidt A, T Po- tapenko, Troppmair J, Goebel W, Rapp UR cal considerations concerning the deriva- (2005) Use of a recombinant Salmonella tion of new human embryonic stem cells. enterica serovar Typhimurium strain ex- The molecular pathways controlling pluri- pressing C-Raf for protection against C- potency and cellular reprogramming are Raf induced lung adenoma in mice. BMC now only beginning to be unravelled. The Cancer 5:15. stem cell biology group focuses on em- Schmittwolf C, Kirchhof N, Jauch A, Hard- bryonic, hematopoietic and mesenchymal er F, Zenke M, Müller AM (2005) In vivo stem cells and asks how global chromatin haematopoietic activity is induced in neu- states guide stem cell behavior (Schmitt- rosphere cells by chromatin-modifying agents. EMBO J 24:554-66. 45 2.18 Institute of Human and Medical Genetics

Professor Dr. med. Holger Hoehn (Head) Mission ly, mutations in VKORC1 were recognized and Structure as cause of warfarin-resistance in both hu- Biocenter mans and rodents. Current efforts are di- Am Hubland Human Genetics is an important area of rected at improving our understanding of 97074 Würzburg biomedicine with increasing impact on the disorders of the vitamin K dependent clot- Tel.: 09 31 / 888-4071 practice of medicine. Human Genetics in- ting factors. In addition, the group has a Fax: 09 31 / 888-4069 vestigates evolution, structure, function, long standing interest in the genetics of E-mail: [email protected] inheritance and disorders of the human inherited muscle disorders, including the http://www.humgen.biozentrum.uni-wuerzburg.de/ genome. Results of these studies are ap- muscular dystrophies, the myotonias, and plied to genetic diagnosis, genetic coun- malignant hyperthermia. Clemens Müller- Professor Dr. rer. nat. Clemens R. Müller-Reible seling and patient care. At the Universi- Reible serves as a member of several Eu- CONTACT DETAILS CONTACT Tel.: 09 31 / 888-4063 ty of Würzburg, human genetics is repre- ropean committees on quality assurance in sented by a basic science-oriented Chair genetic diagnostics. (Prof. Hoehn) and a Division of Medical Genetics (Prof. Grimm) providing genetic services. Both chair and division partici- Somatic cell genetics pate in patient care and teaching for stu- (D. Schindler) dents in the fields of medicine, biomedicine and biology. Located in the Würz- This group investigates the role of human burg Biocenter, the Department belongs caretaker genes (including ATM, WRN, to the University of Würzburg School of NBS, RAD50, LIG IV, MCPH1 and the FANC- Medicine. family of genes) in the maintenance of genomic stability.

Most recently, the group participated in the discovery of three novel FANC-genes Major Research (FANCJ, FANCN, FANCI). Collaborating with Interests groups from Germany and abroad, the Schindler laboratory has made major contri- Cytogenetics and comparative genome butions to the cell genetic, epidemiological research and functional aspects of Fanconi anemia (M. Schmid) (FA) and other caretaker gene syndromes, including Ataxia telangiectasia and the Ni- Using classical and molecular cytogenet- jmegen breakage syndrome. Current efforts ic methods, the group headed by Michael are directed at finding the gene defects Schmid analyses mechanisms of chromo- in unclassified FA patients, and at under- some evolution and chromosome pathol- standing the close connection between ge- ogy. Cooperating with Manfred Schartl netic instability and the emergence of neo- (Chair of Physiological Chemistry I), the plastic cell growth. group uses several model systems, including amphibians, fish, birds and mam- mals to improve our understanding of Human Progeroid Syndromes chromosomal and genomic evolution in (H. Hoehn) vertebrates. In addition, the group provides access to cytogenetic methos (in- In close collaboration with the Schindler cluding FISH, SKY and CGH) to a vari- laboratory, genetic instability syndromes ety of other groups within the biocenter with progeroid manifestations are used and the medical school. Michael Schmid as models for the understanding of nor- serves as editor of a number of genet- mal and pathological ageing. Cells derived ics journals and serials (including Cyto- from patients with the Werner adult pro- genetics and Genome Research, Sexual geria syndrome (WS) show multiple chro- Development, and Monographs in Human mosome rearrangements that have been Genetics). defined via spectral karyotyping. It remains unclear how this genetic instability related to the pleiotropic manifestations Molecular human genetics of WS which only superficially mimic nor- (C. R. Müller-Reible) mal ageing. Cells derived from patients with Fanconi anemia show frequent so- Using a positional cloning approach and matic reversions and are exceedingly sen- collaborating with Johannes Oldenburg, sitive to oxygen, rendering this disorder the group was able to identify VKORC1 as to the only human model system for the the central gene of the vitamin K depen- investigation of the free radical theory of dent blood clotting cascade. Subsequent- ageing.

46 Fig. 1. Genomic instability typical of the Werner adult progeria syndrome: spectral karyo- type showing multiple chromosomal rearrangements in a patient-derived fibroblast culture.

Teaching

The medical school curriculum includes a lecture course entitled “Clinical Human Genetics” which is taught in the 6th semester, together with an interdisciplinary course on “Disease prevention”. Medi- cal students can choose human genetics as an elective during their rotating intern- Kalb R, Neveling K, Hoehn H, et al (2007) ships, with emphasis on genetic diagnosis, Hypomorphic mutations in the gene en- dysmorphology and genetic counseling. In coding a key Fanconi anemia protein, addition to teaching medical students, the FANCD2, sustain a significant group of FA- Department also offers courses to stu- D2 patients with severe phenotype. Am J dents of biomedicine and biology, includ- Hum Genet 80:895-910. ing laboratory courses in human cytoge- Nanda I, Buwe A, Wizenman A, Takata M, netics and human molecular genetics. Un- Haaf T, Schartl, M, Schmid M (2007) Fan- dergraduate biology students can choose coni Anemia genes in vertebrates: evolu- human genetics as one of their major sub- tionary conservation, sex-linkage, and embryonic expression of fancc and fancg in jects. Graduate students can obtain their avian cells. In: Fanconi Anemia. A para- M.S. or Ph.D. degrees within one of the re- digmatic disease for the understanding of search groups of the Department. cancer and aging (Schindler D, Hoehn H, eds) Monogr Hum Genet 15: 183-99.

Neveling K, Bechtold A, Hoehn H (2007) Genetic instability syndromes with progeroid features. Z Geront Geriat 40:1-

SELECTED PUBLICATIONS 10.

Pelz HJ, Rost S, Hünerberg M, Fre- gin A, Heiberg AC, Baert K, MacNicoll AD, Prescott CV, Walker AS, Olden- burg J, Müller CR (2005) The genetic basis of resistance to anticoagulants in rodents. Genetics 170:1839-47.

Reid S, Schindler D, Hanenberg H, et al (2007) Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predis- 47 pose to childhood cancer. Nature Genetics 39:162-4. 2.18.1 Division of Medical Genetics

Mission The center provides diagnostic, therapeutic Professor Dr. med. Tiemo Grimm (Head) and Structure and counselling services, including preventive measures, for women and families af- Biocenter, Verfügungsgebäude, The Division of Medical Genetics is part fected by or at risk for inherited breast and Theodor-Boveri-Weg 11 of the Department of Human and Medi- ovarian cancer. (cf. section 5.2.6) 97074 Würzburg cal Genetics at the University of Würzburg Tel.: 09 31 / 888-4076 School of Medicine. Medical genetics rep- Fax: 09 31 / 888-4434 resents the applied branch of human ge- E-mail: [email protected] netics. As such, medical genetics trans- http://www.humgen.biozentrum.uni-wuerzburg.de/ lates the results of human genetics re- med_genetik/ search into the practice of medicine. Med- Major Research

CONTACT DETAILS CONTACT ical genetics deals with the medical impli- Interests cations of inherited diseases as they are encountered in many of the medical sub- Major research topics are genotype-phe- specialties. Patient contact is established notype correlations, aspects of formal and via genetic counselling and genetic consul- population genetics with emphasis on neu- tations. Genetic counselling is a process romuscular diseases, and the nosological of communication with patients and fami- classification of birth defects. Special relies that is guided by the principle of pa- search projects: tient autonomy. The genetic counsellor lis- tens to patients´ fears and concerns, explains the nature and possible risks of in- Genetics of proximal myotonic dystro- herited disease, and provides information phy (PROMM or DM2) on therapeutic and preventive measures. (W. Kress, T. Grimm) Important subspecialties of medical genetics are syndromology and teratology, which The group tries to answer the questions of aim at recognizing and classifying congeni- clinical heterogeneity and highly variable in- tal malformations and malfunctions. Com- cidence of DM2. An interesting result with prehensive diagnostic and counselling ser- respect to genotype-phenotype correlations vices are provided in close cooperation be- relates to the observation that rare homozy- tween physicians in private practice, Uni- gous DM2 patients (carrying the CCTG ex- versity hospital physicians, and members pansion) apparently are not more severely of the Department of Human and Medical affected than their heterozygous counter- Genetics. Participating physicians and ge- parts. neticists belong to the “Würzburg Center of Medical Genetics”. Statistical and formal genetics The Division of Medical Genetics includes (T. Grimm) the following centers: T. Grimm has longstanding interest and ex- Center for muscle diseases (operated pertise in genetic models, including non- by the German society for muscle dis- mendelian models of inheritance. Numerous eases) investigations of mutation rates as function (Co-Directors: Prof. Dr. K. Reiners, Depart- of gender and mutation types in various dis- ment of Neurology, University Hospital, and eases, including the X-linked muscular dys- Prof. Dr. T. Grimm, Division of Medical Ge- trophies, have provided the scientific basis netics; Coordinator and social worker: An- for clinically relevant risk calculations. gelika Eiler)

In close cooperation with the clinical De- Genetics of dyslexia partment of Neurology, the Center for mus- (T. Grimm) cle diseases coordinates diagnostic efforts, medical and social counselling, and long- Taking into account that approximate- term care of patients affected by neuromus- ly 5% of students are affected by vari- cular diseases and their families ous forms of dyslexia, T. Grimm became interested in the population genetics of dyslexia. Family studies provide evidence Center for hereditary breast and ovar- for familial clustering of dyslexia, includ- ian cancer ing rare pedigrees suggesting monogen- (Co-Directors: Prof. Dr. T. Grimm, Division ic inheritance. Novel candidate dyslexia of Medical Genetics and Prof. Dr. J. Dietl, genes are evaluated in close cooperation Department of Obstetrics and Gynecology, with the Max Planck Institute of Molecular University Hospital) Genetics (Berlin).

48 Ethical aspects of Human and Medical Genetics (T. M. Schroeder-Kurth)

Prenatal and predictive genetic testing cause a variety of ethical dilemmas and questions. In her capacity as a guest schol- ar, Professor emerita T. Schroeder-Kurth provides consultations and recommendations, guidelines and critical evaluations concerning ethical issues in human and medical genetics.

Teaching

The Division of Medical Genetics participates in lectures and courses for advanced students of medicine, biomedicine and biology. In addition, the division offers theoretical and practical training (clerkships, in- terships, “practical year”) in areas such as genetic diagnosis, genetic testing, and genetic counselling. Postgraduate training is provided for MD and PhD professionals specializing in human genetics.

Chandran K, Sullivan NJ, Felbor U, Whel- an SP, Cunningham JM. (2005) Endo- somal proteolysis of the Ebola virus glycoprotein is necessary for infection. Science 308:1643-1645.

Fischer C, Gross W, Krüger J, Cremer M, Vogel F, Grimm T. (2006) Modelling germ- line mosaicism and different new muta- Fig. 1: Large brainstem cavernous malformation of a 3-year-old CCM1 mutation carrier tion rates simultaneously for appropriate with right-sided hemiparesis, epilepsy, and headaches. risk calculations in families with Duch- enne muscular dystrophy. Ann Hum Genet 70:237-248.

Genotype-phenotype correlations in vascular malformations. A rare monogen- Kress W, Schropp C, Lieb G, Petersen craniosynostosis ic form of hemorrhagic stroke caused by B, Büsse-Ratzka M, Kunz J, Reinhart E, (W. Kress) mutations in either of three genes (CCM1, Schäfer WD, Sold J, Hoppe F, Pahnke J, Trusen A, Sörensen N, Krauss J, Collmann CCM2 or CCM3) has most recently pro- H. (2006) Saethre-Chotzen syndrome In close cooperation with the University vided experimental evidence that CCM3 caused by TWIST 1 gene mutations: func-

Hospital Department of Pediatric Neurosur- forms a protein complex with CCM1 and SELECTED PUBLICATIONS tional differentiation from Muenke coro- gery W. Kress was able to show that around CCM2. Functional characterization of the nal synostosis syndrome. Eur J Hum Genet 14:39-48. 20% of patients with evidence for prema- CCM gene products is performed in endo- ture closure of cranial sutures display addi- thelial cell cultures and in zebrafish using Schoser BG, Schröder JM, Grimm T, Stern- tional symptoms (e.g. malformations of the knockdown techniques. Systematic genet- berg D, Kress W. (2007) A large German distal extremities). These complex disease ic testing for CCM gene defects has been kindred with cold-aggravated myotonia entities are caused by a number of gene de- established for the first time in Germany. and a heterozygous A1481D mutation in the SCN4A gene. Muscle Nerve 35:599- fects in receptors and transcription factors With a mutation detection rate of >90% 606. (e.g. FGFR3, TWIST1). for familial CCM and of >60% for isolated CCM, the group has set new diagnostic Stahl, S., Gaetzner, S., Voss, K., Brack- standards. Previous projects of the group ertz, B., Schleider, E., Sürücü, O., Kunze, E., Netzer, C., Korenke, C., Finckh, U., Genetics of vascular diseases addressed the mechanism of action of Habek, M., Poljakovic, Z., Elbracht, M., (U. Felbor) the angiogenesis inhibitor endostatin, and Rudnik-Schöneborn, S., Bertalanffy, H., the molecular events underlying neurode- Sure, U., Felbor, U. (2008) Novel CCM1, The group headed by U. Felbor focuses on generation in cathepsin B and L-deficient CCM2, and CCM3 mutations in patients the molecular pathogenesis of hereditary mice. with cerebral cavernous malformations: in- frame deletion in CCM2 prevents formation of a CCM1/CCM2/CCM3 protein com- 49 plex. Hum Mutat (in press). 3 University Hospital 3.1 Introduction

Tradition and progress don’t contradict ses, 348 employees working as ancillary each other. Both distinguish the Universi- staff and 992 employees active in medi- ty Hospital of Würzburg: In the year 1581, cal-technical work. the first university clinic evolved from the combination of the faculty of medicine Surgical departments, which used to have and the Juliusspital. In times of highly de- different locations on the campus, are veloped health care, Würzburg is among now combined in the Centre of Operative the large clinics for high end medical care Medicine (ZOM) which started its work in in Germany and enjoys a good reputation 2004: the Department of Anesthesia and as a “prime address“ for patient care not Intensive Care, the Department of Surge- only in the region but also international- ry, the Department of Trauma, Hand, Plas- ly, especially in the field of research and tic & Reconstructive Surgery, the Depart- teaching. ment of Thoracic and Cardiovascular Sur- gery as well as the Department of Urolo- Today, 19 clinics and 22 outpatient de- gy/Paediatric Urology. These departments partments as well as four clinical insti- make use of optimized structures, such as tutes are part of the University Hospital. the service of the Institute of Transfusion Four experimentally-orientated institutes, Medicine and Haematotherapy or of the respectively departments, are integrated. Institute of Radiology that both employees Furthermore there are 6 affiliated training and patients benefit from. Apart from sta- colleges of health care, which together of- te-of-the-art medical services, the patient fer more than 500 apprenticeship training is offered the latest comfort available in positions. the Center of Operative Medicine.

Multidisciplinary collaboration is the fo- In the immediate vicinity of the Center cus of attention in nine Centers: the IZKF of Operative Medicine, the Center for In- – Interdisciplinary Center for Clinical Re- ternal Medicine (ZIM) is currently under search, the Center for Heart/Cardiovascu- construction. In the future it will house lar Diseases, the Breast Center, the Pe- the Medical Clinics (I and II), the Depart- rinatal Center, the Center for Stem Cell ment of Nuclear Medicine with the Cen- Transplantation, the Transplant Center, tre for Radiation Accidents, the Institute the Center for Rheumatism and the In- of Radiology, the Institute for Transfusion terdisciplinary Center for Cleft Lip and Pa- Medicine and Haemotherapy as well as late. the Institute of Clinical Biochemistry and Pathobiochemistry with Division of Labo- The new Center for Experimental Mole- ratory Medicine. Its opening is planned for cular Medicine (ZEMM) will intensify the 2009. translation between basic research and clinical research. Another step in that di- Among the constructional activities in the rection was the setup of a central office future are the reconstruction of the ”Kopf- for clinical studies (ZKS). klinik”, which is a Center harboring Neuro- logy, Neurosurgery, Neuroradiology, Oph- According to the official plan 2006, the thalmology and Ear, Nose and Throat Sur- University Hospital provides 1,509 hospi- gery and the construction of a „Mother- tal beds; the utilization ratio of the 1,456 Child-Center“, where the Department of beds having been set up was 76.1% with Obstetrics and Gynaecology and the De- an average residence time of 8.3 days. In partment of Pediatrics will be housed in the year 2006, 48,603 patients received the future. inpatient treatment and a total amount of 401,925 care days were performed. A Comprehensive reconstruction work is total of 176,035 patients received out- currently carried out in the Center of Den- patient treatment. Approximately 81% of tistry, Oral and Macillofacial Surgery, the all patients originate from the administ- Department of Dermatology and in the rative regions of Lower, Middle and Up- Department of Obstetrics and Gynaeco- per Franconia as well as from other parts logy. of Bavaria. 12.5% of all patients come In view of an ideal collaboration between from the adjacent Baden-Wuerttemberg, departments and the field of service and the remaining 6.5% from the rest of Ger- logistics, modernization works – especial- many or from abroad. ly on the kitchen and the pharmacy – are being planned. Furthermore the infra- The University Hospital employs a total structure for information and communica- of more than 4,200 full-time employees, tion systems is currently being expanded among them 742 physicians, 1219 nur- and unified in all departments. Compre-

50 hensive reorganization in the field of pati- Fig. 1: Entrance hall of the Center of Operative Medicine (ZOM). ent management (e.g. in terms of medical informatics, quality management, medical controlling and risk management) and especially the establishment of a separate division for strategy and development are to support the University Clinic of Würzburg cope with the challenges of a constantly changing health care market with increased competition and simultaneously ensure that a prosperous working environment in the fields of research and teaching is fostered.

Professor Dr. med. Chr. Reiners Managing Medical Director

51 3.2 Department of Anaesthesia and Critical Care

Professor Dr. med. Norbert Roewer Mission develop systemic inflammation and further (Head of the Department) and Structure aggravation of the patients condition. With the help of experimental animal models the Zentrum für Operative Medizin The Department of Anaesthesiology annu- interdependency between drugs used in in- Oberdürrbacherstrasse 6 ally performs anaesthesia for approximately tensive care and the motility of the intestine 97080 Würzburg 24.000 surgical and diagnostic procedures is investigated. Tel.: 09 31 / 201-30001 in the various clinical departments including Fax: 09 31 / 201-30019 orthopaedic cases (König-Ludwig-Haus). E-mail: [email protected] The pain centre and the outpatient depart- Evidence Based Medicine wuerzburg.de ment of Anaesthesiology in each case ex- (P. Kranke) www.anaesthesie.uni-wuerzburg.de hibit more than 5.500 patient contacts per

CONTACT DETAILS CONTACT year of patients suffering from acute and “Evidence Based Medicine” tries to pro- chronic pain. The department has an inter- vide best up-to-date quality data for spe- disciplinary Intensive Care Unit with 12 beds cial questions concerning the treatment for critically ill patients after major surgery of patients. The facilitation of an evidence or for those suffering from severe multip- based way of thinking and behaviour in the le traumas. Each intensive care bed is fully perioperative medicine is the aim of the re- equipped with new state-of-the-art bedside search group. For this purpose systematic monitoring and data management systems reviews in the field of anaesthesia, pain as well as ventilators and all available sys- therapy, palliative medicine, intensive care tems to treat all kinds of organ failure. medicine and cognate disciplines are generated. The department further consists of a section for trauma and emergency medicine, which is responsible for clinical education as well Ultrasound applications in anaesthesi- as research in this field of medicine. ology (U. Schwemmer) The department provides as well a modern simulation centre for anaesthesia By means of modern portable ultrasound and emergency cases. An artificial patient, devices it is possible to gently identify de- equipped with computer technology, allows tailed anatomic structures under the body the realistic training of routine anaesthetic surface. The accomplishment of regional procedures as well as the handling of rare anaesthesia requires the injection of local emergency events. anaesthetics with a potential sharp needle close to neural structures. Ultrasound gui- In addition to patient care and education of ded injections allow the clear identificati- students and residents the department runs on of neural structures and the subsequent a laboratory for the diagnosis of malignant blockade of the nerve. The research group hyperthermia. Malignant hyperthermia is a tries to enhance the safety and success rare hereditary disorder, which might occur rate of ultrasound guided regional anaes- quickly and life-threatening during anaesthesia through clinical studies. The impact thesia. of the usage of ultrasound devices on complications, difficulties and the expenditure of time during the installation of central ve- Major Research nous and arterial catheters are investiga- Interests ted as well.

Pain research (G. Sprotte)

Different research groups focus on the pathophysiology of the immunological system and its role in the development of chronic pain, using in-vivo approaches with chronic pain patients or experimental in-vitro techniques.

Intestinal hypomotility in ICU patients (M. Herbert)

ICU patients show a dysfunction of the in- Fig. 1: Planimetry of myocardial infarction testinal motility. Consequence of which may (mouse).

52 Intelligent diagnosis and monitoring systems (J. Broscheit)

The development of intelligent knowledge based systems, which support the anaes- thesiologist during daily work, is the aim of this group. Databases about special question fields are created and with the help of a web-based surfaces the system provides the user solutions for the previously pro- grammed questions. The research group is cooperation with the Lehrstuhl IV, Künstli- che Intelligenz und Angewandte Informatik, Instituts für Informatik of the University of Würzburg.

Trauma emergency room management (T. Wurmb)

The initial diagnostic and therapeutic treatment of polytraumatized patients is per- Fig. 2: Acute lung injury (pig). formed by a multidisciplinary medical staff team in the trauma emergency room. The development of algorithms and operating Transesophageal Echocardiography tegy which allows the lung to recover and procedures to provide optimal support for (B. Steinhübel) heal. The choice of a ventilation profile these patients at high risk are performed by with optimal pressure amplitudes for the clinical investigations. The Transesophageal Echocardiography al- individual patient needs is of vital impor- lows via a miniaturized probe in the eso- tance. With the help of experimentally in- phagus the evaluation of the function and duced acute lung injury in pigs the influ- performance of the heart with its cavities ence of different ventilation modes and and valves. This examination method is profiles on the inflammation and function performed during anesthesia in the the- of the lungs are investigated. In patients atre or during treatment on the intensive the usages of high oscillatory ventilation care unit. modes in combination with extracorporal lung assist devices in patients with acute lung injuries are scientifically accom- Organ-Protection panied. (F. Kehl)

Volatile anesthetics not only induce anes- Microcirculation thesia, but also render organs resistant (C. Wunder) against ischemic damage. The intracellular Lange M, Redel A, Roewer N, Kehl F mechanisms underlying anesthesia induced The term microcirculation denotes the (2007) Beta-blockade abolishes anesthe- reduction of ischemia/reperfusion injury are bloodflow in the smallest vessels and ca- tic preconditioning: Impact on clinical ap- plicability. Anesthesiology 106, 1062. under intense investigation. The projects pillaries. The perpetuation of the microcir- performed by the research group aim to culation in the different organs is funda- Muellenbach R, Kredel M, Roewer N, Bre- identify triggers, mediators and end-effec- mental for the function and metabolism derlau J (2007) High-frequency oscillato- tors of anesthetic-induced pre- and post- of the different cell populations. The pa- ry ventilation reduces lung inflammation: a large-animal 24-h model of respiratory conditioning and to characterize their com- tho-physiological coherences of the mic- distress. Intensive Care Med. 33, 1423. plex intracellular interaction in the heart and rocirculatory disturbances in the liver and the brain. the intestine during systemic inflamma- Wunder C, Roewer N, Eichelbrönner O tory states and shock are the aim of the (2005) Carbon monoxide, but not endo- investigated projects. The organ failure of thelin-1, plays a major role for the hepatic microcirculation in a murine model of ear- Acute lung injury the liver and / or the intestine is asso- ly systemic inflammation. Crit. Care Med. (J. Brederlau) ciated with a high mortality. By means of 33, 2323. small animal models and clinical studies Acute lung injuries in adults, caused by the underlying mechanisms of microcircu- Kranke P, Eberhardt L, Roewer N, Tramer MR (2007) Algorithms for the prevention pneumonia, sepsis and multiple traumas latory failure in the liver and intestine and

SELECTED PUBLICATIONS of postoperative nausea and vomiting: an still show a lethality of 40-60%. The key the potential therapeutic interference are efficacy and efficiency simulation. Eur. J. to survive for patients is a ventilation stra- investigated. Anaesthesiol. 24, 856.

53 3.3 Department of Surgery I

Professor Dr. med. Prof. h.c. Arnulf Thiede Mission Major Research (Head of the Department) and Structure Interests

Oberdürrbacher Str. 6, The Clinic of Surgery I offers services in ge- Clinical Research 97080 Würzburg, neral, visceral, vascular, and pediatric sur- Tel.: 0931 / 201-31000 gery. The clinic has 132 beds, including The clinic applies the latest suture systems Fax: 09 31 / 201-31009 intermediate and intensive care units. Six and laparoscopic operating procedures. The E-mail: [email protected] thousand surgical procedures are perfor- vascular surgery evaluates modern combi- http://www-i.klinik.uni-wuerzburg.de/ med every year. The health care centre of- ned endovascular and operative procedu- deutsch/einrichtungen/kliniken/chirurgie1/ fers specialized services include surgeries res for the treatment of aneurysms and the content.html for tumours (interdisciplinary), oesophagus peri-arterial obstructive disease. The clinic

CONTACT DETAILS CONTACT and gastric illness, gallbladder and pan- is part of one international and several nati- Professor Dr. med. Burkhard Höcht creas, endocrine diseases, gastrointestinal onal multi-centre studies, involving, among Tel.: 09 31 / 201-31071 diagnosis, endoscopy, proctology with en- other things, the therapy of reflux gastritis, dosonography, and vascular and pediatric therapy of rectal cancer, liver metastases, Professor Dr. rer. nat. Karin Ulrichs surgery. and acute cholecystitis. In addition, proce- Tel.: 09 31 / 201-31700 dures for distal/caudel pancreatectomy are evaluated. The oncological group carried Professor Dr. rer. nat. Ana Maria Waaga-Gasser Clinical Services out a random trial on the reconstruction of Tel.: 09 31 / 201-31715 the food passage following gastrectomy and Onological surgery is an important focal a trial following deep anterior rectum resec- point of the clinic. The patients are treated tion. Several publications demonstrate the following recommendations from the inter- quality of the clinic’s medical health care in disciplinary tumour board. Special experti- all working groups. se exists in the care of gastric, pancreatic and intestinal cancer, primary and secondary liver cancer, and thyroid cancer. In the Experimental Research last two year oesophagus, colon, and rectal cancer have been treated with minimal- Experimental Surgery and Molecular Onco- ly invasive surgery. The endocrinology sur- logy have both established their own wor- gery offers thyroid surgery with monitoring king groups for experimental research. Ex- of the recurrent laryngeal nerve. The dys- perimental Surgery, with their main focus on function of parathyroid and adrenal glands immune biology/cell therapy, analyzes tole- is treated with minimally invasive surgery. rance mechanisms following experimental The coloproctology offers therapeutic pro- organ transplantation and cell therapy ap- cedures for hemorrhoids, constipation, and proaches to heal diabetes mellitus. Molecu- complicated anal fistulas. Special expertise lar Oncology analyzes the immune response also exists for the care of abdominal wall to gastrointestinal tumours to develop dia- hernias. Patients with morbid adiposity are gnostic and therapeutic approaches. Close cared for by an interdisciplinary team of sur- cooperations exist with the Harvard Medical geons, internists and psychologists (“Würz- School in Boston/USA, the universities of burger Model”). The pediatric unit provi- Oxford/UK and Rochester (New York)/USA, des the best of care for the full range of the Prince of Wales Hospital in Sydney/Aus- clinical pediatric needs. These include the tralia, the Ludwig-Maximilians University in operative care of premature infants, thera- Munich and, of course, the institutes and py of birth deformities, basic pediatric uro- clinics of the University of Würzburg Hospi- logy, and pediatric traumatology. The vas- tal and the university. cular surgery treats abdominal aortic aneurysms with aorta-iliacal bifurcation prosthe- ses. Aorta and iliacal vascular diseases are treated with endovascular procedures. Our surgeons are well experienced in femur cr- ural artery bypass surgery and in carotid artery surgery.

Fig. 1: Creation of a gastric pouche with minimally invasive surgery.

54 Fig. 2: The goal of transplantation research is to prevent the destruction of organ transplants. In addition to effector immune cells the immune system also has so called regulatory immune cells. They are able to stop immune responses but normally their amount is too low to protect organ transplantats (A). Therefore, increasing the amount of regulatory immune cells and reducing the amount of effector cells after transplantation (B) seems to be promising for experimental and clinical research.

Teaching

All aspects of modern surgery are covered in lectures and seminars; bedside teaching was optimized. An Interdisciplinary Training and Simulation Centre (INTUS) was established in the SkillsLab to give the students Klein I, Cornejo JC, Polakos NK, John B, more opportunities to improve their opera- Wuensch SA, Topham DJ, Pierce RH, Cris- ting skills on training simulators under re- pe IN (2007). Kupffer cell heterogeneity: alistic conditions. Training courses for thy- functional properties of bone marrow de- roid surgery and microsurgery, laparoscopic rived and sessile hepatic macrophages. operation procedures, as well as advanced Blood 110: 4077-4085. training in gastrointestinal diagnostics and Ruhnke M, Ungefroren H, Nussler A, Mar- endosonoscopy are offered on a regular ba- tin F, Brulport M, Schormann W, Hengst- sis. ler J G, Klapper W, Ulrichs K, Hutchinson J A, Soria B, Parwaresch R M, Heeckt P, Kremer B, Fändrich F (2005). Differentia- tion of in vitro modified human peripheral blood monocytes into hepatocyte-like and pancreatic islet-like cells. Gastroenterology 128: 1774-1786.

Sitaru C, Mihai S, Otto C, Chiriac M, Hau- ßer I, Dotterweich B, Saito H, Rose C, Is- hiko A, Zillikens D (2005). Induction of

SELECTED PUBLICATIONS dermal-epidermal separation in adult mice by passive transfer of antibodies to type VII collage. J Clin Invest 115: 870-878.

Schatton T, Murphy GF, Frank NY, Yamaura K, Waaga-Gasser AM, Gasser M, Zhan Q, Jordan S, Duncan LM, Weishaupt C, Fuhl- brigge RC, Kupper TS, Sayegh MH, Frank MH. (2008) Identification of human melanoma initiating cells. Nature 451: 345- 349.

Steger U, Kingsley CI, Karim M, Bushell AR, Wood KJ (2006). CD25+CD4+ regulatory T cells develop in mice not only during spontaneous acceptance of liver allo- grafts but also after acute allograft rejec- 55 tion. Transplantation 82: 1202-1209. 3.4 Department of Trauma, Hand, Plastic and Reconstructive Surgery

Professor Dr. med. Rainer Meffert Mission also reflected in our care statistics of more (Head of the Department) and Structure than 3000 operations. Beside approx. 180 interventions in the traumatised cervical, Oberdürrbacher Str. 6 With appeal of the new ordinay the divisi- chest or lumbar spine, approx. 60 interven- 97080 Würzburg on of trauma became an independent De- tions involving the pelvic ring, approx. 150 Tel.: 09 31 / 201-37000 partment of Trauma, Hand, Plastic & Re- osteosyntheses of long long bones and ap- Fax: 09 31 / 201-37009 constructive Surgery on 01.01.2007. prox. 300 complex joint injuries are perfor- E-mail: [email protected] / Within our department we dispose of an in- med annualy. Another considerable propor- [email protected] dependent section for plastic and aesthe- tion is performed by the hand surgery with www.klinik.uni-wuerzburg.de/unfallchirurgie tic surgery. approx. 500 interventions and the plastic surgery with approx. 300 interventions.

CONTACT DETAILS CONTACT Professor Dr. med. Arnulf Weckbach The Department of Trauma, Hand, Plastic Within the scope of the trauma network Tel.: 09 31 / 201-37010 & Reconstructive Surgery employs 18 me- 100 polytraumatized patients were treated dical doctors. Currently, we are responsib- interdisciplinary in the shock trauma emer- le for 52 patients on the regular wards. In gency room of our hospital. addition, together with the department of anaethesiology and the department of surgery we operate jointly the units for surgical Clinical research and studies intensive care and the Intermediate Care ward. Not a complete year passed by since the new department was founded. As a result Within the Center for operative medicine we both clinical and experimental research are collaborate closely with the departments of developing in structural process. One of the general surgey, of anaesthesiology and of established main interests of the clinical re- radiology in particular view of the treatment search refers to the injuries of the vertebral of severely injured patients. In July 2007 column. Moreover, we are participating in we have founded the trauma networtk of the study group spine of the german soci- „North Bavaria – Würzburg“. 19 medical ety for trauma surgery. Therefore we are in centres of the region join the new network a steady exchange with other main medical for improving the rescue system and treat- centres. Another main focus concerns the ment for trauma victims up to now. treatment of unstable pelvic fractures. We also analyze the oucome of pelvic ring frac- A state-of-the-art shock-trauma unit equip- tures as a participating clinic of the “pelvic ped with spiral CT as well as all modern group” of the German Society for Orthopa- functional facilities, as for example a cen- edic Trauma Surgery. tral sterilisation, operating theatres, intensive care unit and physiotherapy facilities are Within the scope of restructuring the new on the spot. Besides, the department of ra- department a research professorship was diology enacts of the modernest devices for granted for 2008. angiography, CT and MRI diagnostics. Major Research Patient-Care Interests

Because of the different main focuses of The facilities of the trauma research laba- the Department of Trauma, Hand, Plastic ratory extend over 70 m ². Included are an and Reconstructive Surgery, consultation microscopic analysis area combined with hours on account of the further specialisa- a full-digital workplace which enables to tions were required. Next to the consultati- further analyze analogly contact radiographs on hour for spinal fractures, pelvic fractu- e.g.. Besides the labs are provided with ne- res and complex fractures we established west computer equipment which allows not further ones for workers compensation insurance, for hand surgery, for arthroscopic surgeries of the knee and shoulder as well as for arthroplasties and foot injuries. Bey- ond it, we offer special consultation hours for plastic and aesthetic operations.

To improve the patient´s service we have introduced fixed outpatient appointment Fig. 1: Histological image of muscle: No hours to reduce the average waiting peri- trauma (A), increasing soft tissue trauma od while being able to treat the numerous with connective tissue displacing muscle emergency patients. The main focuses are tissue in ascending order.

56 only our doctoral students to be up-to-date concerning literature based knowledge finding. For biomechanical investigations and analyses we installed a Zwick-Roell-2020 as a 2 chanal device. At present we analyze different installations of mini locking implants in bovine metacarpal bones which are of interest for hand surgery. Furthermore, at present we develop new implants with improved anchorage in osteoporotic bone.

In 2007 we have mainly concentrated on the experimentally induced soft tissue and osseous trauma as well as on muscle and Fig. 2: Newly regenerated bone (Callus) bone regeneration. via distractionosteogenesis.

Almost every day we see heavily injured patients with complicated extremity injuries dications we meet twice daily. Four times which involve damage of the bone and the a year we organize additional trauma mee- surrounding soft tissue. tings. Alike these we also oragnize topic- related, interdisciplinary polytrauma con- By means of an experimental model to si- ferences as well as lectures of plastic and mulate the described clinical situation we hand surgery to which we invite members are able to produce a defined musculos- of the rescue services and of the surroun- keletal trauma which leads to a compart- ding hospitals and disciplines. In cooperati- ment syndrom (picture 1). This is treated on with the institute of anatomy (Prof. Dren- by shortening of the extremity followed by ckhahn) we carry out operation courses in distraction osteogenesis (picture 2). More- body donators for the first time in 2008. over we quantified the muscle strength in- vivo which gave us information about the muscle strength regeneration. Additionally, we analysed the preparations histologically, histomorphologically and radiographically.

Next, based on these results, we will examine the regeneration of the soft tissue and bone influenced by angiogentetic and neurotrophic growth factors. Aim of these investigations is to transfer positive results into clinical applications. This project is supported by the IZKF-Würzburg.

Teaching Meffert, R H, S P Frey, H Jansen, S Och- man, M J Raschke, M Langer. (2008) Mu- The apprenticeship is divided into the edu- scle strength quantification in small animals: A new transcutaneous technique in cation of the students and the advanced rabbits. J Orhtop Res (im Druck). training and continuing education of residents and senior registrars. Beside the re- Meffert, R H, H Jansen, S P Frey, M J gular main lecture for trauma, hand, plastic Raschke, M Langer, (2007) The influence of Soft tissue Trauma on Bone Regenera- and reconstructive surgery we offer an ex- tion after Acute Limb Shortening. Clin Or- tensive teaching for the students. Moreover thop Rel Res. 460:202-209. we provide training periods including bedside-teaching, weekly block training periods Morrison R., Thierolf A., Weckbach, A, with concluding final examinations, clini- (2007) Volumetric changes of iliac crest autografts used to reconstruct the anteri- cal investigation courses during our special or - column in thoracolumbar fractures - a consultation hours as well as the possibility follow-up using CT-scans. Spine 32:3030- to assist in surgeries. Students of the last 3035. year are invited to attend a specially taylo- red weekly seminar which is an optimal preparation for their exam. For advanced trai- SELECTED PUBLICATIONS ning of the junior doctors and to discus in-

57 3.5 Institute for Transfusion Medicine and Haemotherapy

Mission Major Research Professor Dr. med. Markus Böck and Structure Interests (Head) The Institute of Transfusion Medicine and Biochemical and functional comparison of Josef-Schneider-Str. 2 Haemotherapy is localized at three positi- different platelet concentrates 97080 Würzburg ons within the hospital area. It provides Tel.: 09 31 / 201-31300 • a laboratory for blood group serology Platelet concentrates are obtained by aphe- Fax: 09 31 / 201-31376 • a laboratory for HLA-typing resis or by buffy coat method. One of the E-mail: [email protected] • a GMP-laboratory for modification and research activities of the Institute of Trans- www.transfusionsmedizin.uni-wuerzburg.de cryopreservation of stem cell concentra- fusion Medicine and Haemotherapy is the tes biochemical and functional characterization

CONTACT DETAILS CONTACT • a blood bank for supplying the university and comparison of these two types of plate- hospital with blood components let concentrates. • a blood donation department • a department for therapeutical apheresis Storage and transport of red cell con- • a register for stem cell donors centrates under different conditions

According to the German directions of Clinical activities blood processing and transfusion red cell concentrates have to be stored at 4° C The Institute of Transfusion Medicine ± 2° C in special blood storage refrige- and Haemotherapy supplies the universi- rators. However, less information is avai- ty hospital of Wuerzburg with all required lable, how long this cooling process can blood products, e.g. red cell concentra- be interrupted without harming the con- tes, platelet concentrates and fresh fro- centrates. Therefore, different storage and zen plasma. Additionally, it is competent transport conditions of red cell concentra- for the production of autologous and al- tes are evaluated. logenic 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 dif- Teaching ferentiation) the Institute of Transfusion Medicine and Haemotherapy provides • Main lecture “transfusion medicine” HLA-testing for the patients of the hospital • Lecture “Blood group serology and with serological and DNA-based methods. transfusion therapy” It is responsible for the search of com- • Lecture “Immunohaematology” patible stem cell donors and organizes a • Lecture “Therapeutical and preparative stem cell donor registry for the national apheresis” and international donor mediation. In ad- • Lecture “Transfusion in difficult patients” dition, the Institute of Transfusion Me- dicine and Haemo- therapy is specialized in the enforce- ment of therapeutical aphereses (e.g. plasmapheresis, immunoadsorption, cell-apheresis). Furthermore, quality assurance in haemotherapy for the university hospital is one of the central functions of the institute.

Fig. 1: Leucocytes from stored and concentrated erythrocytes.

58 • Lecture “Production of blood components” • Lecture “Biology and function of red cells” • Lecture “Transfusion therapy with and without red cells” • Lecture “Stem cell transplantation: from the donor to the transplant” • Lecture “The HLA-system” • Pracitcal training “Transfusion medicine and immunohaematology” • Pracical training “Blood group serology”

R.J. Deleeuw, A. Zettl, E. Klinker, E. Ha- ralambieva, M. Trottier, R. Chari, Y. Ge, R.D. Gascoyne, A. Chott, H.K. Müller-Her- melink, W. L. Lam. (2007) Whole-Genome Analysis and HLA Genotyping of Enteropa- thy-Type T-Cell Lymphoma Reveals 2 Din- stinct Lymphoma Subtypes. Gastroentero- logy 132: 1902 -1911.

F. Gronen, K. Ruprecht, B. Weissbrich, E. Klinker, A. Kroner, H. Hofstetter, P. Rieck- mann. (2006) Frequency analysis of HLA- B7-restricted Epstein-Barr virus-specific cytotoxic T lymphocytes in patients with multiple sclerosis and healthy controls. J Neuroimmunol. 180 :185-92.

I. Shimanovich, S. Herzog, E. Schmidt, A. Opitz, E. Klinker, E.B, Bröcker, M. Goebe- ler and D. Zillikens. (2006) Improved pro-

SELECTED PUBLICATIONS tocol for treatment of pemphigus vulgaris with protein A immunoadsorption. Clin Exp Dermatol. 31: 768-74.

K. Otto, M.H. Andersen, A. Eggert, P. Kei- kavoussi, L. Ostergaard, M. Böck, J.C. Rath. E.B. Bröcker, P. Straten, E. Kämp- gen, J.C. Becker. (2005) Lack of toxicity of therapy-induced T cell responses against the universal tumour antigen surviving. Vaccine 23: 884-889.

J.E. Herrero-Gonzalez, C. Sitaru, E. Klin- ker, E.B. Bröcker, D. Zillikens. (2005) Suc- cessful adjuvant treatment of severe bull- ous pemphigoid by tryptophan immunoad- 59 sorption. Clin Exp Dermatol.; 30: 519-522 3.6 Department of Thoracic and Cardiovascular Surgery

Mission Major Research Professor Dr. med. Rainer G. Leyh and Structure Interests (Head of the Department) The department of Thoracic and Cardio- Cardiac surgery: Zentrum Operative Medizin vascular Surgery is a 56-bed department Oberdürrbacher Str. 6 with 3 operating theaters and operates ist Ross operation: 97070 Würzburg own 14 bed intensive care/intermediate By means of MR and CT-scanning we Tel.: 09 31 / 201-33001 care unit plus. At present 24 physicians evaluate the impact of different implant Fax: 09 31 / 201-33009 and 1 psychologist are working in this de- techniques of the pulmonary autograft E-mail: [email protected] partment. on postoperative RV function (Dr. Gorski, www.htc-wuerzburg.de Dr. Sommer). Data from all Ross proce-

CONTACT DETAILS CONTACT Approximately 1600 procedures are pe- dures are forwarded to the German Ross formed annually covering the entire field registry. of adult heart and thoracic surgery. 700 procedures are open heart surgeries with Transplant vasculopathy after heart trans- extracorporeal circulation. plantation: After establishing a heterotopic rat heart In 2007 an assist device program was transplant model (Dr. Lange) we are cur- established and the heart transplant pro- rently investigating the effect of CD28- gram relaunched. Specialized outpatient antibodies on tolerance induction. The clinics care for transplant and VAD pati- second step will be the reversal of tole- ents and for patients requiring aortic sur- rance induction by CTLA4-antibodies. gery. In addition there is a tumour outpatient clinic for thoracic tumours. Furthermore, we are preparing experimental studies to assess the immuno- Within a radius of 100 kms we repre- suppressive properties of inhibitory blo- sent the sole institution which offers the cking peptide (IBP, Dr. Lange in coope- full range of adult heart surgery including ration with PD Dr. Ritter from the depart- heart transplantation and simultaneous ment of cardiology). IBP inhibits the pro- management of any kind of thoracic sur- tein which is respponsible for transferring gery including tracheal surgery. calcineurin into the nucleus without the dramatic side effects of classical calci- Main areas of interest are total arterial neurin inhibitors like cyclosporine A or ta- revascularization, beating heart bypass crolimus. surgery, reconstrucitve valve surgery including DAVID-, YACOUB-procedures. In Knock-out- mice will serve as study ani- selected patients we also offer the ROSS mals for Nrf-2 transcription factor and ist procedure. effect on oxidative stress.

Recently, we have introduced a mobi- Heart / lung transplantation: le heart-lung-machine (Lifebridge) for Two large animal studies will assess the further improving the management of role of resveratrol for amelioration of pul- heart or lung failure patients. Such pa- monary and cardiac ischemia/reperfusi- tients are transferred to our hospital th- on injury (IRS), respectively. Resveratrol rough a dedicated team from our depart- had favourable effects on IRS of different ment. organs like kidneys and liver. However, effects on cardiac and pulmonary func- Approx. 400 thoracic cases are perfor- tion after transplantation have not been med per year. Main areas of interest are elucidated fully yet (Dr. sommer, Dr. Oez- extrapleural pneumonectomies for meso- kur). thelioma and minimally-invasive procedures and laser resections. We are proud Transfusion requirements: to offer the only laser system in this regi- Due to the large need for blood products on. The laser enables us to perform can- in cardiac surgery studies with cryopre- cer surgery with a maximum protection of served erythrocytes have been initiated by healthy tissue. Dr. Hickethier. Funding through the Ger- man army was available. Dr. Hickethier In addition we cover the entire field of ar- has resumed his previous acitivities and rhythmia surgery. Apart from pacemaker, will obtain new data on in vitro function of ICD and biventricular device implantati- cryopreserved leucocytes and platelets. ons we routinely perform Mini-MAZE pro- Additional studies highlighting the func- ceudres fort he surgical treatment of at- tion of the coagulation system after cryo- rial fibrillation. preservation are in preparation.

60 Neuropsychological studies and cardiac A new weekly crdiology7 cardiac surgery surgery: conference is a mainstay for the education Dr. Krannich, our clinical psychologist, is in- of our residents. vestigating neuropsychological deficts and In addition we are proud to offer a new se- ist reversability during rehabilitation therapy minar on „ethics in surgery“ starting in fall after surgery for coronary artery disease. 2007.

Prior to bypass surgery 45 to 80% of pati- This department ist the only one in the state ents have cognitive deficits. This proporti- of Bavaria which offers German board certi- on increases postoperatively. Data on these fied training in cardiac surgery, cardiac sur- deficts and their potential reversibility du- gical intensive care medicine and thoracic ring rehabilitation are scarce. Since reha- surgery within one department. bilitation is performed after percutaneous In 2008 we are planning to host two clini- interventions as well, different interventions cal fellows from Serbia and Jordan, respec- and their impact on neuropsycholgical func- tively. tion can be compared.

A similar test battery will examine patients after operations uitlizing deep hypother- mic circulartory arrest. By comparison with coronary artery disease patients operated upon without circulatory arrest the effects of deep hypothermia, circulatory arrest and extracorporeal circulation, respectively can be determined.

Thoracic surgery Surgery for pulmonary metastases is an established therapeutic approach. However, the psychological benefit of these procedures has not been investigated at all yet. At the same time, this is the main justifi- cation for these procedures, because there is hardly any symptomatic improvement in these mostly asymptomatic patients. Therefore, all our patients referred for me- Eich C, Bräuer A, Timmermann A, Schwarz tastasectomy are investigated by means of SKW, Russo SG, Neubert K, Graf BM, questionnaires pre- and postoperatively (Dr. Aleksic I. (2007) Outcome of 12 drowned Krannich, Dr. Bohrer, Dr. Neukam). children with attempted resuscitation on cardiopulmonary bypass: An analysis of Ongoing projects assess the role of liver cir- variables based on the “Utstein Style for Drowning”. Resuscitation 75: 42-52. rhosis on outcome after cardiac and thoracic surgery and the impact of concomitant Erasmi A, Sievers HH, Bechtel JF, Han- meningiomas on neurological outcome af- ke T, Stierle U, Misfeld M. (2007) Remo- ter cardiac surgery utilizing the heart-lung- deling or reimplantation for valve-sparing aortic root surgery? Ann Thorac Surg 83: machine (PD Dr. Aleksic, Dr. Gorski, Dr. 752-756. Sommer). Krannich JH, Weyers P, Lueger S, Herzog M, Bohrer T, Elert O. (2007) Presence of depression and anxiety before and after coronary artery bypass graft surgery and their relationship to age. BMC Psychiat- ry. 7:47.

Teaching SELECTED PUBLICATIONS Schimmer C, Sommer SP, Bensch M, Leyh R. (2007) Primary treatment of deep ster- All topics of cardiothoracic surgery relevant nal wound infection after cardiac surgery: to the medical student are covered by a lec- a survey of German heart surgery centers. ture series and regular „bed-side“-teaching Interact Cardiovasc Thorac Surg. 6:708- plus grand rounds. Since 2007 2-3 medi- 711. cal students spend one week in the depart- Schimmer C, Reents W, Elert O: (2006) ment as part of a mandatory surgical rotati- Primary closure of median sternotomy: a on. Final year medical student spend a 16 survey of all German surgical heart centers week rotation in our department. and a review of the literature concerning sternal closure technique. Thorac Cardio- 61 vasc Surg. 54:408-413. 3.7 Department of Urology and Paediatric Urology

Mission Professor Dr. med. Hubertus Riedmiller and Structure (Head of the Department) The Department of Urology and Paediatric Zentrum Operative Medizin (ZOM) Urology is a tertiary referral centre with two Oberdürrbacher Str. 6 general wards (54 beds), intensive care unit 97080 Würzburg (8 beds) with haemodialysis facility, a busy Tel.: 09 31 / 201-32001 outpatient clinic with uroradiology section, Fax: 09 31 / 201-32013 point-of-care lab and a research laboratory E-mail: [email protected] with an emphasis on molecular urooncolo- www.urologie.uni-wuerzburg.de gy. Three state-of-the-art operating theat- Fig. 1: Generation of a transgenic mouse

CONTACT DETAILS CONTACT res allow the surgical treatment of approxi- model to inactivate mismatch repair acti- mately 2.500 adults and 350 children and vity in the prostate using the Cre-loxP sys- adolescents with 2.500 conventional open tem. and laparoscopic procedures and more than 1.800 endourologic interventions per year. The equipment comprises a multi-function malignancy in men. However, the impact unit for extracorporal shockwave lithotripsy, of MMR defects on pathogenesis and pro- a computer-assisted (video)urodynamic gnosis of these tumors is not well defined set-up, lasers of the most recent genera- and up to now it is unknown whether MMR tion and several ultrasound machines with defective tumors represent a distinct clini- colour-coded duplex sonography and trans- cal risk group. To answer the question what rectal probes. impact MMR defects play for tumor development we generated novel mouse mo- The surgical spectrum encompasses the dels that will allow to study the biological entire speciality of urology (high volume function of MMR defects during develop- centre) with special expertise in uroonco- ment and progression of PCa in vivo. One logy (particularly orthotopic bladder substi- of the proposed mouse models is based on tution and continent cutaneous/heteroto- a prostate specific inactivation of the MMR pic urinary diversion following radical cyst- system using the Cre-LoxP system. It will ectomy, nerve-sparing; radical perineal provide the opportunity to study the mole- and retropubic prostatectomy/nerve-spa- cular and genetic mechanisms of the early ring; nephron-sparing resection of renal development, progression and eventually cell cancer; polychemotherapy; immune- metastasis of the PCa and will further al- modulation); paediatric urology (correction low to functionally explore different thera- of complex congenital malformations), re- pies in vivo. constructive urology (ileal ureter replacement, open urethral reconstruction, complex fistula repair) including implantati- Aberrant expression of spindle check- on of artificial urinary sphincters and pe- point genes in high grade prostate can- nis prosthesis, urogynaecology and renal cer transplantationen (cadaver and living rela- (B. Kneitz, E. Gerharz) ted transplantation). Defects in the mitotic spindle checkpoint (MSC) are discussed to be involved in cancer development. To understand the role of aberrant expression of MSC genes for the development of prostate cancer (PCa) we analysed the expression of two MSC genes in PCa specimens. In addition we studied Major Research the effect of Bub1b haploinsufficiency for Interests induction of genomic instability and resistance against therapeutic agents in vitro. Impact of mismatch repair defects on We could show that spindle checkpoint ge- pathogenesis and prognosis of prosta- nes are frequently down regulated in high te cancer grade PCa. Our results suggest that the ex- (B. Kneitz, E. Gerharz) pression of MSC genes may be helpful biomarkers for advanced PCAs and that spind- Defects in the mismatch repair (MMR) sys- le checkpoint defects caused by aberrant tem play a critical role for the development expression of spindle checkpoint genes of microsatellite instable colorectal cancer might be involved in malignant progression and cancer of various other tissues. Pro- of PCa and failure of treatment using cyto- state cancer (PCa) is the most common toxic agents.

62 Identification of tumor supressors or are offered along with integrated and in- onco- microRNAs in prostate cancer terdisciplinary approaches. Participation and renal cell cancer in skills lab, e-learning-programmes, in- (B. Kneitz, M. Spahn, F. Hillig) terdisciplinary oncology (seminar and lecture), emergency medicine, integrated Micro-RNAs (miRNA) are a class of small seminars in tumor biology, interdisciplina- (19-25-nt long) non-coding regulatory ry paediatric pathophysiology and courses RNAs. According to the current understan- in prevention, epidemiology and biostati- ding the main function of miRNAs is to re- stics. Hospitation in the operating theatre gulate gene expression. A number of pre- and outpatient clinic is possible throug- vious studies detected frequent alterations hout the entire academic year. of miRNA expression in various cancers. Functional studies of individual miRNAs have shown that they might function biologically either as tumor suppressor or onco- miRs. The aim of our studies is to analy- Fig. 2: MiRNA expression signature of re- se the role of miRNAs for the development nal cell cancer. and progression of prostate cancer and renal cell cancer. in patients sera samples. In further scree- Using microarrays and qRT-PCR miRNA ana- ning tests immune response specifically in- lysis we detected specific miRNA signatures duced by BCG immunotherapy will be infor both types of cancer (Figure 2). By bio- vestigated. informatics and statistical analysis specific miRNAs were identified, which are linked to the development and progression of cancer. Treatment of patients with high risk pro- To study the molecular mechanisms of such state cancer miRNAs we are currently studying the func- (M. Spahn, H. Riedmiller) tion of specific miRNAs in vitro. In the era of PSA based screening a trend towards more favourable stages at initial Characterization of the humoral immu- clinical presentation is observed. Unfor- ne response and identification of new tunately, the percentage of patients with diagnostic molecular marker in transiti- high risk prostate cancer (1992 AJCC cli- onal cell carcinoma nical category >T2c, or PSA >20 ng/ml, (P. Ardelt) or Gleason score >8) is still significant (1990: 39%; 2003: 22%). In this group of The aim of this project is to identify a se- patients the risk of biochemical progres- rological marker in transitional cell carcino- sion within a 5-year period is approxima- T. Heinke, E.W. Gerharz, R. Bonfig, H. ma of the bladder for early detection and tely 40%. Riedmiller: (2003) Ventral onlay urethro- followup. plasty using buccal mucosa for complex Treatment of these patients is controversi- stricture repair. Urology, 61: 1007-1007. Using the phage display technique three oli- al and radiation therapy is often combined gopeptide sequences were isolated. They with androgen deprivation as the preferred E.W. Gerharz, L. Mosekilde, J.S. Thom- sen, J.A. Gasser, C. Moniz, P.J. Barth, are recognized by the circulating patient’s option. Only few studies analysed surgical P.G. Ransley, C.R.J. Woodhouse: (2003) antibody pool and represent fragments of strategies in these patients. We therefore The effect of enterocystoplasty on bone tumor-associated antigens. For these oligo- evaluate the outcome of different surgical strength assessed at four different skeletal peptides binding specificity was verified by techniques (radical prostatectomy, radical sites in a rat model. Bone 33: 549-556. competitive binding inhibition studies. The cystoprostatectomy) combined with stage R. Bonfig, E.W. Gerharz, H. Riedmiller: antibody response against one sequence dependent androgen deprivation in patients (2004) Ileal ureter replacement in com- indicates the presence of a carcinoma in with high risk and locally advanced prosta- plex reconstruction of the urinary tract. situ (flat lesion) of the bladder, which is no- te carcinoma. BJU International 93: 575-580. toriously difficult to detect by plain cysto- E.W. Gerharz, A. Mansson, S. Hunt, E. scopy; a drop in titer suggests successful Skinner, W. Mansson: (2005) Quality of treatment. For this sequence mycobacterial life after cystectomy and urinary diversion:

heat shock protein HSP65 could be identi- SELECTED PUBLICATIONS An evidence-based analysis. J Urol, 174: fied as corresponding antigen. 1729-1736.

Teaching E. Avdievich, C. Reiss, S. J. Scherer, Y. Corresponding antigens of all selected oli- Zhang, S. M. Maier, B. Jin, H. H. Jr., gopeptides will be characterized (Western Traditional teaching formats (lecture with A.Rosenwald, H. Riedmiller, R. Kucher- Blot, affinity chromatography, MALDI-TOF) clinical case presentation and live trans- lapati, P. E. Cohen, W. Edelmann and B. and both, sensitivity and specificity of anti- mission of surgical procedures from the Kneitz: (2008) Distinct Effects of the Re- current Mlh1G67R Mutation on MMR body response will be determined by ELISA operating theatre; clerkships/electives) Functions, Cancer and Meiosis. Proc. Natl. Acad. Sci. (USA) 105: 4247-4252. 63 3.8 Department of Orthopaedics

Professor Dr. med. Jochen Eulert Mission Key Issues in ambulatory and in-patient (Head of the Department) and Structure care for orthopedic patients are

König-Ludwig-Haus The Orthopedic Clinic König-Ludwig-Haus • Shoulder and Elbow Surgery Brettreichstr. 11 is a top level hospital for musculoskel- • Ankle and Foot Surgery 97074 Würzburg etal diseases and injuries and their se- • Pediatric Orthopedic Surgery Tel.: 09 31 / 803-1102 quelae. The hospital is operated by the • Spine Surgery Fax: 09 31 / 803-1109 district of Unterfranken. The chair for Or- • Endoprostheses of hip, knee, shoulder E-mail: [email protected] thopedics, the University Outpatient Clinic and elbow joints www.orthopädie.uni-wuerzburg.de for Orthopedics and a Competence Cen- • Arthroscopies of knee, shoulder, elbow, ter for Osteology are integrated into this ankle and wrist joints

CONTACT DETAILS CONTACT Professor Dr. med. Franz Jakob hospital. The director in Chief of the Chair • Sports Orthopedics Tel.: 0931 803-1580 and Department, 1 full Professor of Os- • Osteology (metabolic and degenerative teology, 6 Senior Physicians and 22 Re- diseases with a special focus in osteo- sidents are running patient care and tea- porosis and malignant bone disease) ching. The hospital holds 140 beds, more than 3.800 operations per year are per- Orthopedic Advice is offered for several formed in 5 operating theatres. The Uni- other hospital and centers for disabled. versity Outpatient Clinic provides ambulatory care for app. 10.000 patients per year. The König-Ludwig-Haus also runs own departments for x-ray diagnosis and physiotherapy. Major Research The Orthopedic Center for Musculoskel- Interests etal Research is an interactive platform between basic science, translational re- The Orthopedic Centre for Musculoskele- search and clinical implementation of in- tal Diseases is located in a 500 sq. m la- novative therapeutic strategies. Its main boratory area which comprises scientific topics of research are Mesenchymal Stem laboratories and working rooms (S1, S2, Cell Biology and their differentiation into radioactivity). The Center is supported by mesenchymal tissues and the develop- the District of Unterfranken. It is funded ment of cell based therapeutic strategies by the German Research Society (Clini- for tissue regeneration. The Center espe- cal research Unit KFO 103, DFG Research cially supports the chair in the represen- unit FOR 793, several single projects), by tation of teaching and research. It is also the German Ministry of Research BMBF, an important partner for the development the IZKF of our Medical Faculty, the Ar- of the emerging Wuerzburg Interdiscipli- beitsgemeinschaft Osteosynthese (AO), nary Musculoskeletal Research and Treat- Arbeitsgemeinschaft Arthrose, and by the ment Center. Research Fund of the State of Bavaria as

Fig. 1: Endoprosthesis of the shoulder for treatment of omarthrosis.

64 • 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

Fig. 2: Tracking of human mesenchymal stem cells using superparamagnetic Iron-oxide nanoparticles (VSOP): histological demonstration of particles in the cytoplasm using Ber- liner Blau Staining (Heymer et al. 2008). well as several industry sponsored unrestricted grants. The number of positions fun- Teaching ded is 19 as of 2007. • Course in clinical examination techni- Key Issues in Research ques for operative and conservative or- • Biology of Mesenchymal Stem Cells (F. thopedics Jakob, R. Ebert, T. Schilling) • Lectures in Basics of Orthopedics (also • Molecular Orthopedics and Cell Biology accompanying the practical course) (N. Schütze, T. Schilling, R. Schenk, K. • Practical Course in Orthopedics (bedsi- Schlegelmilch) de teaching in small groups, demonst- • Tissue Engineering (U. Nöth, M. Weber, rations in physiotherapy, plaster techni- A. Heymer) ques and orthopedic technical devices Steinert AF, Weber M, Kunz M, Palmer GD, • Gene therapy in Musculoskeletal Di- and corselets Nöth U, Evans CH, Murray MM. (2008) In seases (A. Steinert, N. Armbruster, C. situ IGF-1 gene delivery to cells emerging Weber) from injured anterior cruciate ligament. Bi- • Molecular and Classical Biomechanics omaterials 29: 904-916. (F. Jakob, L. Seefried, J. Stehle, S. Mül- Nöth U, Rackwitz L, Heymer A, Weber M, ler-Deubert) Baumann B, Steinert A, Schütze N, Jakob • Fracture Healing in Trauma and Oste- F, Eulert J. (2007) Chondrogenic Differen- oporosis (KFO 103 in Kooperation mit tiation of Human Mesenchymal Stem Cells KFO 102 Berlin; FOR 793) in Collagen Type I Hydrogels. J Biomed Mat Res 83A: 623-635. • Particle Disease (B. Baumann) • Special techniques in shoulder joint re- Schilling T, Küffner R, Klein-Hitpass L, Zim- construction (F. Gohlke, O. Rolf) mer R, Jakob F, Schütze N. (2007) Mi- • Special pediatric surgery and spine croarray analyses of transdifferentiated surgery (P. Raab, V. Ettl) mesenchymal stem cells. J Cell Biochem. 103: 413-433. • Clinical Studies on Osteoporosis (F. Ja- kob, L. Seefried, S. Goebel) Ebert R, Ulmer M, Zeck S, Meissner-

• Development of innovative cell based SELECTED PUBLICATIONS Weigl J, Schneider D, Stopper H, Schupp therapeutic strategies for Musculoskel- N, Kassem M, Jakob F. (2006) Selenium supplementation restores the antioxidative etal Diseases (U Nöth, A. Steinert, L. capacity and prevents cell damage in bone Rackwitz, T. Barthel) Fig. 3: Demonstration of micronuclei in marrow stromal cells in vitro. Stem Cells. • Endoprosthesis of hip and knee joints human mesenchymal Stem Cells. Antio- 24:1226-35. (J. Eulert, B. Baumann, O. Rolf) xidative enzymes are able to reduce the- • Pain Research in Orthopedics (S. Goe- se indicators of genotoxic stress during ex Baumann B, Hendrich C, Barthel T, Bock- holt M, Walther M, Eulert J, Rader CP. bel, J. Eulert) vivo cell culture (Ebert et al. 2006). (2007) 9- to 11-year results of cemented titanium mueller straight stem in total hip 65 arthroplasty. Orthopedics. 30: 551-7. 3.9 Department of Obstetrics and Gynecology

Major Research of LASP in breast cancer metastases in or- Professor Dr. med. Johannes Dietl Interests der to elucidate a possible significance of (Head of the Department) this protein in tumour progress. Cell cultu- Fetomaternal interface re studies investigate the function of LASP Josef-Schneider-Str. 4 (U. Kämmerer, L. Rieger, S. Segerer, J. in the biology of tumour cells. The project 97080 Würzburg Dietl) is funded by the Deutsche Krebshilfe (No Tel: 09 31 / 201-25251 107706). Fax: 09 31 / 201-25406 The interactions between the maternal im- E-mail: [email protected] mune system and placenta are that lead www.frauenklinik.uni-wuerzburg.de to tolerance of the fetus analyzed,. A sub- Therapeutic strategies for the treat- project studies the effect of soluble factors, ment of premature labour (IZKF Project

CONTACT DETAILS CONTACT such as cytokines, growth factors and hor- E-38) mones, which influence cellular interac- (T. Frambach, M. Ivanisevic) tions. As part of a clinical research group (KFO 124, cooperation with the depart- Tocolytic drugs have different mechanisms ment of dermatology, J. Becker), placenta- of action. During long-term treatment, ho- tion serves as a model system for tumours. wever, it comes to a rapid loss of effect, and Under a new “first applicant” programme by often a premature birth cannot be avoided. the IZKF Wuerzburg, a project on the role of In a collaborative project with the institu- thrombopoietin in early pregnancy is prote of pharmacology (M. Lohse), fundamen- moted (Dr. S. Segerer). tal mechanisms of these substances at the myometrium of pregnant uteri are elucidated. The goal is to identify new and to op- Mission Research Project „Immune escape of timize established therapeutic strategies to and Structure tumours“ reduce fetal morbidity and mortality due to (J. Wischhusen, C. Weidler, Y. Dombrowski, preterm delivery caused by premature la- The Woman’s Hospital (bed capacity of 84, S. Häusler) bour. 33 doctors, 102 nurses, 14 midwives, 6 assistant medical technicians) has two obs- Funded by the IZKF, a group of young re- tetrical and three gynecological wards, 5 searchers investigates the mechanisms Metabolism of tumours / Clinical study labour and delivery rooms and a Level I Pe- that underlie the immune escape of tu- on carbohydrate deficient nutrition in rinatal Centre with six neonatal intensive- mour cells. Particular attention is paid the malignant tumours care beds, three operating rooms of most members of the TGF-β superfamily, as TGF- (M. Schmidt, N. Pfetzer, U. Kämmerer) modern standards, an operating room for β with promoting effects on migration, inva- caesarean sections, an intermediate-care sion and angiogenesis seems to be a factor Many tumour cells show a strikingly high unit, outpatient clinics for gynecology and of tumour progression in various tumours. sugar uptake. The reason for this is usu- obstetrics, gynaecological oncology, breast In addition, members of the TGF-β family ally a disproportionate increase in glyco- cancer, dysplasias of the cervix, child and exert extensive immune-inhibitory effects lysis. Possible therapeutic approaches by adolescence gynecology, urogynecology, on immune cells and thus contribute to the targeted inhibition of glycolytic enzymes endocrinology and reproductive medicine, “immune escape“ of tumour cells. Further, are investigated both in vitro (cell cultu- prenatal diagnostics. There are laborato- in cooperation with the department of der- res) and in vivo (in mice, cooperation with ries for endocrinology, cytology and repro- matology (JC. Becker) the group participa- the experimental transplant surgery, C. ductive medicine with andrology. Programs tes in a DFG project (BE: 1394/9-1) on the Otto). In a clinical study, the effect of car- include a midwifery school. In the women’s research of tumour stem cells. bohydrate deprivation under a carbohyd- clinic are also department of the Clinic for rate-poor oil/protein-rich diet on tumours Radiation Therapy (external radiation; bra- In close association with the junior research of different entities is analyzed. The study chytherapy) and the Institute of Radiology group, the role of the macrophage migra- was sponsored by „Hilfe im Kampf gegen (mammography, vacuum biopsy) and the tion inhibitory factor (MIF) in the interac- Krebs e.V.”. Department of Anaesthesiology (pain am- tions between the immune system and ova- bulance). rian cancer cells is analyzed (IZKF project Z- 4/72). (M. Krockenberger, A. Hönig). New GnRH antagonists in the treatment In 2007, 2,264 operations, 1,386 delive- of gynaecological malignancies ries, 5411 DRG cases, 22,080 outpatient (J. Engel, A. Hönig, M. Ivanesevic) therapies (3577 chemotherapies) have Studies on function and prognostic va- been performed. Centres of the clinic are: lue of LASP in the dissemination of bre- GnRH seems to act as a local growth fac- The interdisciplinary treatment of gyneco- ast and ovarian cancer tor in a variety of tumours. GnRH antago- logical cancers, including breast (certified (PA. Hönig, M. Kapp, U. Kämmerer) nists show anti-tumour efficacy in vitro and breast centre), the centre for hereditary in vivo, but it remains unclear whether aty- breast and ovarian cancer, the treatment LIM and SH3 domain protein (LASP) is an pical GnRH I- or GnRH II-receptors mediate of urinary incontinence and pelvic floor actin-binding protein that plays a role in cel- these effects. „Peptidomimetic“-GnRH an- dysfunction, care of risk pregnancies and lular migration. In a study in collaboration tagonists, whose advantage lies in the oral infertility treatment including in vitro ferti- with the institute of clinical biochemistry bioavailability, represent a new pharmaco- lisation. (E. Butt), we try to analyze the expression logic strategy. With the help of in vitro tu-

66 With gynaecological models and case studies, students learn to deal with clinical situations and to handle diagnostic equipment. The training is complemented by a number of interdisciplinary subjects like ethics, preventive medicine, emergency medicine, infectious diseases, tumour biology and oncology. For doctors in private practice, we organize regular interdisciplinary conferences as part of the perinatal centre.

Fig. 1: Premature infant in the incubator. mour models of endometrium, ovarian and diation therapy on local relapse in low-risk breast cancer, the effect of these new non- invasive breast cancer in a multi-centre peptidic GnRH antagonists in terms of their study. effectiveness and mechanism of action is investigated. Optimization of In Vitro Fertilisation (IVF) Matrix Metalloproteases and galectines (C. Rennemeier, E. Horn) in placentation and tumours (J. Anacker, A. Köhrmann, N. Kohrenha- The focus of the work of the IVF laboratory gen) consists in the continuous improvement of Dietl J, Engel JB, Wischhusen J. (2007) existing protocols in order to increase the The role of regulatory T cells in ovarian Matrix Metalloproteases (MMPs) are en- success rates of IVF. On this regard, we op- cancer. Int J Gynecol Cancer. 17: 764- zymes, which play an essential role in cell timized laboratory procedures concerning 770. migration. Galectines are important com- the processing of gametes and embryos ponents of the cellular matrix. In addition and their culture conditions. A new method Engel JB, Schally AV, Dietl J, Rieger L, Hö- nig A. (2007) Targeted therapy of breast to their function regarding tissue structure for vitrification of multi-cellular embryos or and gynecological cancers with cytoto- they possess immunoregulatory properties. blastocysts has been introduced. xic analogues of peptide hormones. Mol The role of these important factors in the Additionally, several research projects have Pharm. 4: 652-658. placentation and dissemination of tumours been initiated. They include the study on Engert S, Rieger L, Kapp M, Becker JC, (cancer of the breast and cervix) is inves- the influence of seminal plasma on the Dietl J, Kämmerer U. (2007) Profiling che- tigated. function of different cell types in the uteri- mokines, cytokines and growth factors in ne endometrium. human early pregnancy decidua by protein array. Am J Reprod Immunol. 58:129- Interstitial brachytherapy versus exter- 137. nal radiation therapy after breast-con- Grunewald TG, Kammerer U, Kapp M, Eck serving surgery Teaching M, Dietl J, Butt E, Honig A. (2007) Nucle-

(A. Hönig, J. Dietl) SELECTED PUBLICATIONS ar localization and cytosolic overexpression The curricular teaching in Obstetrics and of LASP-1 correlates with tumor size and nodal-positivity of human breast carcino- In collaboration with the department of Gynaecology consist of a main lecture (8th ma. BMC Cancer. 7:198. radiation therapy (M. Flentje, J. Goebel), semester), seminars, clinical visits (9th se- we investigate the influence of partial in- mester) and a practical training (10th se- Krockenberger M, Honig A, Rieger L, Coy terstitial brachytherapy (partial breast ir- mester). Additionally, a „Skills Laboratory“ JF, Sutterlin M, Kapp M, Horn E, Dietl J, radiation) versus conventional external ra- focuses on practical aspects of the subject. Kammerer U. (2007) Transketolase-like 1 expression correlates with subtypes of ovarian cancer and the presence of dis- 67 tant metastases. Int J Gynecol Cancer. 17:10110-6. 3.10 Department of Pediatrics

Professor Dr. med. Christian P. Speer FRCP Mission Malignant brain tumors in children and (Edin.) (Head of the Department) and Structure adolescents

Josef-Schneider-Straße 2 The Children’s` Hospital of the University of For more than 20 years, the Children’s Hos- 97080 Würzburg Würzburg (staff: 53.2 MD`s, 163.5 nurses, pital of the University of Würzburg has been Tel.: 09 31 / 201-27830 33.75 technicians / administrative staff) coordinating the prospective multicenter Fax: 09 31 / 201-27833 comprises 113 beds including a pediatric- phase II and phase III studies of the “Soci- E-mail: [email protected] neonatal intensive care unit (12 beds) and ety for Pediatric Oncology and Hematology” www.kinderklinik.uni-wuerzburg.de a neonatal intensive care unit (12 beds) in (GPOH) to optimize treatment for medullo- the perinatal centre (obstetrics and gynae- blastomas, PNETs, and ependymoma con- Professor Dr. med. Hermann Girschick cology). The Children’s` Hospital is divided ducted in Germany and Austria. In order to CONTACT DETAILS CONTACT Tel.: 09 31 / 201-27731 into the following functional sections: neo- increase survival rates these studies evalu- natology (Prof. Dr. C. P. Speer, Dr. W. Tho- ate age-adapted treatment strategies such Professor Dr. med. Helge Hebestreit mas, Dr. J. Wirbelauer, Dr. R. Wössner), pe- as radiation and chemotherapy, and inves- Tel.: 09 31 / 201-27889 diatric intensive care (Prof. Dr. C. P. Speer, tigate the value of biological parameters for Dr. W. Thomas, Dr. J. Wirbelauer), oncology prognostic assessment (see Fig. 1). Professor Dr. med. Paul-Gerhard Schlegel / haematology / stem cell therapy (Prof. Dr. Tel.: 09 31 / 201-27888 P.-G. Schlegel, Dr. F. Deinlein, PD Dr. M. Ey- rich, PD Dr. S. Rutkowski), cardiology (Dr. Reconstitution of the immune system Professor Dr. med. Hans-Michael Straßburg J. Wirbelauer), pulmonology / cystic fibrosis after stem cell therapy Tel.: 09 31 / 201-27734 / sports medicine (Prof. Dr. H. Hebestreit), gastroenterology (Dr. A. Dick), nephrology After the opening of the stem cell transplan- (Fr. Dr. A Beissert), endocrinology (Prof. Dr. tation unit in 2005 the reconstitution of the H. Hebestreit), diabetes (Dr. R. Wössner), immune system after the transplantation of neuropediatrics / social pediatrics (Prof. Dr. highly purified hematopoietic stem cells H.-M. Straßburg), immunology / infectiology across beyond HLA-barriers is studied. The (Prof. Dr. H. Girschick), rheumatology (Prof. objective of this project is to optimize es- Dr. H. Girschick), and others. Patients of all tablished immunotherapeutic approaches pediatric age groups ranging from prematu- such as the transfusion of donor lympho- re infants up to adolescents are treated for cytes in order to enhance the antileucemic the entire spectrum of pediatric diseases effect of stem cell transplantation. in hospital as well as in outpatient clinics. The Children’s Hospital is in close cooperation with pediatric neurosurgery, pediatric New cellular therapeutic concepts for surgery, urology with pediatric urology and brain tumors the section for pediatric neurosurgery. Every year, around 6500 patients are treated as With the establishment of a new EU Network inpatients and 7500 as outpatients. cellular therapies like vaccination with patient-specific dendritic cells loaded with the patient‘s tumor antigens and tumor-specific Major Research cytotoxic T-cells are being developed for the Interests treatment of malignant brain tumors.

Inflammation of the lungs during acute and chronic diseases in premature infants and newborns.

The aim of this project is to analyze pathogenetic mechanisms in order to establish new strategies for prevention and therapy for this disease.

Characterization of “airway remodelling” processes in chronic pulmonary inflammatory reactions

The purpose of this set of studies is the mo- Fig. 1: Event-free survival of 101 children lecular characterization of transmitters that with medulloblastoma participating in the are involved in pulmonary remodelling pro- HIT´91 study grouped according to clinical cesses in premature infants with broncho- criteria and the biological markers c-myc pulmonary dysplasia (BPD), as well as in and trkC (Rutkowski et al., Clinical Cancer children with asthma. Research 2007).

68 Inflammation processes in autoimmune diseases

A series of research projects entailing basic research and clinical studies investigates pathomechanisms, diagnostic and therapeutic options for inflammatory processes in autoimmune diseases (rheumatism, systemic lupus erythematosus), infections Fig. 2: Borrelia within a synovial fibroblast (Lyme disease, borreliosis, see Fig. 2), and (confocal laser scanning microscopy); the metabolic disorders (hypophosphatemia) in bacterium may persist intracellularly for the human organism. months and hence induce the inflammatory responses associated with Lyme-arthritis. Magnetic resonance imaging techniques for examination of the lungs

This interdisciplinary project assesses the ted States of America this symposium rep- value of low- and high-field MRI scans of resents the largest scientific forum for ne- the thorax for the diagnosis of pathological onatology. In 2007 the Annual Meeting of changes in the lungs and for the functional the “Süddeutsche Gesellschaft für Kinder- evaluation of ventilation and perfusion. heilkunde” took place in Würzburg.

Exercise testing methodology and training effects in healthy children and in children with chronic diseases

Several studies evaluate the preventative effects of physical activity in healthy children, and the positive effects on patients with chronic diseases. Furthermore, the mechanisms possibly involved are investigated. The validity of exercise testing for diagnosis and the follow-up of therapeutic effects is determined in other studies. Hebestreit H, Kieser S, Rüdiger S, Schenk T, Junge S, Hebestreit A, Ballmann M, Posselt HG, Kriemler S. (2006) Physical activity is independently related to aerobic Teaching capacity in cystic fibrosis. European Respi- ratory Journal 28:734-739. The Children’s Hospital of the University of Würzburg offers several courses for me- Kunzmann S, Schmidt-Weber C, Zingg JM, dical students. Students have repeatedly Azzi A, Kramer BW, Blaser K, Akdis CA, Speer CP. (2007) Connective tissue growth evaluated the main lecture in pediatrics re- factor expression is regulated by histamine gularly as one of the best courses in the in lung fibroblasts: Potential role of hista- faculty of medicine. Prof. Dr. C. P. Speer is mine in airway remodelling. Journal of Al- authorized to fully train MD`s in pediatrics, lergy and Clinical Immunology, 119:1398- 1407. as well as in neonatology and pediatric intensive care. The heads of the sections for Kunzmann S, Speer CP, Jobe AH, Kramer pediatric haematology and oncology, neu- BW. (2007) Antenatal inflammation indu- ropediatrics, pediatric pulmonology and ced TGF-beta1 but suppressed CTGF in pediatric rheumatology are qualified to preterm lungs. American Journal of Physi-

SELECTED PUBLICATIONS ology: Lung Cellular and Molecular Physio- train MDs in their respective subspecial- logy 292:L223-L231. ties. The Children’s Hospital organizes regularly clinical rounds and educational se- Rutkowski S, Bode U, Deinlein F, Ottens- minars for pediatricians on a regional and meier H, Warmuth-Metz M, Soerensen N, Graf N, Emser A, Pietsch T, Wolff J, Kort- national level. In addition every year scien- mann R, Kuehl J. (2005) Treatment of tific meetings and symposia are organized early childhood medulloblastoma by post- in Würzburg, e.g. every 3rd year the inter- operative chemotherapy alone. New Eng- national symposium “Recent Advances in land Journal of Medicine 352:978-986. Neonatal Medicine“ with participants from Singh SK, Girschick HJ. (2004) Molecular more than 45 nations. Outside of the Uni- survival strategies of the Lyme disease spi- rochete Borrelia burgdorferi. The Lancet 69 Infectious Diseases 4:575-583. 3.11 Department of Internal Medicine I

Professor Dr. med. Georg Ertl dy upward trend) with a variety of diseases hoc procedure. In the cardiac pacema- (Head of the Department) of the veins, arteries, and lymphatic ves- ker outpatient clinic, the rhythm clinic, sels have been admitted to the service. and the ICD outpatient clinic, more than Josef-Schneider-Str. 2 Available diagnostic tools include Doppler 2,500 patients were registered. In co- 97080 Würzburg ultrasonography, vascular CW-Doppler, ple- operation with the Department of Tho- Tel.: 09 31 / 201-36300 thysmographic and optical pulse wave ana- racic and Cardiovascular Surgery, 150 Fax: 09 31 / 201-36302 lyses, treadmill testing, ankle brachial index cardiac pacemaker systems and – for E-mail: [email protected] measurements, and specific laboratory as- the prevention of malignant rhythm dis- http://www.klinik.uni-wuerzburg.de/deutsch/ sessment. Surgical and interventional reva- turbances – 140 ICDs were implanted. einrichtungen/kliniken/MedizinischeKlinikund- scularisation procedures are planned by an PoliklinikI/content.html interdisciplinary team including specialists • Non-invasive Cardiology

CONTACT DETAILS CONTACT from the Departments of Vascular Surgery (C. Angermann, W. Voelker) Professor Dr. med. Bruno Allolio and Interventional Radiology. This diagnostic unit offers the entire ran- Tel.: 09 31 / 201-36209 ge of non-invasive cardiac procedures. In 2007 a total of over 10,000 ECGs, Professor Dr. med. Christiane Angermann Endocrinology and diabetology 1,500 stress-ECGs, 850 24-hour ECGs, Tel.: 09 31 / 201-70460 (B. Allolio) 8,600 2D- and Doppler-echocardio- grams (also including stress and tran- Professor Dr. med. Peter Josef Schanzenbächer 1,145 patients were treated as inpatients sesophageal ECGs), and 850 24-hour Tel.: 09 31 / 201-36347 on the ward of the endocrinology-diabe- blood pressure measurements were tology division in 2007. More than 5,000 performed. The ‘Center of Cardiology Professor Dr. med. Wolfram Voelker patients were seen in two special outpati- at the Medizinische Poliklinik’ serves as Tel.: 09 31 / 201-36328 ent clinics (endocrinology and metabolism, a vital interface between physicians in respectively). A total of some 900 functio- private practices and the Cardiovascu- Professor Dr. med. Christoph Wanner nal diagnostic tests and more than 50,000 lar Center of the University of Wuerzburg Tel.: 09 31 / 201-36330 hormone measurements were carried out offering unrestricted access to all car- in the endocrinology laboratory. Additional- diological and pulmonary examinations ly, more than 300 patients were examined Here, clinical and health care research using thyroid ultrasonography. Since 2003, is closely coupled to routine outpatient this unit has been the reference center for clinical care. In these two outpatient cli- adrenal carcinoma, and more than 90 pati- nics, more than 4,000 patients were at- ents were attended to in the year 2007 alo- tended to in 2007. ne. Regular, structured, and evaluated education programs for patients with diabetes mellitus take place in the outpatient clinic Center for Internal Intensive Care Me- on an individual or group basis. dicine (H. Langenfeld, S. Maier)

Cardiology The center includes an intensive care and a (G. Ertl, J. Bauersachs) critical care unit with 24 beds and an emer- Mission gency room. Here, patients with diseases and Structure • Invasive Cardiology from the entire field of internal medicine are (P. Schanzenbächer) admitted. In 2007, 1,455 and 2,030 pati- The Department of Medicine I includes six In two catheterization laboratories more ents were treated in the ICU and CCU, resections of internal medicine in research, than 3,000 invasive coronary proce- spectively. In the ER, a total of 5,630 pa- teaching, and patient care: angiology, en- dures are carried out per year, 800 of tients were admitted or received outpati- docrinology, cardiology, intensive care medi- which are percutaneous coronary inter- ent treatment. In order to optimize the care cine, nephrology, and pneumology. The de- ventions. In 2007, 150 direct corona- for patients with heart attacks, the Herzin- partment has 57 MD positions and 33 post- ry interventions were performed in pa- farktnetz Mainfranken, was established in doctoral research positions from third-party tients with ST-elevation myocardial in- 2007 and is coordinated by the intensive funding. There are 165 planned beds (inclu- farction. Furthermore, catheter-based care unit. ding an intensive care unit with 24 beds), closure of atrial septal defects and pa- and some 10,000 patients a year receive in- tent foramen ovale were performed in patient treatment. 1,200 outpatients are at- the catheterization laboratory. Nephrology tended to in the emergency room every year. (C. Wanner) More than 12,000 patients are attended to • Electrophysiology in numerous special outpatient clinics. (W. Bauer) In the 5 functional units, patients were at- The electrophysiological division offers tended to as follows: (1) hemodialysis chro- the entire spectrum of interventional nic-inpatient 3,500 treatments, hemodia- Angiology and non-interventional electrophysio- lysis acute renal failure 1,500 treatments, The Division of Angiology has been rapid- logy. In the majority of 380 interven- (2) peritoneal dialysis - IPD and CAPD - 15 ly developing since May 2007. Since that tions a therapeutic high-frequency or patients, (3) ward with 930 patients, (4) time, 60 patients per month (with a stea- Cryo ablation was performed as an ad special outpatient clinics with 2,200 pati-

70 ent contacts: kidney outpatient clinic 520 been initiated by different pharmaceutical patients, vasculitis outpatient clinic 75 pa- companies, are carried out. tients, transplantation postoperative care 110 patients, Fabry Center 133 patients, (5) from 2005-2007, 120 kidney trans- Cardiology plantations were performed (including live Molecular Cardiology donor program). (J. Bauersachs, G. Ertl) Fig. 1: Detection of apoptotic cells by spe- Various teams investigate molecular me- cific MR contrast media in the heart of a Pneumology chanisms of heart failure and cardiac hy- rat after acute ischemia. (M. Schmidt) pertrophy using a broad array of in vitro und in vivo techniques. Among others, experi- 830 inpatients were treated (bronchial car- mental studies on the heart itself as well phy apparatus due to potential interac- cinoma, severe pneumonia, severe COPD as on isolated platelets and cultured car- tions. This interaction is to be minimized or interstitial lung disease). 34 polysom- diomyocytes, endothelial (progenitor) cells in the systems to be developed. It is a nographies and 41 polygraphic screenings and smooth muscle cells are performed matter of an interdisciplinary project bet- were performed on patients with sleeping having already led to potential therapeutic ween Hospital I, physics, and industry. apnea. In the special pneumology outpa- approaches. Most of the research is done There is a large-volume support by the tient department, there were more than in interdisciplinary teams with basic scien- Bavarian Research Foundation (Bayeri- 2,500 patient contacts (outpatient che- tists and clinical researchers from various sche Forschungsstiftung). The develop- motherapy with bronchial carcinoma, in- departments (pharmacology, biochemistry, ment of electrophysiological intervention terstitial lung disease, sarcoidosis, tuber- genetics, psychiatry, psychology, neurology in the MR tomography apparatus is inti- culosis). (see also SFB 688). Prof. Ertl is vice spo- mately connected with this project. 2) The kesman of the “Kompetenznetzwerk Herz- development and application of molecu- insuffizienz”. Current projects: lar/cellular contrast agents. In this inter- • Hormonal regulation of cardiovascular disciplinary research area, both platforms Major Research healing processes (J. Bauersachs) and specific ligands for contrast agents Interests • Junior research group of IZKF “Wound of different imaging modalities are to be Healing Post Myocardial Infarction“ (T. developed. Fields of application include, Endocrinology Thum) among other things, the imaging of arte- (B. Allolio) • BMBF GoBio-1 Program: Functional an- riosclerosis and myocardial healing. This tibodies against cardiac beta1-adrener- unit is supported within the framework of One of the main focuses of the team is on gic receptors and their neutralization by SFB 688. translational and clinical studies on ad- cyclopeptides as an approach in heart renal tumors (particularly adrenal carci- failure treatment (R. Jahns) noma). The German Adrenocortical Car- • Role of innate immunity in cardiac is- VR Simulation in Cardiology cinoma Registry and the first randomized chemia (S. Frantz, G. Ertl) (W. Voelker) international therapeutic study with adre- • Calportin pharmaceuticals (O. Ritter) nal carcinoma (FIRM-ACT-Study) are co- • NO-synthases / oxidative stress and The Department of Medicine I is the main ordinated also with the support of Deut- atherosclerosis (P. Kuhlencordt) organizer of the interdisciplinary center for sche Krebshilfe (German Cancer Aid) and • Na-channel subunits of the heart (S. training and simulation in medicine (INTUS) BMBF. In pre-clinical and clinical studies, Maier) at the University Hospital of Würzburg. VR- new therapeutic targets for adrenal carci- • Echocardiography and rare heart di- Simulation technology (supported by fun- noma are evaluated. In the Max-Eder re- seases: strain rate imaging of regio- ding of the DFG) und several studies to eva- search group of German Cancer Aid, hea- nal myocardial function and the role of luate simulation as tool for education in car- ded by PD Dr. M. Fassnacht, immune-the- non-ischemic fibrosis with hypertrophic diology are performed. rapeutic approaches with adrenal carci- cardiomyopathy (Friedreich Ataxie and noma and – in a sub-project of the clini- Morbus Fabry) and aortic valve steno- cal research group of DFG „Tumor Micro- sis in hypertrophic myocardium in clini- Clinical and Health Care Research in environment“ - the role of glucocorticoids cal long-term studies after pharmaco- Cardiology in tumor immune response are examined. logical and/or surgical therapy (F. Wei- (C. Angermann, S. Störk, G. Ertl) Another main focus is on projects, which demann) have been initiated together with the De- The Unit ‚Cardiologie at the Medizinische partment for Nuclear Medicine, dealing Poliklinik’ has established a clinical trial unit with the implementation of new radioacti- Cardiac MRT and Biophysics Team (in cooperation with the Center for Clinical ve tracers for adrenal imaging, and which (W. Bauer) trials in Leipzig) to facilitate high quality cli- are supported by Sander-Stiftung (foun- nical research dation) and IZKF (Interdisciplinary Center Basically, there are two main areas of re- • Biomaterial bank (>7000 blood samp- for Clinical Research). Moreover, several search: 1) The development of MR-com- les of patients with heart failure) “investigator-initiated“ studies on acro- patible pacemaker – ICD systems. This is • Handheld BNP trial Studie for the pri- megaly, hyponatremia, and adrenal in- due to the fact that the increasing num- mary diagnosis of heart failure (BMBF sufficiency as well as studies on diabe- ber of patients with pacemakers or ICDs Kompetenznetz Herzinsuffizienz) tes mellitus and osteoporosis, which have cannot be examined in the MR tomogra- • Prospective trial ‚rheuma and heart’

71 • Clinical trial ‚Aldo-DHF’ (BMBF Kompe- • Study on clinical benefit of epoetin beta Bauer WR, Nadler W. (2006) Molecu- lar transport through channels and pores. tenznetz Herzinsuffizienz) during chemotherapy of lung cancer. PNAS 103: 11446-11451. • Cohort study ‘Interdisciplinary network heart insufficiency’ (BMBF) Burkard N, Rokita AG, Kaufmann SG, Hall- • Clinical manifestation and managment Interdisciplinary projects huber M, Wu R, Hu K, Hofmann U, Bonz of heart failure (INH-Studie/BMBF) Interdisciplinary cooperation is of particu- A, Frantz S, Cartwright EJ, Neyses L, Maier LS, Maier SK, Renne T, Schuh K, Ritter O. • MOOD-HF trial (therapy of depression in lar significance in the clinical and scienti- (2007) Conditional nNOS overexpression heart failure; BMBF) fic areas of the Department of Medicine I. impairs myocardial contractility. Circ Res • Diagnostic trial ‚BetaAk-HF trail’ (Prof. Such interactions are reflected in the nu- 100:e32-44. R. Jahns, Corimmun GmbH) merous projects which are processed joint- Fassnacht M, Hahner S, Polat B, Koschker ly by several teams within the university. AC, Kenn W, Flentje M, Allolio B (2006) Some examplary projects are listed here: Adjuvant radiation therapy of the tumor Nephrology • Interdisciplinary training and simulation bed prevents local recurrences in adreno- (C. Wanner) center (INTUS): multiple hospitals and cortical carcinoma J Clin Endocrinol Metab. institutes 91: 4501-4504. The main focus is the identification of risk • M.Fabry: nephrology, cardiology Huber RM, Flentje M, Schmidt M, Pöllin- factors for cardiovascular diseases in pati- • Cardiac insufficiency projects: cardiolo-

SELECTED PUBLICATIONS ger B, Gosse , Willner J, Ulm K (2006) Si- ents with diabetes type 2 with chronic renal gy, endocrinology, nephrology, human multaneous chemotherapy compared with disease. Questions are answered in huge genetics, psychiatry, psychology, phar- radiotherapy alone after induction chemotherapy in inoperable stage IIIA or IIIB non- multicenter randomized studies and co- macology, neurology small-cell lung cancer: study CTRT99/97 hort studies. Currently, the biobank of the • Cardiac MR tomography: cardiology, by the bronchial carcinoma therapy group. completed 4D-study – Die Deutsche Dia- physics, chemistry, nuclear medicine J Clin Oncol. 24: 4397-4404. betes Dialyse – is being updated and post- • Development of molecular/cellular con- hoc analyses of the database will follow. trast agents: cardiology, chemistry, phy- Nikolaev VO, Boivin V, Störk S, Angermann CE, Ertl G, Lohse MJ, Jahns R (2007) A The SHARP study (Study on Heart And Re- sics, nanotechnology, nuclear medici- novel fluorescence method for the rapid nal Protection) was started in cooperation ne, dept. of medicine II detection of functional beta1-adrenergic with the university of Oxford. 1,789 pati- • New imaging processes for adrenal tu- receptor autoantibodies in heart failure pa- ents with impaired renal function are taken mors: endocrinology, nuclear medicine tients. J Am Coll Cardiol. 50, 423-431. care of by the coordinating center for cli- Schneider R, Sauvant C, Betz B, Otremba nical studies (ZKS). Questions about the The Department of Medicine I together with M, Fischer D, Holzinger H, Wanner C, Gal- progression of rare renal diseases (e.g. M. the Institute for Clinical Biochemistry super- le J, Gekle M (2007) Downregulation of or- Fabry) are answered by prospective cohort vises the special research grant SFB 688 ganic anion transporters OAT1 and OAT3 studies. The transplantation unit with all pa- “Cardiovascular Cell-Cell-Interaction“ (see correlates with impaired secretion of para- aminohippurate after ischemic acute renal tients is integrated into a huge multinatio- p. 127) and is involved in the DFG Clinical failure in rats. Am J Physiol Renal Physiol. nal study. The coordinating center of KfH Research Groups KFO 124 „Tumor microen- 292: F1599-1605. foundation of preventive medicine is set up vironment“ (see p. 159). In addition, clinici- and is in charge of comprehensive cohort ans and scientists of the hospital are active Terzolo M, Angeli A, Fassnacht M, Daffa- ra F, Tauchmanova L, Conton PA, Rossetto studies. In preclinical studies, pathome- in the several research centers (e.g. car- R, Buci L, Sperone P, Grossrubatscher E, chanisms of the damage and recovery of diovascular center, interdisciplinary center Reimondo G, Bollito E, Papotti M, Saeger ischemic acute renal failure are examined for clinical research, interdisciplinary tumor W, Hahner S, Koschker AC, Arvat E, Ambro- in different mouse models with oxidative center, center for infection research). si B, Loli P, Lombardi G, Mannelli M, Bruzzi stress and regulation of eNOS being taken P, Mantero F, Allolio B, Dogliotti L, Berru- ti A (2007) Adjuvant mitotane treatment in into consideration. Further examinations in patients with adrenocortical carcinoma. N cooperation are carried out for the regulati- Engl J Med. 356:2372-2380. on of transport proteins for organic anions OAT1 and OAT3. Thum T, Galuppo P, Wolf C, Fiedler J, Kneitz S, van Laake LW, Doevendans PA, Mum- mery CL, Borlak J, Haverich A, Gross C, Engelhardt S, Ertl G, Bauersachs J (2007) Pneumology MicroRNAs in the Human Heart: A Clue to (M. Schmidt) Fetal Gene Reprogramming in Heart Failu- re. Circulation 116: 258-267. • Recruitment of lung fibroblasts from Wanner C, Krane V, März W, Olschewski blood fibrocytes and characterization of M, Mann JF, Ruf G, Ritz E (2005) German their homing. Diabetes and Dialysis Study Investigators. • Mobilisation of fibrocytes during chro- Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N nic progressive course and acute exa- Engl J Med. 353: 238-248 cerbation of idiopathic interstitial lung disease. Weidemann F, Niemann M, Herrmann S, • A controlled randomized multicentre Kung M, Störk S, Waller C, Beer M, Breu- study on simultaneous radiochemothe- nig F, Wanner C, Voelker W, Ertl G, Bijnens B, Strotmann JM (2007) A new echocar- rapy of NSCLC IIIB. diographic approach for the detection of • Study on clinical benefit of erlotinib in non-ischaemic fibrosis in hypertrophic my- NSCLC IIIB and IV. ocardium. Eur Heart J. 28: 3020-3026. 72 3.12 Department of Internal Medicine II

Professor Dr. med. Hermann Einsele Mission On an inpatient basis, our hospital is specia- (Head of the Department) and Structure lised in the diagnosis and therapy of all kinds of internal diseases within our focus. More- Josef-Schneider Str. 2 The „Medizinische Klinik und Poliklinik II der over, we provide consiliary service for other 97080 Würzburg Universität Würzburg“ (41 physicians, 74 hospitals in Würzburg and its environs. We Tel.: 09 31 / 201-70000 nurses, technical staff comprising 44 mem- especially focus on the following domains: FAX: 09 31 / 201-70731 bers) is located at two sites in the city of E-mail: [email protected] Würzburg: „Klinikstraße/Röntgenring“ and (1) Diagnosis and therapy of hematologic http://www.klinik.uni-wuerzburg.de/medizin2 „Luitpoldkrankenhaus“. neoplasias (MDS, leukemia, lymphoma, myeloma), including high-dose Professor Dr. med. Ralf Bargou chemotherapy and both autologous CONTACT DETAILS CONTACT Tel.: 09 31 / 201-70150 (1) Klinikstraße/Röntgenring: and allogeneic stem cell transplanta- 1. Specialized outpatients’ departments tion. Professor Dr. med. Herbert Csef (for hematology / oncology; rheumatolo- (2) Diagnosis and therapy of solid tumors, Tel.: 09 31 / 201-70220 gy / immunology, and psychosomatics) including the use of novel drugs and as well as outpatients’ department for immunotherapy. Professor Dr. med. Michael Scheurlen the therapy of haematological and on- (3) Early Clinical Trial Unit: Use of novel Tel.: 09 31 / 201-70170 cological diseases cytostatics, novel antibodies, anti- 2. Department of sonography body constructs; immunotherapeutic 3. Laboratory for routine and research ana- treatment of lymphoma, myeloma, lyses (clinical-chemical and immunologi- leukemia, and solid tumors (gastroin- cal analyses; laboratory for experimental testinal tumors in particular) hematology and rheumatology) (4) Care for and therapy of patients suffe- 4. Department of Molecular Internal Medici- ring from acute and chronic infectious ne (research laboratories; Röntgenring) diseases (with focus on HIV and chronic infectious liver diseases, evaluation of new drugs, phase II-IV studies) (2) Luitpoldkrankenhaus 5) Diagnosis and therapy of rheumatic in- 1. Hematology / Oncology wards named flammatory joint diseases, including Virchow and Magnus-Alsleben the use of novel drugs, immunothe- 2. Center for Stem Cell Transplantation rapy, phase II-II studies 3. Interdisciplinary Oncology – Phase-I/II (6) Diagnosis and therapy of systemic in- Unit flammatory diseases (vasculitis, colla- 4. Department of Infectious Diseases genosisdes, connective tissue …) (Center for Infectious Diseases DGI), (7) Diagnosis and therapy of immune de- comprising Infectious Disease-ward ficiencies (CVID, drug-induced immu- “Schottmüller” and outpatients’ depart- ne deficiencies) ment for infectious diseases (8) Diagnosis and therapy of patients suf- 5. Rheumatology Clinical Immunology ward fering from acute and chronic, benign (Schottmüller) and malignant diseases of the gut and 6. Department of Gastroenterology inclu- liver, including invasive endoscopy ding ward “Romberg” and the outpati- (9) Therapy of patients with psychoso- ents’ department for gastroenterologic matic diseases (e.g. anorexia nervo- diseases. Department for Endoscopy sa) and patients with functional or so- and Sonography matoform disorders. Crisis interventi- 7. Infectiological laboratory/Therapeutic on and psychotherapeutic interventi- Drug Monitoring on in cancer patients 8. „Auvera-Haus“ in Würzburg-Grombühl: Gastroenterologic laboratory, Metabolic suite Major Research The hospital is divided into the following de- Interests partments: • Hematology/Oncology (Prof. Dr. R. Bar- Hematology / Oncology gou) • Gastroenterology (Prof. Dr. M. Scheur- (1) Cellular (gene-modified T cells, tumor len) antigen-specific T cells, γδ T-lympho- • Immunology/Rheumatology (Prof. Dr. cytes) and humoral (antibody-based) H.-P. Tony) immunotherapy of malignant diseases • Infectious Diseases (Prof. Dr. H. Klin- (groups Bargou, Kunzmann, Topp, Gri- ker) goleit, Beilhack) • Section of Psychosomatics (Prof. Dr. H. (2) Function and specificity of human T- Csef) lymphocytes (group Kunzmann)

73 (3) Alterations in tumor metabolism as tar- (2) Genetic imprints of B cell receptor in Chatterjee, M., S. Jain, T. Stühmer, M. An- get for therapeutic intervention in mali- autoimmune diseases drulis, U. Ungethüm, R.-J. Kuban, H. Lor- entz, K. Bommert, M. Topp, D. Krämer, H. gnant diseases (group Kunzmann) (3) Therapeutic modulation of the B cell K. Müller-Hermelink, H. Einsele, A. Grei- (4) Characterization of pathogene-specific repertoire in autoimmune diseases ner, and R. C. Bargou. (2007) STAT3 and immunity and its use in immunothera- (4) Immunoreconstitution in immunologic MAPK signaling maintain overexpression of peutic strategies (Topp) diseases heat shock proteins 90 and ß in multiple myeloma cells, which critically contribute to (5) Characterization of signaling pathways (5) TNF receptor signalling in rheumatoid tumor-cell survival. Blood 109: 720 - 728. in activated T cells and their inhibition arthritis for the treatment of GvH. (AG Stuhler/ (6) Transcriptional regulation of the low-af- Adamopoulou E, Diekmann J, Tolosa E, Grigoleit) finity receptor for IgE(CD23) Kuntz G, Einsele H, Rammensee HG, Topp (6) Regulation of viral T cell immunity th- (7) Pathologic immunoregulation in lupus MS. (2007) Human CD4+ T cells dis- playing viral epitopes elicit a functional rough co-stimulation of antigen-presen- erythematodes (LED) virus-specific memory CD8+ T cell re- ting cells and soluble factors (AG Grigo- sponse. J Immunol. 178:5465-72. leit/Stuhler) (7) Characterization of oncogeneic sig- Gastroenterology Mezger M, Steffens M, Beyer M, Manger C, Eberle J, Toliat MR, Wienker TF, Ljung- naling pathways in multiply myeloma man P, Hebart H, Dornbusch HJ, Einsele and identification of therapeutic target (1) Molecular diagnostics in hereditary

SELECTED PUBLICATIONS H, Loeffler J. (2008) Polymorphisms in the structures (AG Bargou) gastroenterological tumors chemokine (C-X-C motif) ligand 10 are as- (8) Development of molecular and immu- (2) Cognitive, emotional, and somatic sociated with invasive aspergillosis after al- nologic therapy approaches in non-Ho- symptoms in patients with chronic he- logeneic stem cell transplantation and influence CXCL10 expression in monocyte-deri- dgkin lymphoma (AG Knop, Bargou) patitis C infection and antiviral interfe- ved dendritic cells. Blood 111: 534-6. (9) Phase-I unit for the realization of inno- ron therapy vative therapy approaches in hemato- (3) Computer-based subgroup analysis for Melcher R, Al-Taie O, Kudlich T, Hartmann oncologic patients and in patients with quality control and data generation in E, Maisch S, Steinlein C, Schmid M, Ro- senwald A, Menzel T, Scheppach W, Luhrs solid tumors (Bargou). gastroenterological sonography using H (2007). SNP-Array genotyping and spec- (10) In vivo Imaging in models of graft versus standardized electronical patient files tral karyotyping reveal uniparental disomy host disease (GVHD) and immunologic (4) Molecular, cytogenetic and functional as early mutational event in MSS- and MSI- anti-tumor response (group Beilhack) characterization of colorectal, neuro- colorectal cancer cell lines. Cytogenet Ge- (11) Identification of markers for the predic- endocrine, and hepatocellular carci- nome Res. 118:214-21. tion of a looming graft versus host di- noma Roll, P., Palanichamy, A., Kneitz, C., Doer- sease (GVHD) (group Beilhack) (5) Antimicrobial activity of human colon ner, T., Tony, HP. (2006) Regeneration of B (12) Immunoreconstitution after allogeneig epithelial cells, considering in particu- cell subsets after transient B cell depletion stem cell transplantation (AG Grigoleit/ lar cathelicidin LL-37 using anti-CD20 antibodies in rheumatoid arthritis. Arthritis Rheum 54: 2377-2386. Stuhler) (6) Nutritional Medicine: Investigation of (13) Tyrosine kinase inhibitors and their ef- novel functional carbohydrates for the Langmann, P., W. Heinz, H. Klinker, D. fects on different immune cells (T cells, prevention of inflammatory and neo- Schirmer, C. Guhl, M. Leyh, R. Winzer NK cells, DCs)(AG Seggewiss) plastic intestinal diseases as well as (2008). High performance liquid chroma- (14) Novel strategies in allogeneic stem cell diabetes mellitus tographic method fort he determination of HIV-1 protease inhibitor tipranavir in plasma transplantation (cord blood transplan- of patients during highly active antiretroviral tation, haploidentical stem cell trans- therapy. Eur J Med Res 13: 52-58. plantation) Infectious Diseases (15) Aberrant signal transduction in tumor Sutinen, J., U. A. Walker, K. Sevastianova, H. Klinker, A. M. Häkkinen, M. Ristola, H. cells (AG Bargou) (1) Antiretroviral therapy in HIV-infection Yki-Järvinen (2007). Uridine supplementati- (16) DC-vaccination against infectious and (2) HIV-proteasinhibitor-plasma concen- on for the treatment of antiretroviral thera- malignant diseases (AG Grigoleit) trations and resistance development py-associated lipoatrophy – a randomized, (17) Development of vaccination strategies (3) Pharmacokinetic interactions of antire- double-blind, placebo-controlled trial. Anti- against HCMV infections (AG Grigoleit) troviral drugs vir. Ther. 12: 97-105. (18) Selective allodepletion of GVHD-indu- (4) Antiviral treatment strategies in chro- Rincon-Orozco B, Kunzmann V, Kabelitz D, cing T cells as a method for optimizing nic viral hepatitis B and C Wrobel P, Steinle A, Herrmann T. (2005) therapy in allogeneic stem cell trans- (5) Pharmacokinetics of ribavirin Activation of V�9V�2 T cells by NKG2D. J Im- plantation (AG Mielke) (6) HCV/HIV coinfection munology 175:2144-51. (19) Optimization of therapy with taxans on (7) Drug monitoring of antiretroviral Schöttker B, Feuchtinger T, Schumm M, the basis of pharmacokinetic, phar- agents Klinker E, Handgretinger R, Einsele H, macodynamic and pharmacogenetic (8) Uridine pharmacokinetics Stuhler G: (2008) Five donors - one reci- knowledge in patients with solid tu- (9) Systemic antifungal therapy of invasive pient: modeling a mosaic of granulocytes, mors; Screening, prophylaxis, and the- fungal infections natural killer and T cells from cord-blood and third-party donors. Nature Clin Pract rapy of chemotherapy-induced periphe- (10) Therapeutic drug monitoring of azole- Oncol (in press). ral neuropathy (AG Mielke) antifungal agents

Westwood JA, Smyth MJ, Teng MW, et al: Rheumatology / Clinical Immunology (2005) Adoptive transfer of T cells modified with a humanized chimeric receptor Psychosomatics gene inhibits growth of Lewis-Y-expressing (1) Development of the B cell system in tumors in mice. Proc Natl Acad Sci USA autoimmune diseases (1) Psychooncology and Psychoneuroim- 102:19051-6. 74 munology. Palliative medicine and medical ethics. (2) Psychosomatic diseases of the gastrointestinal tract (e.g. irritable bowel syndrome, IBS) and of the cardiovascular system (e.g. stress and myocardial infarction).

Teaching

The „Medizinische Klinik und Poliklinik II“ offers numerous courses for medical students and for postgraduate professional education. Prof. Dr. H. Einsele is certified trainer for the whole field of Internal Medicine. In addition, authorized training and education is available for the following specialties (2 years each): PD Dr. F. Weissinger (He- matology/Oncology), Prof. Dr. M. Scheur- len (Gastroenterology), Prof. Dr. H.-P. Tony (Rheumatology) and Prof. Dr. H. Klinker (In- fectious Diseases). The hospital organizes numerous advanced training courses and scientific meetings for both physicians and patients. Often, patient organizations are involved in planning and realization of the events.

75 3.12.1 Division of Molecular Internal Medicine

Professor Dr. rer. nat. Harald Wajant (Head) Mission litates the designated local activation of and Structure TNF receptors without causing systemic Röntgenring 11 side effects. 97070 Würzburg The scientific focus of the division of Mo- Tel.: 09 31 / 201-710 00 lecular Internal Medicine lies on basic bi- E-mail: [email protected] omedical research and applied clinical in- Research group: death receptors http://www-i.klinik.uni-wuerzburg.de/deutsch/ vestigations in molecular immunology and (D. Siegmund) einrichtungen/kliniken/MedizinischeKlinikund- oncology. Allocation of personnel includes PoliklinikII/abteilungfrmolekulareinneremedi- a scientific research position and part time Death receptors, a subgroup of the TNF re- zin/content.html secretary. Further, a transitory scientific po- ceptor family that includes CD95, TRAILR1 sition (Rotationsstelle) is available for clini- and TRAILR2, were initially studied, becau-

CONTACT DETAILS CONTACT cians of the Department of Internal Medici- se of their strong apoptotic effects. Over the ne II to temporarily pursue full time research last years, we and others could show, ho- that fits into the framework of the division. wever, that these receptors can also acti- This initial option for scientific research is vate pro-inflammatory signaling pathways. aimed to enable scientifically interested cli- This is especially apparent in cells, which nicians to acquire preliminary results offe- are resistant towards death receptor-indu- ring a chance to achieve independent exter- ced apoptosis. As inflammation can enhan- nal funding. The various research projects ce metastasis and angiogenesis of tumor of the division of Molecular Internal Medici- cells, it is possible that initial anti-tumoral ne are currently funded by: effects of death receptors are turned into mechanisms of tumor promotion in apopto- • the German Research Foundation sis resistant tumor cells. Research efforts, • the Mildred Scheel Foundation for Can- within this group, are aimed to characteri- cer Research ze precise conditions, when stimulation of • the German José Carreras Leukaemia- death receptors leads to enhanced metas- Foundation e.V. tasis and aggressive tumor growth. Further, • the Federal Ministry for Education and the molecular mechanisms of pro-inflamm- Research atory signal transduction by death receptors • the Wyeth company and are also investigated. • the Interdisciplinary Centre for Clinical Research of the University of Würzburg Research group: co-operations between TNFR1-TNFR2 (F. Henkler) Major Research Interests TNF, the name giving cytokine of the entire ligand family, occur as a transmembrane The research activities of the department and a soluble protein. The two TNF variants are focussed on the ligands and receptors differ in their capacities to activate TNFR1 of the tumor necrosis factor (TNF) -family and TNFR2. Both TNF receptors can induce and TNF receptor family. The development in a cell type-specific manner the produc- of therapeutic useful recombinant variants tion of their own ligand TNF and show coun- of these molecules and clinically relevant teracting, but also synergistic effects de- aspects of TNF receptor signal transduction pendent on the cell type.The precise cellu- are investigated in three research groups: lar effects of TNF depend therefore on TNF- receptor expression, cell type, extracellular setting and, importantly, on the TNF variant Research group: therapeutic fusions that was used for receptor stimulation (Fig. proteins 1). In this research group, the regulatory principles that cause the exceptional com- Some ligands of the TNF family stimulate plexity of TNF signaling are investigated at the immune system or trigger apoptosis. the molecular level. The potential therapeutic applications of these properties, however, are limited due to the serious side effects that are usually associated with systemic activation of TNF receptors. The research group deve- Teaching lops fusion proteins of TNF ligands that become only robustly activated after bin- Courses, colloquia, seminaries und lectures ding to membrane-associated antigens. related to the research topics of the divisi- Utilisation of ‘targeting domains’ that in- on are offered for students of Biology and teract with tumor specific structures faci- Medicine.

76 Fig.1: TNFR1 and TNFR2 are functionally linked in a highly complex manner. Activati- Berg D, Lehne M, Müller N, Siegmund D, on of TNFR2 by transmembrane TNF leads to degradation of the adapter protein TRAF2 Münkel S, Sebald W, Pfizenmaier K, Wa- (1a,b). Because this protein is important for TNFR1-induced NFκB activation and rec- jant H. (2007) Enforced covalent trimeri- ruitment of anti-apoptotic cIAP proteins into the TNFR1 signaling complex (2a,b’), cells zation increases the activity of the TNF li- are sensitized toward TNFR1-mediated cell death. Stimulation of TNFR1 by soluble TNF gand family members TRAIL and CD95L. can induce NFκB-dependent expression of endogenous TNF (2a-2d). In its membrane- Cell Death Differ.14:2021-2034. bound form, it activates TNFR2 and sensitizes cells again for TNFR1-induced apopto- Trauzold A, Siegmund D, Schniewind B, sis, as described above (2e). Another NFκB-target gene is TRAF1 (2a-c). TRAF1 forms Sipos B, Egberts J, Zorenkov D, Emme hetero-complexes with TRAF2 and prevents its degradation by TNFR2 (2d’). TRAF1 can D, Röder C, Kalthoff H, Wajant H. (2006) therefore disaffect TNFR2-mediated enhancement of TNFR1-induced apoptosis. Further, TRAIL promotes metastasis of human pancreatic ductal adenocarcinoma. Oncoge- TRAF1 does also enhance TNFR2-induced non-apoptotic signal transduction (3a-3c), ne. 25:7434-7439. which contributes both to induction of TRAF1 and transmembrane TNF. Watermann I, Gerspach J, Lehne M, Seu- fert J, Schneider B, Pfizenmaier K, Wajant H. (2007) Activation of CD95L fusion protein prodrugs by tumor-associated proteases. Cell Death Differ. 14:765-774.

SELECTED PUBLICATIONS Henkler F, Behrle E, Dennehy KM, Wi- covsky A, Peters N, Warnke C, Pfizenmai- er K, Wajant H. (2005) The extracellular domains of FasL and Fas are sufficient for the formation of supramolecular FasL- Fas clusters of high stability. J Cell Biol. 168:1087-1098.

Kreuz S, Siegmund D, Rumpf JJ, Samel D, Leverkus M, Janssen O, Häcker G, Dittrich- Breiholz O, Kracht M, Scheurich P, Wajant H. (2004) NFkappaB activation by Fas is mediated through FADD, caspase-8, and RIP and is inhibited by FLIP. J Cell Biol. 77 166:369-380. 3.13 Institute of Clinical Biochemistry and Pathobiochemistry – Central Laboratory (IKBZ)

Professor Dr. med. Ulrich Walter Major Research Clinical Molecular Biology Group (Head of the Department) Interests (M. Zimmer)

Josef-Schneider-Str. 2 The major aim is to elucidate pathophysio- The main focus of the group is elucidati- 97080 Würzburg logical, genetic, and diagnostic aspects of on of genetic causes of cardiac diseases Tel.: 09 31 / 201-45144 / -45479 important cardiovascular diseases (throm- and cardiomyopathies. Currently, the bio- Fax : 09 31 / 20145153 bosis, bleeding disorders, coronary artery di- logical function of a novel dilative cardio- [email protected] sease, stroke, heart failure etc.) by investi- myopathy gene is being investigated. Other http://www.ikbz.de gating murine and human model systems, in areas of study include laminopathies resul- particular with regard to platelets and coagu- ting from haploinsufficiency of the lamin A/ Professor Dr. med. Bernhard Nieswandt lation cascades. The projects are supported C gene, and high-throughput SNP-typing CONTACT DETAILS CONTACT Tel.: 09 31 / 201-44060 by the DFG, a DFG center grant SFB 688 using mass spectrometry. (www.sfb688.de), and other sources inclu- Professor Dr. rer. nat. Michael Zimmer ding industry. Additional Groups Tel.: 09 31 / 3293619 The independent Junior Research Group in Clinical Chemistry (PD Dr. rer. nat., Dr. Research interest of the chairman med. T. Renné, Tel. 0931 201-36116; (U. Walter) [email protected]) supported 2002-2007 as an SFB355/SFB688 Junior Group, investi- A central goal is to elucidate inter- and int- gates the contact activation pathway stimula- ra- cellular signal transduction pathways ted by coagulation factor XII (Hagemann-Fac- which are involved in the inhibition of pla- tor). Loss of factor XII does not increase the telets. A major focus is analysis of the NO bleeding risk in humans or in mice. Surprisin- / cGMP / PKG / VASP (Vasodilator-stimu- gly, FXII deficiency in mice protects against lated phosphoprotein) signal transduction arterial thrombosis and stroke. Therefore, FXII pathway and its cross-talk with pathways is now an attractive target for novel antithrom- stimulated by platelet agonists such as botics which do not pose major bleeding risks. vWF, thrombin and ADP. Previous research A further area of scientific interest entails me- established FACS-analysis of phosphoryla- chanisms for the regulation of endothelial (va- ted VASP (P-VASP) as the most specific scular) permeability with special focus on the laboratory parameter for measurement bradykinin-regulated NO/cGMP/cAMP/VASP of ADP receptor inhibition by antiplatelet signaling pathway. drugs such as Clopidogrel, Prasugrel and Mission others. Within the SFB688 center grant, An independent BayGene Professor of Va- and Structure and in collaboration with Prof. A Sickmann scular Genetics (Prof. Dr. med. Ute Fel- (Rudolf-Virchow-Center) and Prof. T. Dan- bor, Tel: 0931 888-4096; HYPERLINK The institute was founded in 1995, having dekar (Bioinformatics/Biocenter), a sys- „mailto:[email protected]. succeeded a DFG-funded (1989–1995) tems biology approach to platelet analy- de“ [email protected]) Clinical Research Unit. Later, in 2001, the sis is employed. Another group (PD Dr. E. holds a joint appointment with this insti- institute merged with the central diagnostic Butt) investigates (in collaboration with the tute and the Department of Human Gene- laboratory (laboratory medicine) and now Department of Gynecology and supported tics. Major research interests include the consits of the subdivisions by a cancer grant) the biological role of the pathogenesis and molecular diagnostics of a) Clinical Chemistry & Laboratory Medicine human protein LASP-1 for growth and me- cerebral cavernous malformations (CCM1, (including an outpatient hemostasis cli- tastasis of breast cancers cells, also with CCM2, CCM3) which represent inherited nic and a junior research group), and the goal of establishing LASP-1 as a prog- forms of hemorrhagic stroke. (http://www. b) Clinical Biochemistry and Pathobioche- nostic parameter for the spreading poten- baygene.de/pro-dt-3_5a.htm). mistry (Chair & professorships of Vas- tial of these tumor cells. cular Biology and Clinical Molecular Bi- ology The Vascular Biology Group Teaching in research, teaching and patient care. With (joint appointment with the Rudolf Virchow respect to clinical duties, the division of Cli- Center) The institute offers lectures, seminars and nical Chemistry & Laboratory Medicine (di- (B. Nieswandt) practical courses, as well as active participa- rected by Dr. U. Steigerwald) is responsib- tion in research projects, within the area of le for major parts of laboratory diagnostics This group evaluates defects in platelet re- clinical biochemistry & pathobiochemistry and for hospitalized and ambulant patients of ceptors and signaling pathways using ge- laboratory medicine, to undergraduate and the university hospital. The diagnostic areas netically altered murine model systems. A graduate students of medicine, biology, phar- include clinical chemistry, hematology, he- major goal is the elucidation of molecular macy, and chemistry. The institute also parti- mostasis, immunology, serology, molecular mechanisms which regulate adhesion, ac- cipates in the MD-/PhD-program and the In- diagnostics, and emergency diagnostics. tivation and aggregation of platelets. Ulti- ternational Graduate School of Life Sciences. Affiliated with this division is an outpatient mately, these studies should contribute to The Director of the institute is also Medical Di- clinic specializing in disorders of the hemos- development of novel antithrombotic stra- rector of the Training School for Medical Assis- tasis system. tegies. tents (www.mta-schule.uni-wuerzburg.de).

78 Fig. 1: Platelet adhesion to the subendothelium of the injured vessel wall [Sachs U, Nieswandt B (2007) CircRes 100:979-91].

Begonja AJ, Geiger J, Rukoyatkina N, Rauchfuss S, Gambaryan S, Walter U (2007) Thrombin stimulation of p38 MAP kinase in human platelets is mediated by ADP and thromboxane A2 and inhibited by cGMP / cGMP-dependent protein kinase. Blood 109:616-618.

Benz PM, Blume C, Moebius J, Oschatz C, Schuh K, Sickmann A, Walter U, Feller SM, Renné T (2008) Cytoskeleton assembly at endothelial cell-cell contacts is regulated by �II-spectrin-VASP complexes. J Cell Biol, 180:205-219.

Grosse J, Braun A, Varga-Szabo D, Bey- ersdorf N, Schneider B, Zeitlmann L, Han- ke P, Schropp P, Mühlstedt S, Zorn C, Hu- ber M, Schmittwolf C, Jagla W, Yu P, Ker- kau T, Schulze H, Nehls M, Nieswandt B.

SELECTED PUBLICATIONS (2007) An EF hand mutation in Stim1 causes premature platelet activation and bleeding in mice. J Clin Invest 117:3540- 3550.

Grunewald TG, Kammerer U, Winkler C, Schindler D, Sickmann A, Honig A, Butt E (2007) Overexpression of LASP-1 mediates migration and proliferation of human ovarian cancer cells and influences zyxin localisation. Br J Cancer 96:296-305.

Fig. 2: Current model of plasmatic coagulation [Gailani D, Renné T (2007) Art Thromb Zahedi RP, Lewandrowski U, Wiesner J, Wortelkamp S, Moebius J, Schütz C, Wal- Vasc Biol 27:2507-13]. ter U, Gambaryan S, Sickmann A (2008) Phosphoproteome of resting human plate- 79 lets. J Proteome Research 7:526-534. 3.14 Department of Dermatology, Venereology and Allergology

Professor Dr. med. Eva-Bettina Bröcker Mission ducted by Prof. Dr. J. C. Becker und addres- (Head of the Department) and Structure ses several aspects of the biology of cutaneous tumors within the scope of the Klini- Josef-Schneider-Str. 2 The department offers the entire spectrum sche Forschergruppe KFO 124 (http://www. 97080 Wuerzburg of conservative dermatology and dermatolo- tumor-microenvironment.de/index.htm) Tel.: 09 31 / 201-26351 gic surgery in patient care, research and tea- and various third-party funded projects lis- Fax: 09 31 / 201-26700 ching. Residents can obtain a full specialisa- ted as follows: E-mail: [email protected] tion in dermatology and venereology; additio- www-i.klinik.uni-wuerzburg.de/deutsch/ein- nal professional qualifications include allergo- • Tumor stem cells in skin tumors (J.C. richtungen/kliniken/haut/content.html logy, dermatohistology, medicinal tumor the- Becker, R. Houben) (see also figure) rapy and proctology. Apart from the head of • Signal transduction in Merkel cell carci-

CONTACT DETAILS CONTACT Professor Dr. med. Henning Hamm the department, 4 professors of dermatology noma (J.C. Becker, R. Houben) Tel.: 09 31 / 201-26738 and 3 associate professors have been wor- • Melanoma immunology (D. Schrama) king in research and education during the pe- • Melanoma genetics, chemoresistence Professor Dr. med. Jürgen C. Becker riod under report. The department has 9 se- und preclinical testing of innovative the- Tel.: 0931 / 201-26396 nior physicians, 4 further specialists in derma- rapies (S. Ugurel-Becker) tology and 14 assistant doctors. In research • Genesis and molecular diagnostics of projects, 2 natural scientists are employed on melanoma (J.C. Becker, E.-B. Bröcker, regular positions and 10 research associates C. Kauczok) on third-party funds. The department compri- • Cutaneous lymphomas (J.C. Becker, C. ses the following divisions: Kauzcok) • Resistence to therapy of malignant tu- • General outpatient clinic and consultati- mors (M.P. Schön, Ma. Schön): me- ons for specific skin diseases, outpatient chanisms of tumor metastazition, tu- clinic for private patients mor-endothel interactions, resistence • Day clinic to apoptosis, molecular mechanisms of • Wards for conservative dermatology, der- low-molecular substances matooncology and private patients • Apoptotic signal pathways in epithelial • Operating theatre cutaneous tumors (T. Giner) • Outpatient clinic for allergology • Influence of polymorphisms on melano- • Outpatient clinic for phototherapy ma prognosis (J.C. Becker, S. Ugurel- • Dermatohistology, immunofluorescence Becker, D. Schrama) • Laboratory for dermatologic infectiology • Cell migration (P. Friedl): collective in- • Research laboratories vasion of tumor cells; RAS/RAF regulation of tumor invasion; tumor invasion along vessels; multi-photon microscopy Focuses of clinical interest of small tumor masses; cell-based tumor therapy • Dermatooncology (J.C. Becker, E.-B. Bröcker, S. Ugurel-Becker) • Allergology and occupational dermatolo- Immunology and inflammation gy (A. Trautmann) • Autoimmune skin diseases (E.-B. Brö- • Interaction between T-lymphocy- cker, C. Seitz, E. Schmidt) tes and keratinocytes in dermatitis • Hair diseases, hyperhidrosis (H. Hamm) (A.Trautmann, A. Kerstan) • Dermatologic surgery (N. Berens, H. • Imunotherapy with wasp venom as mo- Hamm, G. Weyandt) del for therapeutic immune modulation • Phlebology und proctology (N. Berens, G. in humans (A. Trautmann, A. Kerstan) Weyandt) • Interaction of T-cells with dendritic cells • Pediatric dermatology (H. Hamm) and target cells (P. Friedl) • Dermatologic infectiology (A. Kolb-Mäu- • Leukocyte recruitment in inflammatory rer) skin diseases (Mi. Schön) • Dermatohistology (E.-B. Bröcker, C. • Interaction of dendritic cells with patho- Kauczok) gen microorganisms (A. Kolb-Mäurer) • Signal pathways in the pathogenesis of pemphigus (E. Schmidt) Major Research Interests Genodermatoses Tumor biology and tumor immunology (H. Hamm)

This continuing main field of research initi- Clinical and genetic characterization of ge- ated by the head of the department is con- nodermatoses in cooperation with the Ger-

80 Fig. 1: Tumor initiating cells (tumor stem cells) are resistant to cytotoxic drugs. They may possibly get vulnerable by induction of a suited immune response. man Network for Ichthyoses and Related Curtin JA, Fridlyand J, Kateshita T, Patel Cornification Disorders, the German Net- HN, Busam KJ, Kutzner H, Cho KH, Aiba work Epidermolysis Bullosa and the de- S, Bröcker EB, LeBoit PE, Pinkel D, Bas- partment of dermatology, University of tian BC. (2005) Distinct sets of genetic Maastricht, the Netherlands (BMBF). alterations in melanoma N Engl J. Med. 353: 2135-2147.

de Zwart-Storm EA, Hamm H, Stoeve- sandt J, Martin P. Steijlen PM, van Geel M, Teaching van Steensel MA. (2008) A novel missen- se mutation in GJB2 disturbs gap junction protein transport and causes focal palmo- The entire realm of dermatology, venere- plantar keratoderma with deafness. J Med ology, allergology and dermatooncology is Genet. 45: 161-166. taught to medical and dental students in lectures and practical courses. The depart- Schön MP, Schön M: (2008) TLR7 and ment is also involved in the interdisciplina- TLR8 as targets in cancer therapy. Onco- gene 27:190-199. ry education of medical students and in the degree program biomedicine. Main topics Ugurel S, Schrama D, Keller G, Schaden-

of doctoral theses derive from the research SELECTED PUBLICATIONS dorf D, Bröcker EB, Houben R, Zapat- projects listed above. ka M, Fink W, Kaufmann HL, Becker JC. (2008) Impact of the CCR5 gene polymorphism on the survival of metastatic melanoma patients receiving immunotherapy. Cancer Immunol Immunother. 57: 685- 691.

Wolf K., Wu Y.I, Liu Y., Tam E., Geiger J., Overall C., Stack M.S., Friedl P. (2007) Multistep pericellular proteolysis controls the transition from individual to collective cancer cell invasion. Nat Cell Biol. 9:893- 81 904. 3.15 Institute of Radiology

Professor Dr. med. Dietbert Hahn Duties (Head of the Department) and Structure

Josef-Schneider-Str. 2 The Institute of Radiology is responsible 97080 Würzburg for the entire modern radiological diag- Tel.: 09 31 / 201-34320 nostic at the University Hospital of Würz- Fax: 09 31 / 201-34251 burg. Two professors, 13 senior staff ra- E-mail: [email protected] diologists, 20 residents and scientists as wuerzburg.de well as 53 technicians work together to www.uni-wuerzburg.de/radiologie ensure modern diagnostic imaging within the clinic. The Institute of Radiology in-

CONTACT DETAILS CONTACT Professor Dr. med. Lásló Solymosi cludes a section of Neuroradiology and (Head of the Division Neuroradiology of the of Pediatric Radiology. With 5 Spiral-CT Institute of Radiology) scanners and 4 MRI systems, which are Fig.1: High resolution imaging of the pul- Tel.: 09 31 / 201-34790 available for emergency patients 24 hours monary vessels a day, more than 60.000 people are examined each year. A main emphasis in medical diagnostics is modern sonography. Thus more than 30.000 in- and out- med at the Institute of Radiology with the patients are examined at the University aim of introducing lung MRI in clinical rou- Hospital each year with 6 high end ultra- tine. Special topics are the evaluation of sound systems. A further main topic in the functional information perfusion and diagnostic imaging and preventive medi- ventilation of the lung, the imaging of the cine is the verification of lesions of the morphological structures and the lung va- breast, using mammography, sonography sculature. The interstitial lung disease and and MR-mammography. In order to exclu- mucoviszidosis were evaluated in several de cancer each year about 8.000 women studies. undergo examinations at the Institute of Radiology. A further main task in medical attention for in- and outpatients at the Non-invasive Cardiac Imaging University Hospital is the treatment of di- (M. Beer, C. Ritter, H. Köstler, T.Pabst) seases of the vascular and the bilary system. With the help of modern interventio- One of the major research programs of the nal radiology it is possible to dilate vessels Institute of Radiology is the methodical and with balloon catheters and metal stents in clinical development of non-invasive MR- nearly every part of the body, avoiding the techniques for assessment of coronary ar- risks of an operation. tery disease as well as of secondary non-ischemic cardiomyopathies. Besides the in- The section of Pediatric Radiology offers vestigation of morphological and functional state-of-the art imaging including conventi- parameters, the depiction of possible meta- onal X-rays with a strong focus on radiation bolic alterations using MR-Spectroscopy is protection, ultrasound and magnetic reso- of upmost interest. Additionally, quantitati- nance imaging. Main topics of the section ve first pass perfusion analyses are evalua- of Pediatric Radiology are radiation pediatric tued in several studies. urology, oncological diagnostic, diagnostic of skeletal age and pediatric malformation. Cardiac computed tomography The Institute of Radiology offers a post- (M. Beissert, M. Weininger) graduate training in Radiology including the subspecialities Pediatric Radiology and The availability of high-end multi-slice CT Neuroradiology. scanners using fast rotation times of up to 0.33 seconds has the potential to allow non-invasive cardiovascular imaging. Thus, Major Research a focus of cardiovascular imaging research Focus is the non-invasive imaging of the heart and coronary arteries, evaluating novel imaging Basic Research and clinical investigati- techniques for coronary artery stenosis, as- on of the lung using MRI sessment of myocardial infarction, diag- (T. Pabst, H. Köstler, C. Ritter, M. Beer, M. nosis of acute chest pain, and congenital Beissert) cardiovascular disorders. Ongoing research projects include quantification of coronary Basic research and clinical investigations artery calcifications and CT coronary angio- in the field of lung diagnosis are perfor- graphy

82 Fig. 2: 3-D reconstruction of the heart de- picting the vascular anatomy of the coronary arteries and allowing the diagnosis of a coronary artery aneurysm (white arrow).

Whole-body imaging using magnetic resonance imaging and computed tomography (M. Beissert, M. Weininger, T. Pabst)

Whole-body imaging using state-of-the art magnetic resonance imaging and computed tomography offers new diagnostic possibilities. In oncology whole-body imaging has the potential to allow a new level of flexibi- lity, accuracy and speed to acurately stage patients. Another focus of our research in- Ritter C., del Savio K., Brackertz A., Beer cludes the evaluation of available imaging M., Hahn D., Köstler H.. (2007) Hochauf- methods for the diagnosis of different on- gelöste quantitative MR-tomographische cological diseases. Bestimmung der subendo-und subepimy- okardialen Perfusion unter Stress und in Ruhe. Fortschr. Röntgenstr. 179:945-952.

Pediatric Radiology Weininger M, Ritter C, Beer M, Hahn D, (M. Beer, M. Stenzel) Figure 3: 16 year old boy with c-ALL. Who- Beissert M.. (2007) Evaluation of the opti- le body MR-imaging with T2-weighted se- mal image reconstruction interval for coro- The main focus lies on the development quences (TIRM) at the onset of clinical nary artery imaging using 64-slice computed tomography. Acta Radiol. 48:620-7. and clinical application of high-resolution symptoms demonstrates typical lesions of MR-techniques for the assessment of in- multiple osteonecrosis in both humeri, fe- Köstler H, Landschütz W, Koeppe S, Sey- flammatory and malignant diseases as well mora and tibiae (white arrows). The con- farth T, Remmert H, Lipke C, Sandstede J, as for the investigation of musculoskeletal ventional X-rays showed no pathologies at Spindler M, von Kienlin M, Hahn D, Beer diseases. Main aims are an early and sen- the same time. M.. (2007) Age and gender dependence of human cardiac phosphorus metabolites sitive evaluation of therapeutic regimes wi- determined by SLOOP 31-MR-Spectrosco- thout any radiation exposure. py. Magnet Reson Med 56: 907-11. SELECTED PUBLICATIONS Beer M, Weidemann F, Breunig F, Knoll A, Koeppe S, Machann W, Hahn D, Wanner New MR-acquisition strategies C, Strotmann J, Sandstede J. (2006) Late (H. Köstler) Teaching Enhancement and Fabry Cardiomyopathy: Impact of Enzyme Replacement Therapy New acquisition strategies for magnetic re- Continuing medical education is regularly on Cardiac Morphology and Function. Am sonance images can simultaneously reduce offered for radiologists in private practice, J Cardiol 97:1515–1518. the image noise and improve the resolution. senior radiologists, fellows and residents. Beer M, Wirbelauer J, Buchner S, Fuchs For this purpose density weighted magnetic In addition colleagues from other depart- J, Machann W, Beissert M, Darge K, Hahn resonance sequences will be developed for ments are trained in several diagnostic pro- D, and Köstler H,. (2007) MR-Bildgebung clinical use and investigated systematically. cedures. und Spektroskopie zur Charakterisierung von Kardiomyopathien bei Jugendlichen . Rofo-Fortschr Gebiet Rontgenstrahlen 83 Bildgeb Verfahr 179, 932-937. 3.15.1 Division of Neuroradiology

Professor Dr. med. László Solymosi (Head) technicians, 4 third-party funded residents and 5 research assistants (part-time). Josef-Schneider-Str. 11 97080 Würzburg Due to the regrettable shortage of neurora- Tel.: 09 31 / 201-34790 diological departments in Germany, our in- Fax: 09 31 / 201-34803 stitution accommodates a large and stea- E-mail: a-neuroradiologie@neuroradiologie. dily increasing number of patients from far uni-wuerzburg.de beyond the catchment area of the Universi- www.neuroradiologie.uni-wuerzburg.de ty Hospital per se.

Interventional neuroradiology (i.e. endo- D

CONTACT DETAILS CONTACT vascular treatment of aneurysms, arteri- C ovenous malformations, intracranial neo- A plasms as well as of stenoses and occlusi- B ons of supra-aortic vessels) constitutes a main focus of the department. The num- Fig. 1: Areas of brain volume gain induced ber of treated cases is among the highest by abstinence from alcoholism. in Germany. The Stroke-Unit supplies additional diagnostic and therapeutic tasks. Further emphasis is placed on neuroonco- centric, pediatric neurooncological studies. logy (i.e. diagnostic evaluation of CNS tu- MR-examinations are evaluated to assess mors together with the pediatric, neuros- the therapy of experimental gliomas and urgical and neurological specialties). Close novel MR contrast agents. Third-party fun- collaboration with the Department of Ped- ded. iatric Neurosurgery and of Pediatrics characterizes the second diagnostic focus of pediatric neuroradiology. A quite unique Pediatric Neuroradiology feature of the department pertains to the (M. Warmuth-Metz) neuroradiological diagnostic evaluation of peripheral nerve injuries and myopathi- Close collaboration with the Department of es which attracts patient referrals from all Pediatric Neurosurgery in the diagnosis and over Germany. Pre-surgical functional MR treatment of CNS neoplasms, spinal and imaging is performed for surgical targeting vascular malformations. and prior to cochlear implantaton to limit the surgical risks and to increase the pre- dictable benefits, respectively. MR Imaging of Neuromuscular Diseases Mission (M. Bendszus) and Structure Major Research Animal experiments and clinical studies on The independent Department of Neurora- Interests the detection of peripheral nerve injuries diology is integrated into the Head Clinic of and denervated muscles. the University Hospital Würzburg and was Neuroimaging founded in 1977. All modern diagnostic (M. Bendszus) exams and therapeutic interventions avai- MR-Diffusion Imaging lable to the neuroradiological specialty are This focus is funded by an endowed profes- (A. Bartsch) practiced at the technically highest stan- sorship assigned to Dr. Bendszus in con- dard. The following equipment is linked into junction with the Department of Neurology. Development of new analysis methods for the PACS: a modern digital imaging system Here, new innovative contrast media are in- MR-diffusion data to establish white mat- for X-ray diagnostics, a multifunctional X-ray vestigated in inflammatory and regenerati- ter integrity (e.g. Tract Based Spatial Stati- imaging system with fluoroscopy and DSA ve processes of the central as well as peri- stics) and establishing and testing of diffusi- capability, a multislice CT scanner, a bipla- pheral nervous system. Furthermore, pros- on tractography under aversive conditions. ne digital subtraction angiography system pective studies are conducted on brain re- with flat panel technology and Dyna-CT, a generation after toxic insults (such as from most up-to-date 3T magnetic resonance alcohol) and on the occurrence of specific Functional MR-Imaging (MR) scanner with multi-channel und –nuc- neuropsychological deficits in the course of (A. Bartsch) lear support operated exclusively by the de- various procedures. partment and two 1.5T MR scanners ope- In cooperation with the Depts. of Neurosur- rated in alternation with the radiological de- gery, ENT, Neurology and Psychiatry. DFG- partment. Neurooncology (German Research Council) funded subpro- (M. Warmuth-Metz) ject in the Clinical Research Group on ADHD. Staff: 3 senior physicians, 4 residents, one Characterization and quantification of neuro- resident of the radiological department in The department acts as the neuroradio- nal resting-state networks by fMRI. Mapping neuroradiological training, 9,5 medical logical reference site to all German multi- prior to neurosurgical resections and coch-

84 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).

Participation on therapy studies of inflammatory CNS diseases.

Fig. 2: Aneurysm in the posterior brain circulation before (A, B) and after (C, D) embolization by platinum coils. lear, brainstem and midbrain implants. Ex- on the evaluation of treatment of carotid Bartsch AJ, Homola G, Biller A, Smith SM, amination of the effects of a series of elec- stenoses (SPACE). Weijers HG, Wiesbeck GA, Jenkinson M, troconvulsive therapies and acute alcohol in- De Stefano N, Solymosi L, Bendszus M: gestions on the brain. FMRI and quantified (2007) Manifestations of early brain reco- perfusion in malignant brain tumors. very associated with abstinence from alco- Teaching holism. Brain 130: 36–47. Bartsch AJ, Homola G, Thesen S, Sahmer Interventional Neuroradiology – Vessel- The department participates in the univer- P, Keim R, Beckmann CF, Biller A, Knaus occlusive Therapies sity education of students by conducting C, Bendszus M (2007) Scanning for the (L. Solymosi) lectures and courses within the radiological scanner: FMRI of audition by read-out omissions from echo-planar imaging. Neu- and neuroradiological teaching. The head of roImage 35: 234–243. Endovascular treatment of vascular malfor- the department is authorized to full neuro- mations and highly-vascularized tumors in radiological training (3 years). Bendszus M, Bartsch AJ, Solymosi L. international and national studies. Optimi- (2007) Endovascular Occlusion of Aneu- zation of embolization materials and -tech- The department organizes regular teaching rysms Using a New Bioactive Coil. A Mat- ched Pair Analysis With Bare Platinum niques. Third-party funded. and training events with national and inter- Coils. Stroke 38: 2855-2857. national neuroradiological lecturers. Its staff

is constantly active in various in- and out-of- SELECTED PUBLICATIONS Bendszus M, Stoll G. (2006) Silent cereb- Interventional Neuroradiology – Vessel- house courses (such as refresher programs ral ischaemia: hidden fingerprints of invasive medical procedures. Lancet Neurol 5: recanalizing Therapies at the annual Convention of German Radi- 364-372. (L. Solymosi) ologists and regular neuroradiological training for the Bavarian Medical Association) SPACE Collaborative Group; Ringleb PA, Improvement of the effectiveness of vessel and organizes or instructs various courses Allenberg J, Bruckmann H, Eckstein HH, recanalization. Examination of pharmacolo- at the international level (such as the FSL Fraedrich G, Hartmann M, Hennerici M, Jansen O, Klein G, Kunze A, Marx P, Nie- gical and mechanical recanalization. Diag- & Freesurfer Courses 2006 in Siena and derkorn K, Schmiedt W, Solymosi L, Stin- nostics and interventional treatment of va- 2007 in Cardiff or the Clinical FMRI Course gele R, Zeumer H, Hacke W. (2006) 30 sospasms after subarachnoidal hemorrha- on the Human Brain Mapping Conference day results from the SPACE trial of stent- ges. Part of the SPACE Collaborative Group 2007 in Chicago). protected angioplasty versus carotid en- darterectomy in symptomatic patients: a randomised non-inferiority trial. Lancet 85 368: 1239-1247. 3.16 Department of Nuclear Medicine

Professor Dr. med. Christoph Reiners Emergency Medical Preparedness and As- Institute of Radiobiology the induction, per- (Head of the Department) sistance Network) of the World Health Or- sistence and disappearance of DNA-dama- ganization (WHO). ges are being studied using induced gam- Josef-Schneider-Str. 2 ma-H2AX-foci after radiation exposure to I- 97080 Würzburg 131. As a model, the in-vivo exposition of Tel.: 09 31 / 201-35868 Major Research mononuclear peripheral blood cells of pati- Fax: 09 31 / 201-35247 Interests ents with differentiated thyroid carcinoma E-mail: [email protected] after ablation treatment with I-131 (activi- wuerzburg.de Diagnostics and Therapy of Thyroid Dis- ties of more than 3 GBq) is being used. In www.klinik.uni-wuerzburg.de/nuklearmedizin orders comparison with physical dosimetry, the ex- (Chr. Reiners, M. Luster, J. Biko, P. Schnei- tent and the duration of H2AX-Foci is tes-

CONTACT DETAILS CONTACT Professor Dr. rer. nat. Samuel Samnick der) ted to which extent it reflects the acquired Tel.: 09 31 / 201-35079 radiation dose. The main focus of scientific activities is thyroid cancer, for which in cooperation with the cancer centre, a regional incidence re- WHO/REMPAN-Centre gistry is kept. Of special interest is radiation (Chr. Reiners, R. Schneider, M. Laßmann) Mission induced thyroid carcinoma in children. A and Structure close collaboration exists with our partner The WHO/REMPAN-Centre was accredited institution in Minsk, Belarus, to improve in 2005. Its key activities are the organisati- The department of nuclear medicine is in the diagnosis, therapy and aftercare of radi- onal improvement of the medical treatment charge of all use of open radioactive sub- ation induced thyroid cancer in children. The of radiation accident patients in Germany, stances in humans for research, education department regularly participates in drug the administration of a radiation accident and patient care. Within the scope of the approval studies of new medications for the database as well as training and education interdisciplinary PET centre, close coope- treatment of thyroid carcinoma (i.e. rhTSH in medical radiation accident management rations with many animal research groups and ZD6474). (http://www.rempan.de). As one of the Re- have been established. The division of expe- An important focus in the field of the di- gional Centres for Radiation Protection the rimental nuclear medicine with radiophar- agnostics of thyroid disorders is the stan- department is responsible for the treatment macy is headed by Prof. Dr. S. Samnick. dardization and advancement of ultrasound of patients exposed in occupational radia- To this end a GMP certified radiochemical/ (i.e. fusing 3D-Ultrasound with SPECT in the tion accidents. radiopharmaceutical laboratory is availab- scope of „hybrid thyroid imaging“). le. A cyclotron for radionuclide production The department of nuclear medicine partici- will be installed, after the commissioning of pates in (and is partially in charge of) several Neuromuscular-Skelettal System the new Zentrum für Innere Medizin. Since international epidemiological studies of iodi- (P. Schneider) 2006/2007 a micro-PET scanner has been ne deficiency induced thyroid disorders. available for preclinical research. Studies The quantification of bone mineral con- using small animal SPECT and –ultrasound tent is strongly related to force producing are also possible. Radiation Safety/Medical Physics muscles. The densitometric measurement With the equipment available for clinical rou- (M. Laßmann, H. Hänscheid, S. Schlögl) methods also allow assessment of bone tine (6 gamma cameras, 1 PET, 1 SPECT/ strength, which is one of the main re- CT-gamma camera, 1 thyroid gamma ca- The main point of interest is the field of inter- search focuses. In this context, methods mera, 3 ultrasound, as well as, 3 bone den- nal dosimetry for radionuclide therapy. Cur- were developed, to further assess muscu- sity measuring devices and 1 whole body rently, new imaging procedures like SPECT/ lar properties in humans. These methods counter) the department performs around CT and PET using non standard nuclides are were ceded to the university to file for pa- 15,000 examinations a year. Additionally, being evaluated for dosimetry and are imp- tents. (PCT WO2006/005279 A1; PCT / about 800 in-patients are treated, mainly lemented into clinical practice. In this con- EP2007/005847). for thyroid disorders and about 150 out-pa- text, especially radionuclides are of interest, tients receive treatment for chronic inflam- which can be used for pre-therapeutic dosi- mation of the joints or bone metastases. metry in radionuclide therapy (i.e. I-124). Experimental Nuclear Medicine – Radio- In the biodosimetric laboratory, new methods Another focus of research is the methodical chemistry/Radiopharmacy are being developed to retrospectively deter- development of 3D-ultrasound and high re- (S. Samnick, A. Schirbel) mine the extent of an accidental radiation solution multi-pinhole-scintigraphy for small exposure. The laboratory for iodine analytics organs (thyroid) and small animals. In ad- The work group is in charge of the deve- is an acknowledged reference laboratory for dition, the workgroup is operating a state- lopment of innovative radiopharmaceuticals research studies, in which the amount of licensed whole body counter as an official for imaging and therapy in nuclear medici- stable iodine has to be determined in body li- recording point of the State of Bavaria for ne. The new probes are evaluated precli- quids or the thyroid gland (by means of HPLC the incorporation monitoring workers. nically in-vitro, as well as in-vivo, by using or X-ray fluorescence analysis). small animal imaging (small animal PET and The department serves as a Regional Cen- SPECT). The most promising tracers then tre for Radiation Protection (RSZ) of the Biodosimetry are being further medically assessed in co- Employer’s Liability Insurance Association. (K. Hempel, M. Laßmann, R. Lorenz) operation with clinical partners (please refer It is also a national Collaborating Centre of to subject area oncology, cardiology, neuro- the worldwide REMPAN network (Radiation In close cooperation with the Bundeswehr logy-psychiatry).

86 Fig. 1: Projec- prostate carcinoma F-18-Choline, are ad- phrology, the value of nuclear medicine as- tion image: By ministered. For the imaging of neuroendo- sessment of renal function was determined. using small animal crine tumours, Ga-68-DOTATOC is currently SPECT and the ad- being established. renocortical tracer A special focus in oncology is in develop- Neurology/Psychiatry/Child- and Adole- [123I]Iodometomidate ment; preclinical and clinical assessment of scent Psychiatry (IMTO) it is possib- radiotracers for imaging adrenocortical can- (R. Lorenz, K. Nerlich, A. Schirbel) le to image murine cer (together with the department of endo- adrenal glands (ar- crinology). Here the SPECT tracer I-123-Me- Together with the department of neurology, rows), which have tomidate, as well as, the PET tracer I-124- transcranial ultrasound was compared with a size of less than Metomidate could be successfully establis- dopamine transporter scintigraphy in patients a millimeter in dia- hed. On a compassionate use basis, pati- with Morbus Parkinson and atypical Parkin- meter. A high and ents with untreatable metastatic adrenocor- son syndromes. In children and adolescents specific binding of tical cancer are treated with I-131-Metomi- with attention deficit hyperactivity disorder, the tracer is noted. date. the effect of medical treatment on dopami- For better orientati- ne transport was assessed. For the diagnosis on the kidneys (de- of dementia, an automated parametric image picted in blue) were Preclinical imaging analysing procedure was introduced and eva- also visualized using the kidney specific (M. Kreißl, M. Laßmann, A. Schirbel, S. luated in corticobasal dementia. tracer [99mTc]DMSA. Samnick)

Both, small animal PET, as well as, small Oncology animal SPECT are non-invasive imaging mo- Teaching (R. Lorenz, M. Kreißl, M. Luster, P. Schnei- dalities which are being employed in-vivo to der, S. Samnick, A. Schirbel) evaluate the new radiotracers developed by In a project funded by the „Virtuellen Hoch- the radiochemistry-radiopharmacy group. schule Bayern“, the department of nuclear Together with the ENT-clinic, the localiza- In cooperation with other research groups, medicine, together with the institute for In- tion of the „sentinel lymph node“ in head studies to assess the tumour response to formatics IV, developed an interactive pro- and neck tumours was further optimized. various chemotherapy regimens and to stu- gram for teaching medical students. The For imaging of brain tumours, the radio- dy the regulation of cardiac metabolism in department of nuclear medicine is opera- chemistry/radiopharmacy group made I- Type-2 diabetes are being conducted. ting a CIP-Pool for students and is integra- 123-IMT available. 3D-ultrasound was adapted for the use in ted into the interdisciplinary lecture and se- small animals. It facilitates, after co-regist- minar program in oncological diagnostics. In the field of PET, F-18-FDG is being used ration with small animal PET and –SPECT, a on a routine basis. For brain tumours, F-18- correlation of anatomical with functional ima- FET, as an analogue to I-123-IMT and for ging. Demidchik YE, Demidchik EP, Reiners C, Biko J, Mine M, Saenko VA, Yamashita S. (2006) Comprehensive clinical assess- Cardiology ment of 740 cases of surgically treated (M. Kreißl, R. Lorenz) thyroid cancer in children of Belarus. Ann Surg. 243: 525-32.

At the department of nuclear medicine, the Lassmann M, Haenscheid H, Luster M, influence of the normal reference database Reiners Chr. (2004) The impact of I-131 on the automated analysis of myocardial per- diagnostic activities on the biokinetics of fusion studies was systematically assessed thyroid remnants. J Nucl Med. 45: 619- 25. and the process was further optimized. The effect of physical stress on cardiac function Hänscheid H, Lassmann M, Luster M, was investigated in patients with coronary ar- Thomas Sr, Pacini F, Ceccarelli C, Laden- tery disease (CAD). Furthermore, tracers for son Pw, Wahl Rl; Schlumberger M, Ricard imaging matrixmetalloproteinases, which are M, Driedger A, Kloos Rt, Sherman Si, Hau- gen Br, Carriere V, Corone C, Reiners C known to play a crucial role in CAD and the (2006) Iodine Biokinetics and Dosimetry inflammatory processes after myocardial in- in Radioiodine Therapy of Thyroid Cancer:

farction, are also being developed. SELECTED PUBLICATIONS Procedures and Results of a Prospective International Controlled Study of Ablati- on after rhTSH or Hormone Withdrawal. J Nucl Med 47:648–654. Fig. 2: 58 year old patient with right si- Nephrology-Urology ded adrenocortical adenoma: Five (R. Lorenz, O. Tiedge) Lyshchik A, Drozd V, Demidchik Y, Reiners hours after administration of 184 MBq C. (2005) Diagnosis of thyroid cancer in [123I]Iodometomidate a strong accumu- In cooperation with the children’s hospi- children: value of grayschale and power Doppler US. Radiology. 235 :604-13. lation of the radiotracer is observed in tal and the clinic of urology, the functional the right adrenal gland (left: planar who- scintigraphy on children with dysfunctions of Peinsipp E, Wultsch T, Shahbazian A, le body scintigraphy in a dorsal projection; urinary transport was further optimized. For Edelsbrunner M, Kreissl MC, Schirbel A, right: SPECT & SPECT/CT). Morbus Fabry patients of the clinic of ne- Bock E, Pabst MA, Thoeringer CK, Huber HP, Holzer P. (2007) Experimental gastritis in mice enhanced anxiety in a gender-rela- 87 ted manner, Neuroscience 2007;150. 3.17 Department of Radiation Oncology

Professor Dr. med. Michael Flentje Mission on, tracking of moving targets by means (Head of the Department) and Structure of portal images and external body markers, development of recipes for optimisa- Josef-Schneider-Str. 11 The clinic for radiotherapy (17.5 physici- tion and adaptation of intensity modula- 97080 Würzburg ans, 8 medical physicists, 19 radiogra- ted radiotherapy, dose measurement and Tel.: 09 31 / 201-28891 phers, 16 nurses) uses 5 modern line- dose calculation in inhomogeneous bodies Fax: 09 31 / 201-28396 ar accelerators (including IGRT with an in and for small fields. The aims are effecti- E-mail: [email protected] room cone beam CT), a short distance X- ve sparing of organs at risk and increase www-i.klinik.uni-wuerzburg.de/deutsch/ein- ray unit and afterloading units for remo- of the tumour control rate, hence a higher richtungen/kliniken/strahlentherapie/content. te controlled radioactive inserts. Patients accuracy and safety of treatment with io- html are treated in a policlinic department, in a nizing radiation.

CONTACT DETAILS CONTACT ward with 20 beds in the Kopfklinikum and in a day ward with 10 treatment places. Spiral-CT, ultra sound and a user connec- Prediction of individual radiation sensi- tion to the Institute of diagnostic radiology, tivity especially related to MR-tomography for treatment planning provide the anatomical About 5% of oncology patients treated by and physical basis data for a computerised radiation therapy develop acute or late treatment planning. Planning, dose calcu- radiotoxic effects, the molecular mecha- lations and the calibration of the treatment nisms of which remain poorly understood. units are carried out by the section of me- Our radiobiological laboratory (2 scien- dical physics (8 physicists, 2 technicians). tists, 2 technicians, 6 grant positions) is About 2200 patients (mainly ambulatory) appropriately equipped to carry out basic are treated annually. By means of the day research of the biological effects of io- ward it is possible to avoid hospitalisation nizing radiation in human cells. We have also in more intensive parts of the treat- evaluated the potential role of the chro- ment (concurrent chemotherapy, treat- matin structure, genomic instability, DNA ment of acute side effects). In addition to repair proteins and several other factors the typical spectrum of a modern radiati- in the hypersensitivity of cancer patients on therapy special techniques are offered to radiation therapy. Using the fibroblasts like intra and extracranial radio surgery, to- of hypersensitive cancer patients, neither tal body irradiation before stem cell trans- the clonogenic survival assay nor Western plantation, contact irradiation for tumours blot analysis of DNA repair proteins re- of the eye and interstitial brachy therapy vealed any abnormalities in the cellular of tumours in the head and neck, prosta- radiosensitivity in vitro and in protein ex- te, abdominal tumours, and tumours of the pression levels or migration patterns. In extremities after implantation of catheters contrast, in vitro irradiated cells from ra- or permanent seeds. diosensitive patients exhibited a significantly higher number of nuclei with focal- ly concentrated DNA repair protein Rad50 Major Research than that in control groups (see Fig. xx). Interests The observed alteration of the distribution of radiation-induced Rad50 foci in cells Development of conformal treatment derived from cancer patients with acute techniques side reactions to radiotherapy might contribute to their radiation therapy outcome. The realisation of an optimal dose concen- In a recent study, we also found, using the tration in the tumour forms a major part micronucleus test, that cells from cancer of the research effort. The development of patients with an adverse skin reaction stereotactic techniques in the region of the to radiotherapy displayed increased fre- body, the development of inverse planning quencies of both spontaneous and radia- techniques using intensity modulation and tion-induced micronuclei as compared to dynamic multi leaf collimators and integra- healthy control or the group of unselected tion of time dependent changes (intra- and breast cancer patients. interfractional) are part of this.

Clinical trials and quality assurance Medical physics The department is responsible for the con- Research concerns image guided radio- ception and realisation of radiation thera- therapy, optimisation and adaptation of py in national and international therapy stu- dose distributions and dosimetry. Topics dies for head and neck tumours and lung are: patient positioning, image registrati- cancer.

88 Fig. 4: Immunofluorescence analysis of nuclear hMre11 (red fluorescence) and Rad50 (green fluorescence) foci in irradiated skin fibroblasts derived from a healthy individual (top images) and from a cancer patient with increased early reaction to radiotherapy (HS fibroblast, bottom images). Fig. 1: Solitary metastasis of the spine (Salivary gland carcinoma). Dose distribution with Cells were irradiated with 8 Gy, fixed 2 h chord sparing. Two years after 20 x 3 Gy image guided radiotherapy recalcification and post-irradiation and double stained with persistent local control has been achieved. No treatment related side effects. anti-hMre11 and anti-Rad50 antibodies. Left-hand images show DAPI staining of the nuclei. A protracted Rad50 foci formation was found in irradiated cells derived Major contributions concern randomized from cancer patients with increased early studies for organ preservation in Larynx/hy- reactions to radiotherapy. Moreover, the- popharynx Cancer (Delos 2) and in cinciur- se cells displayed also an increased num- rent radiochemotherapy in advanced lung ber of Rad50 foci per cell after irradiation cancer (GILT-CRT). A quality circle for Unter/ (bottom images). Oberfranken as well as the radiation safety board (§ 83 StrSCHV) of Bavaria is chaired by the director of the department.

Guckenberger M., Meyer J., Wilbert J., Baier K., Bratengeier K., Vordermark D., Fig. 2: Test set-up for tracking a moving Flentje M. (2007) Precision required for object in order to keep it within the thera- dose-escalated treatment of spinal meta- py beam. stases and implications for image-guided radiation therapy (IGRT). Radiother. Oncol. 84:56-63.

Guckenberger M., Wilbert J., Krieger T., Richter A., Baier K., Meyer J., Flentje M. (2007) Four-dimensional treatment planning for stereotactic body radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 69:276- 285.

Meyer J., Wilbert J., Baier K., Guckenber- ger M., Richter A., Sauer O., and Flentje M. (2007) Positioning accuracy of cone- beam computed tomography in combination with a HexaPOD robot treatment table.

SELECTED PUBLICATIONS Int. J. Radiat. Oncol. Biol. Phys. 67:1220- 1228.

Meyer J., Richter A., Baier K., Wilbert J., Guckenberger M., and Flentje M. (2006) Fig. 3: Conical “organ at risk” surrounded Tracking moving objects with megavolta- by a target volume. Left: Rotation irradiati- ge portal imaging: a feasibility study. Med. on. Right: 2-Step Intensity modulated arc Phys. 33:1275-1280. therapy. The additional 2-Step IMAT seg- Djuzenova C.S., Mühl B., Fehn M., Op- ment remarkably increases the dose ho- pitz U., Müller B., Flentje M. (2006) Ra- mogeneity. diosensitivity in breast cancer assessed by the Comet and micronucleus assays. Brit. 89 J. Cancer 94:1194-1203. 3.18 Department of Oto-Rhino-Laryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery

Professor Dr. med. Rudolf Hagen Mission the institute of clinical biochemistry and (Head of the Department) and Structure pathobiochemistry, U. Walter, and the Univ. ORL-Department Bochum, St. Dazert) Josef-Schneider-Str. 11 The clinic of Otorhinolaryngology, plastic 97080 Würzburg and aesthetic surgery (28 physicians, 5 sci- Effects of reversible and irreversible ototoxi- Tel.: 09 31 / 201-21701 entists, 8 research fellows) has 113 regular cal substances on the active cochlear amp- Fax: 09 31 / 201-21248 beds including 4 intensive care units. Besi- lifier system to further investigate pathophy- E-mail: [email protected] des the complete basic care in the field of siological processes in inner ear diseases; www.hno.uni-wuerzburg.de ORL there exist the following clinical speci- in vitro and in vivo investigations of neuro- alities: device based and surgical supply of trophic substances (FGFs, NT-3, CNTF, LIF) Prof. Dr. med. Norbert Kleinsasser all kind of hearing disabilities by special di- on survival and growth patterns of hair cells CONTACT DETAILS CONTACT Tel.: 09 31 / 201-21322 agnostics, conventional middle ear surgery, and spiral ganglion neurite extension in new active middle ear implants, implantab- the mammalian cochlea; effects of recom- le hearing aids as well as cochlear implan- binant adenoviruses on cochlear cells to tation (international reference centre), in- transducer cochlear tissues for future gene terdisciplinary skull base surgery (tumours, therapy, inner ear and hearing development traumas), diagnostics and therapy of head in CNTF and LIF knockout mice, creation of and neck tumours with main focus on or- transgenetic mice with a cell specific gene- gan and function preserving and microsur- knock-out in cochlear and spiral ganglion gical techniques and plastic-reconstructive cells; investigations of function of vasodi- surgery, national reference centre for surgi- lator stimulated phosphoproteins (VASP) in cal treatment of pediatric sarcomas, pho- terminal hair cell innervation. niatrics (including phonosurgery), pedaudi- ology, allergology, sleep medicine (devices based and surgical treatment), neurootolo- Pedaudiological tests and newborn hea- gy, plastic and aesthetic interventions of the ring screening head and neck. Support of foreign ORL cli- (W. Shehata-Dieler, C. Völter, R. Keim) nics in all continents by visitant professorships and practical education of foreign ENT Testing of hearing in all newborns by means doctors. National and international surgical of complete screening, application and courses with 3D-Video-Live-Transmission of comparison of different objective audiolo- surgical interventions. gical testing methods, development of new testing devices, specification of auditory neuropathy in children by special studies. Major Research Interests Cochlear- and brain stem implants Middle ear biology (J. Müller, W. Shehata-Dieler, A. Radeloff, S. (R. Mlynski, M. Schmidt, R. Hagen) Brill, S. Kaulitz in cooperation with the department for neurosurgery and the Univer- Histological morphometry and surface cha- sity of Innsbruck, Austria) racteristics of middle ear implants; immunology and immunhistology of cholesteato- Investigations to improve speech intelligi- mas for research of origin and maintenance bility following cochlear implantation, de- of chronic otitis media, expression of bone velopment of new surgical techniques and morphogenetic protein-2, MMP-9 and cyto- innovative implant models, physiology and kines in cells of cholesteatoma. pathophysiology of the auditory pathway following uni- and bilateral electro stimulation considering functional anatomical correlati- Biophysics of middle ear ons while stimulating different parts of the (J. Müller, S. Brill, F. Kraus, R. Hagen) auditory pathway.

Investigations of middle ear structures as a dynamic-mechanical system in sound Experimental audiology transmission processes using LASER vibro- (M. Cebulla, R. Keim) metry; EDP supported documentation and evaluation of surgical and audiological out- Further development of diagnostic tools for come in patients with tympanoplasty and objective frequency specific measurement implantation of electronic hearing devices. of the absolute threshold of hearing, stan- dardisation of different methods of acou- Inner ear biology metry, investigations in the fine structure of (R. Mlynski, M. Bürklein in cooperation with responses to click-stimuli in comparison to the institute of neurobiology, M. Sendtner, transit time corrected stimulation.

90 Hearing research Tissue engineering in laryngology (M. Vollmer, T. Bremer in cooperation with (N. Kleinsasser, K. Frölich, K. Kampfinger, the University of California, Prof. Beitel, and A. Technau) the Ludwig-Maximilians University Munic, Prof. Grothe) Establishment of stabile cartilaginous structures with different scaffold materials. Animal experiments in gerbils for investigation of central neuronal interactions in electric acoustical stimulation of the cochlea, central neuronal processing of interaural Teaching time differences (ITDs) in acoustical and electrical stimulation of the cochlea, effects Coworkers with postdoctoral lecture quali- of long term deafening to temporal and spa- fication take part in the medical main lec- tial discrimination of intracochlear electrical ture and in the clinical courses for medical stimulation in the colliculus inferior and the students. Initiation and coaching of experi- primary auditory cortex, psychophysical and mental and clinical medical dissertations. neuronal models for temporal integration of Annual german and english speaking surgi- electrical stimuli, neurotrophic effects of cal courses for microsurgery of the ear, skull GM1 gangliosides and electrical stimulati- base surgery, phonosurgery, reconstruc- on to spiral ganglion cells following neona- tive laryngeal surgery, endonasal surge- tal deafening ry with live-3D-transmission and practical exercises for consultants. The foreign twin clinics are served by course instructors Tumour biology and functional rehabili- (DAAD) in all the participating countries, 4 tation following tumour surgery training fellowships for practical education (R. Hagen, M, Schmidt, M. Scheich) (actually doctors from China, Mongolia, Ka- sachstan, Peru). Full-time hospitations for Molecular biological investigations in head consultants. and neck carcinomas (HNC), induced expression of a deletional mutant of Pseu- domonas exotoxin A in cell lines of HNC, development of a new control plasmid by subcloning (pGeneA-EGFP), investigations in chemotaxis and angiogenesis of tumour cells, effects of herbal anti-tumoural ex- tracts on paclitaxel sensitive and – resistant HNC cell lines, development of new Buehrlen M, Harréus UA, Gamarra F, Ha- surgical reconstructive techniques of larynx gen R, Kleinsasser N: (2007) Cumulative and trachea. genotoxic and apoptotic effects of xenobi- otics in a mini organ culture model of human nasal mucosa as detected by the al- Functional magnetic resonance ima- kaline single cell microgel electrophoresis assay and the annexin V-affinity assay. To- ging xicol Lett 169:152-161. (C. Knaus, M. Unkelbach, M. Bendzus, L. Solymosi, A. Bartsch) Elberling C, Don M, Cebulla M, Stürzebe- cher E: (2007) Auditory steady-state responses to chirp stimuli based on coch- Development of new techniques for testing lea travelling wave delay. J.Acoust Soc the auditory pathway in cooperation with 122:2772-2785. the institute of neuroradiology Mlynski R, Volkenstein S, Hansen S, Bro- ros D, Ebmeyer J, Dazert S: (2007) Inter- action of cochlear nucleus explants. Laryn- Ecological toxicology of the upper aero- goscope 117:1216-1622. digestive tract (UADT)

(N. Kleinsasser, C. Köhler, C. Ginzkey, G. SELECTED PUBLICATIONS Martinez R, Setien F, Voelter C, Casado Friehs) S, Quesada M, Schackert G, Esteller M: (2007) CpG island promoter hyperme- thylation of the pro-apoptotic gene cas- Investigations on the toxicological effects pase-8 is a common hallmark of relapsed of ecological toxins in tumour initiation tes- glioblastoma multiforme. Carcinogenesis ting human tissue cultures of the UADT, 28:1264-1268. characterisation of genotoxical effects of Vollmer M, Beitel RE, Snyder RL, Lea- tobacco smoke and environmental toxins ke PA: (2007) Spatial selectivity to intra- (nitrogen dioxide) on mini organ cultures cochlear electrical stimulation in the in- of UADT. ferior colliculus is degraded after long- term deafness in cats. J.Neurophysiol 98: 91 2588-2603. 3.19 Department of Ophthalmology

ProfessorDr. med. Dr. h.c. Franz Grehn Mission (Head of the Department) and Structure

Josef-Schneider-Str. 11 A staff of 29 physicians and 76 nur- 97080 Würzburg ses, technicians and scientists cares for Tel.: 09 31 / 201-20601 18.000 outpatients and more than 5.500 Fax: 09 31 / 201-20245 inpatients annually. In 2007, more than E-mail: [email protected] 6.500 surgical procedures and 1.500 la- www.augenklinik.uni-wuerzburg.de ser treatments were performed. As one of the largest eye hospitals in Germany, we Professor Dr. med. Gerd Geerling provide the full range of medical and sur- CONTACT DETAILS CONTACT Tel.: 09 31 / 201-20610 gical eye care and diagnostics. The hospital comprises a renowned glaucoma center Professor Dr. med. Heimo Steffen with distinct experience in pediatric glau- Tel.: 09 31 / 201-20487 coma. The retina service specializes in reti- novitreal diseases and ocular trauma. Spe- cialized teams care for eyelid affections, Fig. 1: Crosslinked actin cytoskeleton me- conjunctival, corneal and orbital diseases shworks (CLANs) in human trabecular me- as well as childhood eye diseases, neuro- shwork cells. CLANs may have a role in ophthalmological disorders or strabismus. defective intraocular pressure regulation in An increasing number of patients treated glaucoma. Colocalization of F-actin (red) for eye disease suffers from multiple sys- and smooth muscle actin (green). temic ailments and requires inpatient care. At the same time it is our goal to improve and expand outpatient surgery facilities to provide the best possible care for all pa- these techniques were adapted to study tients. lateral retinal interactions, to characterize genetically encoded maculopathies, to determine retinocortical transmission speed, and to study basic mechanisms in Major Research visual perception (e.g. long-term poten- Interests tiation).

Clinical Research Biometry and Optics Research activities focus on the fields of The proper selection of lens implants in ca- cornea, glaucoma and retina. New strate- taract surgery rests on an accurate deter- gies are developed to treat ocular surface mination of intraocular distances. Interna- disease, novel wound healing modulation tionally renowned for its research and de- techniques are assessed to prevent scar- velopment, the biometry lab has played a ring following glaucoma surgery, new agents crucial role in the emergence of laser in- to treat age-related macular degeneration terference biometry techniques as the cur- are evaluated and genetic glaucoma pre- rent gold standard. Two instruments that disposition is studied. The glaucoma center are now widely used in clinical practice leads the clinical assessment of innovative were developed in a close ongoing colla- methods to measure intraocular pressure boration with Carl Zeiss Meditec AG. Ano- and develops new electronic data acquisi- ther focus of the lab is the development of tion and management networking systems algorithms to validate refractive implants. to improve national and international colla- These algorithms are being tested in an in- borations in patient care. ternational network and are provided to the scientific community as an open access internet resource. Basic Research

Electrophysiology Cell Biology Minimally invasive electrophysiological Ocular wound healing, intraocular pressu- methods allow for a differential examina- re regulation and ocular surface regeneration of distinct components of the visual tion are at the focus of the cell biology lab. pathway. The electrophysiology lab deve- Central to these issues are cell-cell and lops and validates new recording methods cell-matrix interactions which drive cellu- and specializes in multifocal techniques lar signal integration mechanisms to direct to simultaneously detect signals from dis- and coordinate cell functions. Based on tinct areas in the visual field. Recently, these mechanisms, specific kinase inhibi-

92 Fig. 3: Subretinal neovascularization in “wet” age-related macular degeneration. Fluid is leaking from newly formed vessels, thus leading to distorted vision and concomitant decline in visual acuity due to retinal edema. Subretinal lipid deposits (dru- sen) appear as white dots. Fluorscence angiogram.

Fig. 2: Optic nerve head of a glaucoma patient with a diminished optic nerve fiber layer.

tors were characterized as wound healing modulators in vitro and are currently being Grehn F, Hollo G, Khaw P Overton B, Wil- tested in advanced models. Similarily, the son R, Vogel R, Smith Z. (2007) Factors role of tissue elasticity emerges as an im- affecting the outcome of trabeculecto- portant determinant of trabecular mesh- my: an analysis based on combined data work cell functions with possible implica- from two phase III studies of an antibody tions in glaucoma. to transforming growth factor beta2, CAT- 152. Ophthalmology 114: 1831-8.

Meigen T, Krämer M. (2007) Optimizing electrode positions and analysis strategies for multifocal VEP recordings by ROC ana- Teaching lysis. Vision Res. 47: 1445-54. Meyer-ter-Vehn T, Sieprath S, Katzenber- Lectures, practical training and special ger B, Gebhardt S, Grehn F, Schlunck G. interest seminars are offered to medical (2006) Contractility as a prerequisite for students. The residency program compri- TGF-beta-induced myofibroblast transdifferentiation in human tenon fibroblasts. In- ses daily morning rounds with case pre- vest Ophthalmol Vis Sci. 47: 4895-904. sentations and a weekly CME-certified se-

minar series that is also open to guest SELECTED PUBLICATIONS Keilhauer CN, Meigen T, Weber BH. visitors. Another series of four extensive (2006) Clinical findings in a multigenera- tion family with autosomal dominant areo- seminars per year is dedicated to update lar choroidal dystrophy associated with an colleagues in private practice on the most Arg195Leu mutation in the peripherin/RDS recent developments in the field. In ad- gene. Arch Ophthalmol. 124: 1020-7. dition, the University Eye Hospital hosts regional and international ophthalmology Weisschuh N, Dressler P, Schuettauf F, Wolf C, Wissinger B, Gramer E. (2006) conferences. Novel mutations of FOXC1 and PITX2 in patients with Axenfeld-Rieger malformations. Invest Ophthalmol Vis Sci. 47: 3846- 93 52. 3.20 Department of Neurosurgery and Division of Pediatric Neurosurgery (until October 2007)

Professor Dr. med. Klaus Roosen modern technological devices such as neu- (Head of the Department) ronavigation, neuro-endoscopy, intraoperative ultrasound and micro-dopplersono- Josef-Schneider-Str. 11 graphy as well as continuous neuro-anes- 97080 Würzburg thesiological and neuro-physiological mo- Tel.: 09 31 / 201-24800/-24801/-24802 nitoring. Special interdisciplinary treatment Fax: 09 31 / 201-24635 protocols have been established for pati- E-mail: [email protected] ents with vascular malformations (in close http://www.klinik.uni-wuerzburg.de/deutsch/ cooperation with the Department of Neu- einrichtungen/kliniken/nch/content.html roradiology), furthermore for patients with brain tumours together with radiotherapists

CONTACT DETAILS CONTACT Professor Dr. med. Niels Sörensen and neuro-oncologists as well as for skull Fig. 1: Electrode array of an auditory brain (Head of Division of Pediatric Neurosurgery) base lesions, namely vestibular schwanno- stem implant placed onto the brainstem. Tel.: 09 31 / 201-24803/-24804 mas and meningiomas with ENT surgeons. Spine surgery for complexe neoplastic and Professor Dr. med. Cordula Matthies neurovascular lesions as well as for dege- Tel.: 09 31 / 201-24808 nerative disease is performed at high inci- proaches for human brain disease using dence and for certain indications together cell culture and animal models of brain Professor Dr. Anna-Leena Sirén with colleagues from orthopedic and trau- trauma. The group could recently report Tel.: 09 31 / 201-24579 ma surgery. on brain atrophy and late cognitive deficits after experimental neurotrauma that Regular conferences on quality control gua- can be prevented by early neuroprotecti- rantee an ongoing high standard in routine ve treatment with the anti-apoptotic and and in most sophisticated operations. neurotrophic growth factor erythropoietin. Neuroprotective signalling cascades are Mission being explored in cell culture and transge- and Structure nic animal models. On-going animal work Major Research focuses on regeneration using growth fac- The Department of Neurosurgery employs Interests tor and cell based therapies for brain inju- 22 medical doctors, 3 scientists, 96 nur- ry and on the changes in synaptic struc- ses and 4 technicians. The clinical wards Brain injury: Neurovascular neuro-inten- tural plasticity and their impact on func- are comprised of a total of 87 beds with sive medicine tional deterioration after brain injury using single, double and triple patient rooms and (E. Kunze, T. Westermaier) newly established in vivo 2-photon micro- an intensive care unit of 20 beds provi- scopy-based imaging. A proof-of-concept ding treatment for patients with cranial and Main focus of research is on monitoring and clinical study is aiming at better prediction spinal trauma, vascular malformations and maintenance of cerebral oxygenation and of outcome using dynamic mathematical spontaneous hemorrhage, with brain or spi- brain metabolism in acute brain disease modeling of the complex pathophysiologi- nal cord surgery as well as early neurologi- (bleeding/ stroke/ cerebrovascular disease/ cal cascades after traumatic brain injury. cal rehabilitation within a subunit for inter- traumatic brain injury/ increased intracrani- mediate care. The operating unit consists al pressure). Besides invasive monitoring, of 4 operating theatres and one additional transcranial dopplersonography and perfu- Functional Neurosurgery: Functional Mi- OR for out-patients and emergencies. Over sion imaging are used for control of vascu- crosurgery & Neurostimulation the passed 5 years (2003-2007) 1700 to lar dynamics in the clinical setting during (C. Matthies) 2000 patients were treated surgically and surgery and neurosurgical intensive care 4000 to 4600 patients in the out-patient as well as in the experimental setting using Functional microsurgery is the refined mi- department. The latter offers consultation animal models. These approaches are com- crosurgical technique guided by online infor all neurosurgical diagnoses in speciali- bined with electrophysiological techniques formation from continuous neurophysio- zed clinics such as brain tumors, degene- in order to develop novel brain tissue saving logical monitoring. This optimized method rative spine and disc disease, pain synd- therapeutic strategies, especially to coun- of micro-neurosurgery provides a break- romes, peripheral nerve lesions, pituitary teract vasospasm. Further studies deal with through for achieving microsurgical cure tumors and dysfunction, neurovascular di- the comparison of interventional and surgi- of pathologies at the skull base, brains- sease, skull base tumors (jointly with De- cal aneurysm treatment and with dural ar- tem, medulla and specific functional partment of ENT) and movement disorders teriovenous fistulas. brain areas along with functional integrity (jointly with Department of Neurology). of neural structures. Prospective clinical studies are being run on improving current Infants and children with inborn malforma- Brain injury: Translational neurotrauma techniques of monitoring and adapting tions of the nervous system and of the skull research them to the microsurgical process. Motor and spine as well as children with neoplasia (A-L Sirén) evoked potentials of the cranial nerves in and trauma are taken care of by the Division comparison to conventional electromyo- of Pediatric Neurosurgery. Main focus of research is on the mecha- graphy monitoring and the improved con- nisms of neuroprotection and regenera- trol of the auditory pathway are main to- The whole range of neurosurgery is perfor- tion after brain injury and translation of pics. Neurostimulation therapy has been med at latest technique and supported by this knowledge into new therapeutic ap- established at the clinic and is scienti-

94 fically investigated for two clinical indications: 1. retrocochlear deaf- Teaching ness and 2. movement disorders. 1. For retrocochlear deafness an Weekly neurosurgical lectures and as- ongoing cooperation with the De- sociated bedside teaching are offered to partment of Otorhinolaryngolo- medical students of all clinical years. Third gy has been extended and, since and fourth years students undergo a joint 2006, has been acknowledged as introduction to neuro-intensive medicine, a centre for “new diagnostic and neurological-neurosurgical history taking treatment modalities” (NUB) in and examination in a cooperative teaching the application of auditory brains- programme by the Departments of Neu- tem implants. Clinical studies on rology and Neurosurgery. Throughout the patient selection, brainstem side year medical students of the last clinical and site selection and on sophis- year may perform their period of choice or ticated intraoperative neurostimu- an elective period and are fully integrated lation tests are been carried out into the clinical programme and supervised along with application of latest sti- by neurosurgeons and consultants. At the mulation strategies with very en- Section of Experimental Neurosurgery, the couraging results. 2. In 2005, in Laboratory of Tumorbiology and the Neuro- cooperation with the Departments Fig. 2: Excitatory synapses in hippocampus-neu- physiology Laboratory students from medi- of Neurology, Neuroradiology and ron-cultures (double-immunofluorescence for pre- cine and related sciences as well as post- Psychiatry high frequency stimula- synaptic marker synapsin-1 (green) post-synaptic doc students are integrated to perform tion therapy has been started for density (red)). their thesis or diploma within the research movement disorders (tremor, dys- programmes. tonia and Parkinson’ disease) in patients with fluctuating response to me- malignant tumors are further focus of cur- dication or medication side effects. Ste- rent interests. reotaxy guided electrode implantation in the basal ganglia is performed for intra- Benign pathologies operative micro-recording and micro-sti- For investigation of tumor biology in benign mulation tests in the thalamus, pallidum pathologies such as schwannomas and me- or subthalamic nucleus. The established ningiomas, cooperations have been estab- indications for deep brain stimulation are lished in national and international settings. extended after careful investigation for ex- Especially, factors such as cell de-differenti- Flaiz C, Kaempchen K, Matthies C, Hane- ample for patients with previous ischemic ation, adhesion molecules, tumor invasion, mann CO: (2007) Actin-rich protrusions brain lesions and life threatening dysto- promotors of apoptosis are targets of inves- and non-localised GTPase activation in nic storms. A further newly developing to- tigation and are being compared for diffe- merlin-deficient schwannomas. J Neuropa- pic is the combination of neuroprotective rent clinical courses despite identical histo- thol Exp Neurology 66: 608-616. and regenerative factors (See above Siren logy. A basis for these laboratory investiga- Rutkowski S, Bode U, Deinlein F, Ottens- and development of Schwann cell cultu- tions are large regular outpatient clinics for meier H, Warmuth-Metz M, Soerensen res) and neurostimulation. patients with skull base tumors, sporadic N, Graf N, Emser A, Pietsch T, Wolff JEA, and genetically based vestibular schwanno- Kortmann RD, Kuehl J: (2005) Treatment mas and meningiomas (neurofibromatosis of early childhood medulloblastoma by postoperative chemotherapy alone. New Neuro-oncology types 1 and 2). England Journal of Medicine 352: 978- (G. Vince and C. Matthies) 986.

Malignant pathologies Craniofacial malformations Sirén A-L, Radyushkin K, Boretius S, Käm- A large patient population is being treated (H. Collman, J. Krauß) mer D, Riechers C-C, Natt O, Sargin D, Watanabe T, Sperling S, Michaelis T, Price neurosurgically for glioblastomas and low J, Maier B, Frahm J, Ehrenreich H: (2006) grade astrocytomas by the interdisciplina- A cooperative group from neuropediatrics, Global brain atrophy after unilateral parie-

ry team of neuro-oncologists and radiothe- neuroradiology, maxillo-facial surgery and SELECTED PUBLICATIONS tal lesion and its prevention by erythropoi- rapists and followed long-term in longitu- of seven further disciplines performs the etin. Brain 129:480-489. dinal studies. They provide the base for a treatment of children with craniofacial mal- Vince GH, Bendszus M, Schweitzer T, unique collection of tumor cell lines. In-vi- formations, especially craniosynostosis Goldbrunner RH, Hildebrandt S, Tilgner tro tumor cell lines and in-vivo animal mo- and cares long-term for over 800 children J, Klein R, Solymosi L, Tonn JC, Roosen dels are used for investigation of tumorbi- all over the country. Investigations focus K. (2004) Spontaneous regression of ex- ology with regard to tumor invasiveness, on underlying causes of the disease, refi- perimental gliomas--an immunohistochemical and MRI study of the C6 glioma progression and aggressiveness. The iden- nement of phenotypic classification, mo- spheroid implantation model. Exp Neurol. tification of the importance of metallo-pro- lecular genetic diagnostics, secondary di- 190:478-85. teinases and their proteolytic activity has seases and improvement of surgical tech- significantly influenced the understanding niques. Longitudinal studies investigate Westermaier T, Eriskat J, Kunze E, Günth- ner-Lengsfeld T, Vince GH, Roosen K. of tumor progression. Different grades of problems of social integration and psycho- (2007) Clinical features, treatment, and tumors and the edge between benign and logical stress. prognosis of patients with acute subdural hematomas presenting in critical conditi- 95 on. Neurosurgery. 61:482-7. 3.21 Department of Neurology

Professor Dr. med. Klaus Viktor Toyka Mission chanisms of immune-mediated tissue dama- (Head of the Department) and Structure ge and new immunotherapies; analysis of endogenous mechanisms of immune tolerance Josef-Schneider-Str. 11 The Department of Neurology and its asso- in the periphery and the CNS compartment; 97080 Würzburg, Germany ciated hospital department cover the entire role of regulatory and dendritic cells; contribu- Tel.: 09 31 / 201-23751 spectrum of neurological disorders. The cli- tion of cytotoxic T-cells in neuroinflammation Fax: 09 31 / 201-23697 nical service includes 89 beds with a 6 bed and of specific potassium channels in T cell E-mail: [email protected] Stroke Unit and a 10 bed specialized Neurolo- activation and neuronal responses to immu- www.klinik.neurologie.uni-wuerzburg.de gical Intensive Care Unit with about 2800 in- ne-mediated injury; molecular mechanisms patients per year. The outpatient department of breakdown of the blood-brain-barrier; de- Professor Dr. med. Karlheinz Reiners cares for over 8000 out-patients and 2500 velopment of novel MR-contrast agents for CONTACT DETAILS CONTACT Tel.: 09 31 / 201-23758 through the consultation service per year. more sensitive detection of demyelinating in- Our specialties encompass neuroimmunolo- flammatory lesions in the CNS. Professor Dr. rer. nat. Rudolf Martini gical diseases (multiple sclerosis, autoimmu- Tel.: 09 31 / 201-23268 ne nerve and muscle disorders), degenerative neuromuscular disorders including integrated Stroke and Neuroimaging Professor Dr. med. Guido Stoll nerve/muscle pathology, cerebrovascular dis- (G. Stoll, M.Bendszus, W. Müllges) Tel.: 09 31 / 201-23769 orders, movement disorders, epilepsy, neuro- genic pain and neurointensive care. The De- Molecular mechanisms of thrombus forma- Professor Dr. med. Heinz Wiendl partment has integrated a Division of Clinical tion in experimental cerebral ischemia using Tel.: 09 31 / 201-23756 Neurophysiology, a Clinical Research Group pharmacological and transgenic mouse mo- for Multiple Sclerosis and Neuroimmunolo- dels; development of novel and safer treat- gy, a Section of Developmental Neurobiology, ment options in acute stroke by blockade of and numerous experimental and clinical labo- platelet receptors GPIb, GPVI and the intrinsic ratories allowing translational research from coagulation cascade (Factor XII); functional in- molecular basics to the bedside. The Depart- farct imaging by 17.6 T-high-field MRI (in co- ment holds 36 full time academic members, operation with the Department of Physics V); 88 on the nursing staff, 24 technicians and development of novel MR contrast agents for 11 employees in administration and special in-vivo visualization of inflammation and ner- services. Additional 11 academics are sup- ve regeneration; participation in clinical stroke ported by extramural grants. Two endowed trials; studies on the aetiology of neurological professorships for „Neuroimaging“ (Bayer-) complications during heart surgery. Schering AG) and „Multiple Sclerosis, in particular Blood-Brain-Barrier“ (Teva und Sano- fi-Aventis) and one lecturership (Merck-Se- Neuromorphology and Pain Research rono) further support the research activities. (C. Sommer) The Department contributes to the Sonder- forschungsbereiche (Program Project Center Role of pro- and anti-inflammatory cyto- Grants) 581 und 688. An intensive coopera- kines in neuropathic pain; assessment in tion is established with the Research Institute different lesion models and evaluation of for Clinical Neurobiology (Head: Prof. Dr. Mi- underlying molecular signalling pathways; chael Sendtner; see separate section) which determination of cytokine profiles in pati- had been transformed out of the Neurology ents with chronic neuropathic pain; estab- Department from the previous integrated Cli- lishment of new diagnostic procedures for nical Research Group for Motor Neuron Dis- small-fiber-neuropathies. orders in 2000.

Experimental Developmental Neurobio- Major Research logy Interests (R. Martini)

Multiple Sclerosis and Neuroimmunolo- Investigation of pathomechanisms under- gy (Clinical Research Group, previously lying genetically-mediated demyelination in BMBF, now University of Würzburg) the central and peripheral nervous system (H. Wiendl, P. Rieckmann, G. Stoll, K.V. Toy- using mouse mutants with spontaneous and ka) genetically engineered defects of myelin and other nerve components as disease models. Pathogenesis of multiple sclerosis, polyneu- Morphological methods, such as confocal- ritis, myasthenia gravis and myositis in hu- and electronmicroscopy, combined with the mans and experimental models (experimen- assessment of molecular alterations are tal autoimmune encephalomyelitis (EAE) und used for the analysis of neuronal and glial neuritis (EAN), transgenic mouse models); damage. Particular emphasis is on the role studies on immune regulation, effector me- of disease-modifying mechanisms, like the

96 molecular and genetic investigations on disease modifying factors in sporadic and familial ALS (in cooperation with the Institute for Clinical Neurobiology).

Laboratory Medicine (K. Toyka, A. Weishaupt)

Laboratory support of all groups and projects in neuromorphology, neurogenetics and neuroimmunology. Research focus: The role of autoreactive antibodies in the diagnosis and prognostic assessment of neurological diseases (anti-MAG-, anti-GM1, anti-aquaporin-4 antibodies, anti-acetylcholine-receptor-antibodies).

Teaching Fig. 1: In-vivo imaging of macrophage infiltration by magnetic resonance imaging (MRI). After systemic application iron particle-containing MR contrast agents are phagocytosed In the lectures, seminars and mandatory in the circulation by macrophages. Upon migration into injured nerve tissue, the iron-la- courses of general neurology the basics in den macrophages can be identified microscopically as blue cells (arrows; on left). Iron clinical neurology are taught accompanied leads to a signal loss on T2-weighted MRI. Infiltration of iron-laden macrophages can by bed-side teaching in small groups of stu- thus be visualized in-vivo along the course of the injured sciatic nerve as dark structure dents. The Department of Neurology more- marked by white arrowheads (experimental nerve trauma model on right). This MR-tech- over provides special seminars in differential nique is suitable for assessment of acute macrophage infiltration into tissues in general diagnosis of neurological disorders, neuro- (Source: Bendszus & Stoll (2003) J Neurosci). muscular diseases and nerve/muscle pathology and participates in numerous interdis- impact of the immune system and emerging ments of evoked potentials in the evaluati- ciplinary seminars (Anatomy, Physiology, Tu- treatment strategies in the mouse models. on of multiple sclerosis and ALS. mour Center, Pain-Curriculum, Psychology, Neurobiology, and all classes of the Internati- onal Graduate School of Life Sciences). Tea- Motor Control and Movement Disorders Autoantibodies in Neuroimmunological ching languages are German and English. (J. Classen) Disorders (K. Toyka, C. Sommer) Feger U, Tolosa E, Huang YH, Waschbisch Human cortical physiology; development A, Biedermann T, Melms A, Wiendl H. and evaluation of human models of cortical Studies on the functional role of humoral (2007) HLA-G expression defines a novel plasticity; functional significance of neuro- serum factors in immune-mediated neuro- regulatory T-cell subset present in human nal plasticity in inflammatory, ischemic and pathies and on the pathophysiology of the peripheral blood and sites of inflammati- degenerative brain diseases; pathophysio- anti-amphiphysin- and anti-GAD-associa- on. Blood 110:568-577. logy and treatment of disorders of motor ted stiff-person-syndrome; establishment Gentner R, Classen J (2006) Modular or- control; deep brain stimulation in coopera- of in-vivo models and cell culture systems; ganization of finger movements by the hu- tion with the adjacent Department of Neu- assessment by in-vivo- and in-vitro-electro- man central nervous system. Neuron 52, rosurgery. physiology (Patch-Clamp, reflex studies), 731-742. STED-microscopy (in cooperation Institute Ip CW, Kroner A, Bendszus M, Leder C, for Clinical Neurobiology). The pathogenic Kobsar I, Fischer S, Wiendl H, Nave KA, Clinical Neurophysiology and Neuromu- role of thymus abnormalities in myasthe- Martini R (2006) Immune cells contribu- scular Center (NMC) nia gravis (in cooperation with the Institute te to myelin degeneration and axonopathic (K. Reiners, K.V. Toyka) of Pathology). changes in mice overexpressing proteolipid protein in oligodendrocytes. J. Neurosci. 26, 8206-8216. Neurophysiological investigations in patients

with neuromuscular problems and CNS dis- Motor Neuron Diseases SELECTED PUBLICATIONS Kleinschnitz C, Stoll G, Bendszus M, orders (> 25,000 investigations per year); (K. Toyka, M. Beck) Schuh K, Pauer HU, Burfeind P, Renné C, Gailani D, Nieswandt B, Renné T (2006) Co-Chairman of the Interdisciplinary Neu- Targeting coagulation factor XII provides romuscular Center together with Prof. Dr. Development of neurophysiological para- protection from pathological thrombosis in T. Grimm, Department of Human Genetics; meters for monitoring disease progression cerebral ischemia without interfering with morphological assessment of nerve and and treatment effects in amyotrophic late- hemostasis. J. Exp. Med. 203, 513-518. muscle disorders by magnetic resonance ral sclerosis (ALS). In 1996 an ALS data Sommer C, Weishaupt A, Brinkhoff J, Biko imaging and correlation with neurophysio- base has been established for collection of L, Wessig C, Gold R, Toyka KV (2005) Pa- logical parameters; validity of serial assess- clinical data and samples; support of basic raneoplastic stiff-person syndrome: passive transfer to rats by means of IgG antibo- 97 dies to amphiphysin. Lancet 365: 1406- 1411. 3.22 Institute for Clinical Neurobiology

Mission by defects in mechanisms for motoneuron Professor Dr. med. Michael Sendtner (Head) and Structure survival, but by defects in axon growth and maintenance. This disturbance is due to a Zinklesweg 10 The Institute for Clinical Neurobiology disruption in β-actin mRNA transport, re- 97078 Würzburg emerged in 2000 from a clinical research sulting in a depletion of actin filaments in Tel.: 09 31 / 201-44000 group of the Deutsche Forschungsge- the growth cones and presynaptic regions Fax: 09 31 / 201-44009 meinschaft (“clinical research group for of neuromuscular endplates. This finding in E-mail: [email protected] Neuroregeneration”), which had been es- isolated motoneurons and in animal mo- www-i.klinik.uni-wuerzburg.de/deutsch/ tablished and funded from 1994-2000 at dels for spinal muscular atrophy correlates einrichtungen/kliniken/InstitutfrKlinische the Department of Neurology at the Uni- with clinical observations in patients with Neurobiologie/content.html versity of Würzburg. It exists as an inde- spinal muscular atrophy. On the basis of

CONTACT DETAILS CONTACT pendent institute at the University Hospi- these experiments, new therapeutic stra- tal since 2000 and is since then suppor- tegies for this disease can now be deve- ted with substantial funding by the Herr- loped. mann und Lilly Schilling-Stiftung. The In- stitute for clinical neurobiology is mostly The Institute for Clinical Neurobiology is working in basic science, but it is also also involved in the patient care of the involved in sustaining the special health special care centre for motoneuron di- care centre for motoneuron diseases at seases (Dept. of Neurology, Director Prof. the Department of Neurology (Director: K. V. Toyka), in order to ensure the transfer Prof. K.V. Toyka), in order to allow and of basic science into clinical applications. ensure the transfer of scientific know- The research results of the Institute for ledge into clinical applications. In the ye- Clinical Neurobiology have been publis- ars 2005 and 2006, the spectrum of me- hed in the last years in important interna- thods and scientific focuses has been ex- tional journals (Nature Medicine, Nature panded due to the appointment of Prof. Neuroscience, Nature Genetics, Journal Heckmann and Prof. Sigrist as heads of of Cell Biology, PNAS, and others). independent research groups at the In- stitute. Due to the appointment of Prof. Heck- mann in 2005 as an independent group leader, the spectrum of methods and themes at the Institute has been expanded. This group focuses on the mechanisms Major Research of synaptic communication, the main fo- Interests cus next to postsynaptic receptor channels being the presynaptic exocytosis and The research group headed by M. Sendt- endocytosis and the differentiation and ner at the Institute of Clinical Neurobio- maturation of synaptic contacts. This re- logy focuses on mechanisms of neuronal search group has left the Institute due to cell death, the establishment and analy- the appointment of Prof. Heckmann at the sis of animal models for motoneuron di- University of Leipzig, and it is planned to seases, as well as the development of re-establish this group as soon as pos- therapeutic strategies for the treatment sible in 2008 by appointing a successor of amyotrophic lateral sclerosis and spi- for Prof. Heckmann, in order to preserve nal muscular atrophy, the most common this technical and thematic focus at the forms of motoneuron disease in children Institute. and adults. The group headed by Prof. Stefan Sigrist One focus is the investigation of the sig- is co-funded by the Bio-Imaging Centre of nal transduction pathways by which neu- the University of Würzburg and the Institu- rotrophic factors influence survival and te for Clinical Neurobiology. This research axonal growth of motoneurons. The ge- group focuses on molecular, cell biologi- neration and analysis of gene knockout cal and pathophysiological mechanisms mice allows investigating which signal that mediate the development and acti- molecules are involved in mediating such vity-mediated plasticity of neuromuscu- essential cellular effects of neurotrophic lar synapses at motor endplates. This re- factors. search group follows a “vertical research approach”, using a broad variety of mole- Another research focus is the analysis of cular biology and biochemistry methods the pathophysiology of spinal muscular at- as well as electrophysiological, ultrastruc- rophy, the most common form of motoneu- tural and state-of-the-art optical techno- ron disease in children. It has been shown logy (confocal microscopy, 2-photone mi- that this disease is not primarily caused croscopy).

98 Fig. 1: Disruption of the presynaptic differentiation of the active zone of motoneurons from a mouse model of spinal muscle atrophy (B,D,F). While control motoneurons (A,C,E) form clusters of Ca2+- channels (red) with other components of the active zone (piccolo, green), this process is distorted in motoneurons from a mouse model for spinal muscular atrophy. This results in functional distortions of the signal transduction at neuromuscular synapses.

Linker, R.A., Mäurer, M., Gaupp, S., Mar- Teaching tini, R., Holtmann, B., Giess, R., Rieck- mann, P., Lassmann, H., Toyka, K.V., The Institute for Clinical Neurobiology is in- Sendtner M. and R. Gold. (2002) CNTF is volved in the training of students in neurolo- a major protective factor in demyelinating gy as well as the training of biology students CNS disease: a neurotrophic cytokine as modulator in neuroinflammation. Nature (Diplomstudiengang, from 2008/9 Master Medicine 8, 620-624. students) with focus on neurobiology. Ano- ther focus is the training of students in the Götz, R., Wiese, S., Takayama, S., Ca- MD/PhD program. Further courses are of- marero, G.C., Rossoll, W., Schweizer, U., Troppmair, J., Jablonka, S., Holtmann, B., fered for students of the course molecular Reed, J.C., Rapp, U.R. and M. Sendtner. medicine within the training program for MD (2005) Essential role of bag-1 for diffe- students. rentiation and survival of neural precursor cells. Nat. Neurosci. 8, 1169-1178.

Barnabé-Heider, F., Wasylnka, J.A., Fern- andes, K.J.L., Porsche, C., Sendtner, M., Kaplan, D.R. and F. D. Miller. (2005) An

SELECTED PUBLICATIONS extrinsic cortical timer mechanism: evidence that embryonic neurons regulate the onset of cortical gliogenesis via cardio- trophin-1. Neuron 48, 253-65.

Jablonka, S., Beck, M., Lechner, B.D., Mayer, C. Sendtner, M. (2007) Defective Ca2+-channel clustering in axon termi- nals disturbs excitability in motoneurons in spinal muscular atrophy. J Cell Biol.179, 139-149.

Wiese, S., Jablonka, S., Holtmann, B., Orel, N., Rajagopal, R., Chao, M.V., Sendt- ner, M. (2007) Adenosine receptor A2A- R contributes to motoneuron survival by transactivating the tyrosine kinase receptor 99 TrkB. PNAS 104, 17210-17215. 3. 23 Department of Psychiatry, Psychosomatics and Psychotherapy with Division of Forensic Psychiatry

Professor Dr. med. Jürgen Deckert lized diagnostic and therapeutic options with the Institute of Clinical Neurobiology, (Head of the Department) are provided by the laboratory on thera- the ZEMM and the Biocenter). For clini- peutic drug monitoring and the laboratory cal studies according to GCP-guidelines a Füchsleinstrasse 15 on psychophysiology. The integrated de- specialiced clinical studies group was set 97080 Würzburg partment of forensic psychiatry provides up (J. Deckert, A. Fallgatter), which coo- Tel.: 09 31 / 201-77010 expert opinions on legal aspects of men- perates closely with the ZKS. Studies on Fax: 09 31 / 201-77020 tal disorders. suicide (A. Schmidtke) have already resul- Email: [email protected] ted in defined proposals for suicide pre- www-i.klinik.uni-wuerzburg.de/deutsch/ein- vention. The research environment estab- richtungen/kliniken/nervenklinik/content.html Major Research lished by Prof. Beckmann between 1985 Interests and 2006 therefore is preserved and ex-

CONTACT DETAILS CONTACT Professor Dr. med. Andreas Fallgatter, tended with its characteristic close inter- Tel.: 09 31 / 20177110 The research activities of the clinic are action between translational research la- characterized by their interdisciplinarity boratories of the PPP such as the labora- Professor Dr. med. Helmut Heinsen with research groups of psychiatrists, psy- tories on Molecular Psychiatry (J Deckert, Tel.: 09 31 / 201-76551 chologists, chemists and biologists as well A. Reif), Clinical and Molecular Psychobio- as close cooperations at the level of the logie (K.-P. Lesch), Clinical Neurochemist- Professor Dr. med. Klaus-Peter Lesch UKW in the context of the KFO 125, the ry (P. Riederer), Morphological Brain Re- Tel.: 09 31 / 201-77610 SFB 581, the GKs 1156 and 1253 and search (H. Heinsen) and Psychophysiolo- the IZSF, at the national level in the con- gy and Functional Imaging (A. Fallgatter, Professor Dr. techn. Dipl. Ing. Peter Riederer text of cooperations with institutes of the M.J. Herrmann) with the clinical research Tel.: 09 31 / 201-77210 Max-Planck Society and the Helmholtz So- groups of the clinic on one hand and core ciety and participation in BMBF programs facilities of the UKW and external research Professor Dr. med. Martin Krupinski for Brain Research, Depression, Panic facilities on the other hand. Research to- (Head of Division of Forensic Psychiatry) Disorder and ADHD, and at the interna- pics include clinical neuroscience aspects Tel.: 09 31 / 201-77500 tional level in the context of cooperations such as the therapy of mental disorders, with the NIH and EMBL and participation translational aspects such as the patho- in DAAD programs and EU programs for genesis of mental disorders including the Brain Research and Depression, but also functional characterization of the identi- in the context of projects funded by foreign fied pathomechanisms by means of mo- sponsors such as the NIH, the BBSRC and dern imaging techniques and animal mo- the Ludwig-Boltzmann-Foundation. Metho- dels as well as basic neuroscience aspects dological approaches on the basis of dif- such as emotional and cognitive proces- ferentiated clinical and neuropsychological ses, gene-environment-interactions, neu- diagnostic procedures cover a broad range ronal plasticity and adult neurogenesis from psychopysiological and modern ima- from adult stem cells. ging approaches such as near infrared spectroscopy and functional magnet resononance tomography (in cooperation with the Mission Department of Neurora- and Structure diology and the research center Magnet-Resonanz- The clinic of Psychiatry, Psychosomatics Bayern e.V. as well as the and Psychotherapy (PPP) at the UKWürz- Institute of Psychology I) burg (UKW) offers out-patient, day-care over modern methods of and in-patient diagnostic and therapeu- genomics and proteomics tic services for all mental (psychiatric and such as Highthroughput- psychosomatic) disorders. The therapeu- Genotyping (Core Facility tic focus of the clinic is on affective dis- in cooperation with the In- orders and psychoses of the schizophre- stitute of Clinical Bioche- nia spectrum, but also on dementias and mistry and the IZKF, Brain- substance abuse disorders, as well as ea- Net-Reference Center in ting disorders, anxiety disorders and adult cooperation with the De- attention-deficit-hyperactivity disorder. partment of Neuropatho- Specialized out-patient services as part of logy) and their combinati- the policlinic and the outpatient program on in the context of ima- Fig.1: Cover Image of Human Brain Mapping 28/2007 as well as 16 day-care therapy slots com- ging genomics up to cell (Plichta, M.M., Herrmann, M.J., Baehne, C.G., Ehlis, A.-C., plement the 144 in-patient therapy slots culture and animal mo- Richter, M.M., Pauli, P., Fallgatter, A.J. Event-related func- with two intensive care units and two units dels in particular knock- tional near infrared spectroscopy (fNIRS) based on cranio- spezialized on substance abuse therapy out and transgenic mouse cerebral correlations: Reproducibility of activation? Human and psychotherapy respectively. Specia- models (in cooperation Brain Mapping 28: 733-741, 2007).

100 Fig. 2: Cover Image of Molecular Psychiatry 11/2006 (Reif A, Fritzen S, Finger M, Strobel A, Lauer M, Schmitt A, Lesch KP. Neural stem cell proliferation is decreased in schizophrenia, but not in depression. Mol Psychiatry 11:514-22, 2006).

The main research topics thus are: Reif A, Herterich S, Strobel A, Ehlis AC, • Markers for early diagnosis and inno- Teaching Saur D, Jacob CP, Wienker T, Töpner T, vative therapeutic approaches in af- Fritzen S, Walter U, Schmitt A, Fallgatter fectiven disorders, psychoses of the An integrated lecture and course on psy- AJ, Lesch KP. (2006) A neuronal nitric oxi- schizophrenia spectrum, dementi- chiatry and psychosomatics are organized de synthase (NOS-I) haplotype associated as, substance abuse disorders, an- and held by the PPP in cooperation with with schizophrenia modifies prefrontal cortex function. Mol Psychiatry 11:286-300. xiety disorders and adult ADHD (J. the KJPPP and other clinics and institu- Deckert, A. Fallgatter, K.-P. Lesch, P. tes. Special curricular seminars are provi- Domschke K, Braun M, Ohrmann P, Sus- Riederer, A. Schmidtke, G. Stöber, ded for interns and students interested in low T, Kugel H, Bauer J, Hohoff C, Kers- B. Jabs, B. Pfuhlmann, C. Jacob, M. special aspects of psychiatry and psychoso- ting A, Engelien A, Arolt V, Heindel W, De- ckert J. (2006) Association of the functio- Lauer, A. Reif). matics. In addition to the curricular lecture nal -1019C/G 5-HT1A polymorphism with • Identification of morphological and and course for medical students the PPP prefrontal cortex and amygdala activation neurochemical pathological proces- also provides curricular lectures and cour- measured with 3 T fMRI in panic disorder. ses in psychoses of the schizophre- ses for students of experimental medicine, Int J Neuropsychopharmacol. 9:349-55. nia spectrum and neurodegenerative psychology and biology. Extracurricular se- Fallgatter AJ, Herrmann MJ, Hohoff C, Eh- disorders (P. Riederer, H. Heinsen, E. minars are offered to graduate students of lis AC, Jarczok TA, Freitag CM, Deckert Grünblatt, M. Lauer). medicine, experimental medicine, biology, J. (2006) DTNBP1 (Dysbindin) gene vari-

• Identification of genetic factors in af- psychology. SELECTED PUBLICATIONS ants modulate prefrontal brain function in fectiver disorders, psychoses of the healthy individuals. Neuropsychopharma- col 31: 2002-2010. schizophrenia spectrum, anxiety disorders and ADHD (J. Deckert, K.-P. Schmitt A, Benninghoff J, Moessner R, Lesch, G. Stöber, A. Reif). Rizzi M, Paizanis E, Doenitz C, Gross S, • Imaging of emotional and cogniti- Hermann M, Gritti A, Lanfumey L, Fritzen ve processes in adults, adolescents S, Reif A, Hamon M, Murphy DL, Vesco- vi A, Lesch KP. (2007) Adult neurogenesis and children (A. Fallgatter, M. Herr- in serotonin transporter deficient mice. J mann). Neural Transm. 114:1107-19 • Gene-environment-interactions, neu- ronale plasticity and adult neuroge- Grünblatt E, Löffler C, Zehetmayer S, Jungwirth S, Tragl KH, Riederer P, Fischer nesis in man and in the animal mo- P. (2007) Association study of the 5-HT- del (K.-P. Lesch, J. Deckert, A. Reif, TLPR polymorphism and depression in 75- A. Schmitt). Year-Old nondemented subjects from the Vienna Transdanube Aging (VITA) study. J Clin Psychiatry 67:1373-8. 101 3.24 Department for Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy

Major Research Biomarkers Professor Dr. med. Dipl.-Psych. Interests (M. Gerlach, R. Hümner-Kopf, M. Romanos, Andreas Warnke T. Renner, S. Walitza) (Head of the Department) Attention deficit-/ hyperactivity disorder A biomarker (biological marker) is a charac- (ADHD) teristic that is objectively measured and eva- Fuechsleinstr 15 (M. Gerlach, T. Jans, T. Renner, M. Roma- luated as an indicator of normal biological D-97080 Wuerzburg nos, C. Schwenck, S. Walitza, A. Warnke) processes, pathogenetic processes or phar- Tel.: 09 31 / 201-78000 macological responses to a therapeutic inter- Fax: 09 31 / 201-78040 ADHD is the most prevalent psychiatric dis- vention.The development of biomarkers is es- E-mail: [email protected] order in childhood and adolescence. Pa- pecially promising because a substantial im- www.klinik.uni-wuerzburg.de/kjp thogenesis and the impact of endopheno- provement of the reliability in the diagnostic

CONTACT DETAILS CONTACT types and co-morbid features are investi- of psychiatric disorders could be achieved by gated using formal and molecular gene- this approach. Different paradigms (real-time tics, neuropsychological and neurophysi- PCR, proteomics, olfactory test) are evaluated ologic methods as well as animal models hoping to achieve a substantial contribution and gene expression studies. These stu- to an early and reliable diagnosis of ADHD, dies are conducted in close cooperation autism and schizophrenia. with the Department for Adult Psychiatry and other clinics and departments of the These stdies are conducted in close coope- Mission University of Wuerzburg (Clinic for Nuclear ration with other universities (Prof. Dr. Meh- and Structure Medicine, Department of Psychology I, De- ler-Wex, Ulm; Prof. Dr. H. Reichman, Dres- partment of Radiodiagnostics). Multicentre den; Prof. Dr. J. Thome, Swansea, UK). The clinic for child and adolescent psychiatry, clinical studies are carried out on the ef- psychosomatics and psychotherapy is providing state-of-the-art patient care for children Developmental psychopharmacology and adolescents aged up to 18 years offe- (M. Gerlach, K. Klampfl) ring assessment and treatment for all psychiatric and psychosomatic disorders. The clinic Off-label use, the lack of randomized con- includes inpatient units (the locked ward is trolled trials, pharmacokinetic and phar- under the sponsorship of the “Bezirk Unter- macodynamic differences from adults and franken”), a day clinic and a special school increased vulnerability towards unwanted (sponsorship: “Diakonisches Werk”), a side effects are challenging conditions of parent’s pavilion (sponsorship: “Verein Men- the psychopharmacotherapy in children and schenskinder”), a clinical research group adolescents. Several factors of develop- (sponsored by the German Research Asso- ment, gender, age and individual predispo- ciation, DFG), a neurobiological laboratory. Fig. 1: Formal genetics of ADHD. Genea- sitions have to be considered regarding the The clinical laboratory for therapeutic drug logical tree. Family members affected by choice of medication and dosage finding. monitoring and a lecture hall are joint facili- attention deficit / hyperactivity disorder Since serum levels in adults suggest more ties of this department and the department ADHD are red-coloured. intimate correlations especially with side ef- for adult psychiatry. Therapeutic units (oc- fects, but potentially also with drug effica- cupational therapy, exercise therapy, music ficacy and safety of extended release me- cy than applied dosages, therapeutic drug therapy, orthopedagogy including animal as- thylphenidate in ADHD children and ado- monitoring (TDM) is a promising tool for the sisted therapy) are connected with our three lescents. In cooperation with the Depart- improvement of dosing and drug safety also inpatient units. The staffs comprise 18 phy- ment of Toxicology (Prof. Dr. H. Stopper) in minors. To improve the security of the sicians, 10 psychologists (including 4 psy- the occurrence of possible adverse reac- patients and to establish quality standards chologists attending postgraduate in-service tions (e.g. chromosome aberrations) is in- the clinic is part of the national multicentre training on psychotherapy), 22 members of vestigated during pharmacological treat- competence network on TDM. the medical and technical service, 5 special ment. Within the framework of the BMBF- therapists, 8 members of the administrative network on psychotherapy research in Eating disorders (BMBF-project within department and 50 members of the nursing ADHD (see page 168) the efficacy of a pa- the network „Treatment of anorexia ner- and educational service. Rates of utilisation rent training for the treatment of ADHD in vosa in children and adolescents – day of the 38-bed inpatient unit and the 12-bed children is investigated depending on the clinic vs. inpatient treatment“) day clinic are 100 percent. Main focus of pa- treatment of their mothers also affected (K. Klampfl, J. Romanos, A. Warnke) tient care – supported by special outpatient by ADHD. services – are the assessment and treatment 50 percent of juvenile anorexia nervosa of eating disorders, affective disorders (de- These projects are sponsored by Grants patients are readmitted to inpatient treat- pression), anxiety disorders, psychosis, at- from the DFG (“Klinische Forschergrup- ment within the first year after discharge. tention deficit hyperactivity disorder (ADHD), pe KFO 125”, see page 161), the Federal The study compares a day clinic and an in- obsessive-compulsive disorder, Tourette syn- Ministry of Education and Research BMBF patient treatment to investigate if patients drome, conduct disorder, autism and speci- (see page 168), the Interdisciplinary Centre partly remaining in their family have a more fic developmental disorders, and of co-exis- for Clinical Trials IZKF of Wuerzburg Univer- favourable outcome. The multicentre study ting psychiatric disorders in non-psychiatric sity, the state of Bavaria, and several phar- is conducted at three sites (Universities of diseases and mental retardation. maceutical companies. Aachen, Cologne, Wuerzburg).

102 Obsessive-compulsi- chology. Obligatory lectures and examinati- ve disorder „A pros- ons also refer to study courses on psycho- pective study on the logy, education and special education (diplo- course of obsessi- mas, state examinations). Furthermore, les- ve-compulsive dis- sons and trainings refer e.g. to forensic child order with onset in and adolescent psychiatry, developmental childhood and adole- psychiatry and psychodiagnostics, neurophy- scence “ siological assessment, epilepsy, postgraduate (M. Gerlach, U. Hem- and research colloquia, open lectures on cli- minger, T. Renner, S. nical issues („KJPP- Nachmittage“) and collo- Walitza, A. Warnke) quia on neuropsychiatry conducted together with the Departments of Adult Psychiatry and Despite recent advan- the Department of Neurology. The quality of ces there is a lack of our lecture on child and adolescent psychia- empirical knowledge try has been awarded (“Lehrpreis” of the fa- on the aetiology and culty of medicine). To support university lec- course of obsessi- tures and curricula a fund financed by tuition ve-compulsive disor- fees provides pay for a psychologist (APP) and der (OCD) with onset two lecturing tutors (CAPP). In addition to sci- in childhood or adole- entific congresses (e.g. in 2007 the „1st In- scence. In cooperati- ternational Congress on ADHD“- over 1300 Fig. 2: Tryptophane-hydroxylase 2 is the most important enzy- on with other universi- participants - , and a „patient’s day“ - 300 me in the synthesis of serotonin in the brain; gene variants are ty clinics for Child and attending ADHD patients and their relatives) associated with ADHD. Adolescent Psychiatry there are annual symposia („Arzt-Lehrer-Ta- (Prof. Dr. B. Herpertz- gung“; „Tagung Kinder-Jugendpsychiatrie und Dahlmann, Aachen; Jugendhilfe“). Prof. Dr. E. Schulz, Frei- Dyslexia – a multi-centre trial „Neuro- burg; Prof. Dr. Ch. Wewetzer, Köln, Prof. Dr. physiological, psychometric and gene- J. Hebebrand, Essen) and the Department tic studies on dyslexia” for Medical Biometry and Epidemiology Mar- (A. Warnke, Prof. Schulte-Körne, Munic, burg (Prof. Dr. H. Schäfer) and the Institute Tribl F, Gerlach M, Marcus K, Asan E, Prof. Remschmidt, Marburg) for Pharmacology of the University of Köln Tatschner T, Arzberger T, Meyer HE, Bring- (Prof. Dr. E. Schömig) family studies are mann G, Riederer P (2005) Subcellular Dyslexia as a specific developmental disor- conducted on OCD (coordinator: PD Dr. S. Proteomics of neuromelanin granules iso- der of scholastic skills is based on specific Walitza). Patients and their parents are as- lated from the human brain. Mol Cell Pro- characteristics in structural and functional sessed by standardized diagnostic methods teomics 4: 945-957. brain development with a high hereditabi- to allow for molecular genetic association Hebebrand J, Dempfle A, Saar K, Thiele H, lity (about 80 percent). Research on aeti- studies. The results point to associations of Herpertz-Dahlmann B, Linder M, Kiefl H, ology focuses on correlates of the disorder gene variants in the serotonergic and do- Remschmidt H, Hemminger U, Warnke A, on the genetic level and on the behavioural paminergic neurotransmission. The present Knölker U, Heiser P, Friedel S, Hinney A, Schäfer H, Nürnberg P, Konrad K (2006) level (reading, spelling) accounting for as- study is also the first prospective follow-up A genome-wide scan for attention-deficit/ sociations with psychological (e.g. acoustic study of early onset OCD in a German-spea- hyperactivity disorder in 155 German sib- discrimination) and neurophysiologic (e.g. king country. Preliminary results considered pairs. Mol Psychiatry 11: 196-205. EEG characteristics) endophenotypes. The the question of differences in the sympto- DCDC2-gene which is important for the foe- matology, severity and course of disease of Schumacher J, Anthoni H, Dahdouh F, Kö- nig IR, Hillmer AM, Kluck N, Manthey M, tal brain development was identified to be early onset OCD in dependence of comor- Plume E, Warnke A, Remschmidt H, Huls- associated with dyslexia. There is a correla- bid disorders especially ADHD comorbidity. mann J, Cichon S, Lindgren CM, Propping

tion of the severity of dyslectic impairment In our sample the persistence of symptoms SELECTED PUBLICATIONS P, Zucchelli M, Ziegler A, Peyrard-Janvid, and the genetic influence. Samples are re- is higher in the group of “OCD with ADHD” M, Schulte-Körne G, Nöthen MM, Kere J (2006) Strong genetic evidence of DCDC2 cruited in Wuerzburg and Marburg. Nati- than in the group “OCD without ADHD”. The as a susceptibility gene for dyslexia. Am J onal and international cooperation have studies are sponsored by the DFG. Hum Genet 78: 52-62. been established (Prof Dr. T. Grimm, De- partment of Human Genetics Wuerzburg,; Lazar A, Walitza S, Jetter A, Gerlach M, Prof. Dr. P. Propping, Institute of Human Ge- Warnke A, Herpertz-Dahlmann, Gründe- mann D, Grimberg G, Schulz E, Rem- netics Bonn; Prof. Dr. M. Nöthen, Prof. Dr. J. Teaching schmidt H, Wewetzer Ch, Schömig E Schumacher, Genomics, Life & Brain Cen- (2008) Novel mutations of the extraneuro- ter Bonn; Department of Biosciences Ka- The obligatory lectures for students of human nal monoamine transporter gene in child- rolinska Institute Stockholm; Department medicine comprising the subject matter on ren and adolescents with obsessive-compulsive disorder. Int J Neuropsychophar- of Medical Genetics Helsinki; Prof.Dr Mül- psychosomatics are conjointly hold by the cli- macol. 11:35-48. ler- Myhsok, Max- Planck-Institute of Psy- nic for adult psychiatry (APP), the clinic for chiatry, Munic; Prof.Dr. Ziegler Institute of child and adolescent psychiatry (CAPP), the Walitza S, Werner B, Romanos M, Warn- Medical Biometrics and Statistics Universi- clinic for neurology and other medical clinics ke A, Gerlach M, Stopper H (2007) Does ty Lübeck). as well as by the department for medical psy- methylphenidate cause a cytogenetic effect in children with attention deficit hyperactivity disorder. Environ Health Perspect 103 115: 936-940. 4 Dental Hospital

104 4.1 Introduction

Five departments are integrated in the uni- partments, currently Professor Dr. B. Klai- versity hospital for dentistry and oral and ber. maxillofacial surgery: The university hospital for dentistry and oral and maxillofacial surgery educates appro- • Department of Conservative Dentistry ximately 600 students, half of them in the and Periodontology clinical part of their studies. (Head: Professor Dr. Bernd Klaiber) For education, research and patient care • Department of Oral and Maxillofacial 225 working places are available. Surgery (Head: Professor Dr. Dr. Alexander Küb- Actually, because of third-party-funds and ler) half-time jobs 300 attendants are employed, 70 of them as scientists. • Department of Prosthodontics (Head: Professor Dr. Ernst-Jürgen Rich- Beside education and research continuing ter) education for dentists as well as advanced education for medical and dental specia- • Department of Orthodontics lists are major tasks. (Head: Professor Dr. Angelika Stellzig- Eisenhauer) In 2006 about 28.000 patients were treated ambulatory, 1.200 stationary. • Department for Functional Materials in Medicine and Dentistry (Head: NN)

These principals constitute the board of directors and they elect a chairman which is Professor Dr. B. Klaiber currently.

The chairman of the School of Dental Medi- Professor Dr. med. dent. B. Klaiber cine is elected by the Heads of the five de- (acting Chairman)

105 4.2 Department of Orthodontics

Mission care at the Department of Orthodontics is Professor Dr. med. dent. and Structure also characterized by interdisciplinary coo- Angelika Stellzig-Eisenhauer peration with the other dental disciplines. (Head of the Department) Under the direction of Prof. Dr. Stellzig-Ei- senhauer nine assistant doctors are enga- In particular, there are very close working Pleicherwall 2 ged in patient care, research and teaching relationships with: 97070 Würzburg of students. Department of Oral and Maxillofacial Sur- Tel.: 09 31 / 201-733 20 gery: Fax: 09 31 / 201-733 00 Health care at the Department of Orthodon- • patient with cleft lip and palate E-mail: [email protected] tics comprises all types of malocclusions, • patients with craniofacial dysplasia www.kfo.uni-wuerzburg.de ranging from simple to extremely complex • patients with severe jaw disharmonies

CONTACT DETAILS CONTACT conditions. During childhood and adole- • patients with mandibular condyle frac- Prof. Dr. rer. nat. Kathleen Wermke scence prophylaxis of malocclusions, the- tures Tel.: 09 31 / 201-73430 rapy of skeletal jaw disharmonies by using • patients with ectopic teeth (Fig. 1) and directing bodyown growth, as well as correction of misaligned teeth are important Department of Prosthodontics: issues. A special focus of the Department • pre-prosthetic uprighting or intrusion of of Orthodontics is the comprehensive treat- incisors and molars ment of adult patients using specific fixed • pre-prosthetic arrangement of abut- techniques with regard to the individual pe- ment teeth riodontal and prosthetic situation. Health • pre-prosthetic root extrusion

Department of Conservative Dentistry and Periodontology: • correction of tooth alignment in patients with periodontal disease • therapy of patients with tooth-size discrepancies

Each year approx. 1.500 patients of all ages are treated in the Department of Orthodon- tics with appointments every 3 to 6 weeks. About 600 patients are calling on the De- partment for Orthodontic consultation.

Major Research Interests

Establishment of 3D soft tissue analysis in orthodontics (Cooperation with the Institute of Optics, University Erlangen-Nürnberg; A. Stellzig-Eisenhauer, J. Kochel)

In orthodontics diagnostics of the soft tissues of the face are still based on the analysis of photographs. Actual methods of 3D analysis are not exact because landmarks are used to determine the facial symmetry plane. These landmarks are often located in asymmetric areas of the face or they only have low reliability. Thus, we have used a landmark-independent method for determining the facial symmetry plane, which was developed by the Institute of Optics, University Erlangen-Nürnberg. 3D data acquisition is Fig. 1: A) Before orthodontic treatment. B) done by using the FaceScan3D optical 3D Dislocation of the left upper canine tooth. sensor. The objective of this research pro- C) Orthodontic mobilisation of the canine ject is gaining 3D mean values in a com- tooth after maxillofacial exposure. D) After prehensive collective. So far, 100 adult orthodontic treatment. Caucasians have been analysed.

106 In the courses “Orthodontic treatment I and II” the knowledge of theory is promoted in small study groups and in additional seminars. In addition, diagnostic materials of patients are obtained and appliances for treatment are adapted to different patients and controlled clinically.

Fig. 2: Stereophotogrammetry with the optical sensor FaceScan3D (3DShape, Erlangen) to generate three-dimensional data of the facial soft parts.

3D analyses of facial asymmetries be- Pre-speech development and develop- fore and after orthognathic surgery. mental disorders in patients with cleft (P. Meyer-Marcotty, A. Stellzig-Eisenhauer) lip and palate (K Wermke, A Stellzig-Eisenhauer) In severe skeletal jaw asymmetries combination of orthodontic and surgical treat- In the Centre for Pre-Speech Development ment is required. Especially, the considera- and Developmental Disorders in patients tion of proportions, symmetry and harmony with cleft lip and palate and craniofacial of the soft tissues of the face is essential anomalies early diagnosis and characteri- for surgery planning and evaluation of the sation of pre-speech developmental pro- treatment results. The objective of this re- cesses are investigated. search project is the integration of a 3D soft tissue analysis into pre- and post-surgical diagnostics. Development and testing of non-invasive orthodontic appliances for the therapy of obstructive apnoea in newborns Eye-tracking studies on visual cognition with Pierre Robin sequenze. of adult patients with unilateral cleft lip (ooperation with the University Children’s and palate. Hospital, University of Würzburg. Stellzig- (P. Meyer-Marcotty, A. Stellzig-Eisenhauer) Eisenhauer, J Kochel) Stellzig-Eisenhauer, A., Lux, C.J., Schuster, G.: (2002) Treatment decision in adult patients of Class III malocclusion: Orthodon- The purpose of this investigation is to an- tic therapy or orthognathic surgery? Am J swer the question whether visual cogni- Orthod Dentofacial Orthop 122: 27-37. tion of adults with unilateral cleft lip and Teaching Schuster, G., Lux, C.J., Stellzig-Eisenhau- palate is different from that of a control er, A.: (2003) Children with Class III ma- group. There are orthodontic lectures and clinical locclusion: development of multivariate courses to impart knowledge about the kind, statistical models to predict further need the extent and the etiology of malalignment for orthognathic surgery. Angle Orthod 73: Clinical and molecular genetic investi- of teeth and jaw disharmonies. Moreover, 136-145. gation of patients with primary failure the options of prophylaxis and treatment Wermke, K., Leising, D., Stellzig-Eisenhau- of eruption of permanent teeth are to be pointed out to the students. er, A.: (2007) Relation of melody comple- (Cooperation with the Institutes of Hu- xity in infants´ cries to language outcome man Genetics, Universities of Würzburg In the lecture “Introduction of Orthodontics” in the second year of life: a longitudinal study. Clin Linguist Phon 21: 961-973. and Regensburg; C. Rau, A. Stellzig-Ei- a review of the different kinds and the etio- senhauer) logy of malocclusions is given. Hartmann, J.,Meyer-Marcotty, P., Benz,

SELECTED PUBLICATIONS M., Häusler, G., Stellzig-Eisenhauer, A.: Failure of eruption of permanent teeth wit- The emphasis of the main lecture “Ortho- (2007) Reproducibility of a new method hout an obvious cause is rare. The correc- dontics I and II” is placed on the prepa- for computation of the facial symmetry plane and the degree of asymmetry based tion of affected teeth by orthodontic means ration of the students for the treatment of on three-dimensional data. J Orofac Or- is limited. The underlying genetic factors of patients. thop 68: 477-490. failure of eruption are not identified yet. The objective of the present investigation is the “Orthodontic techniques” is a course in which Meyer-Marcotty, P., Weisschuh N, Dressler, P., Hartmann, J., Stellzig-Eisenhauer, A.: identification of genetic factors that cont- the students are to learn about the different Morphology of the sella turcica in Axen- ribute to failure of eruption of permanent kinds, the indications, the effects and the feld-Rieger syndrome with PITX2 mutation. teeth. manufacturing of orthodontic appliances. J Oral Pathol & Medicine in press

107 4.3 Department of Functional Materials in Medicine and Dentistry

Professor Dr. med. dent. Bernd Klaiber Major Research Research priorities of the department are in (acting Head) Interests the area of metallic materials, ranging from (until 30.09.2006: Prof. Dr.-Ing. Roger Thull) the development of industry-processes for The main research and development focus the production of nanostructured materials Pleicherwall 2 of the Department is in the area of metallic up to theoretical prediction of the expected 97070 Würzburg and ceramic functional materials with appli- properties. A method was developed using Tel.: 09 31 / 201-72420 cations as medical products in contact with decomposition processes in tempered me- Fax: 09 31 / 201-73500 both the oral cavity, hard and soft tissue as dical stainless steel to produce nano-struc- E-mail: [email protected] well as the heart / circulatory system. The tures (Figure 1). For a better understanding www.fmz.uni-wuerzburg.de aim of research is to elucidate the mecha- of the effects of nanomaterials on protein nisms of interactions between materials´ adsorption a software package was develo-

CONTACT DETAILS CONTACT surfaces and the biological environment to ped, which combines molecular dynamics redress the chain of causation between the calculations with the finite element method physical properties of the solid state body and allows a prediction of preferred adsorp- and molecular biological reactions of the bio- tion sites of globular proteins on an arbitra- system. ry definable nanostructure. In the first step the prevailing electrostatic and dispersion potential distributions are calculated, follo- Interface Material – Biosystem wed by the simulation of the resulting protein adsorption process in the force field. The biocompatibility of a material is deter- The results are compared with experimental mined by the surface in contact with the data obtained from measurements of the biological environment which is influenced protein adsorption with quartz crystal mic- by the composition, electrical end electro- rogravimetry (QCM). nical properties and topography of the materials surface. Currently, the influence of nanostructured surfaces on the reaction of Ceramic biomaterials for tissue regene- cells, bacteria and proteins is investigated. ration and drug delivery While structures with a correlation length in the range of 200 nm - 1 µm above all have Main focus are self setting ceramic pas- direct influence on the cells and the biolo- tes derived from calcium orthophosphates gical system, nanostructures of magnitude for bone replacement in low load-bearing 1 - 20 nm affect the adsorption of bioma- areas of the skeletal system. Research ac- cromolecules. Changes of the potential dis- tivities concern the reactivity of cement tributions in the body electrolytes in the im- raw materials, the rheological properties mediate vicinity of peaks and edges of the of the pastes for a minimal invasive appli- surface structure lead to a modified protein cation as well as the mechanical perfor- adsorption on the material and thus have mance of the set cement matrix. Low vis- an indirect effect on the biological system. cosity cement pastes are obtained by an Mission and Structure

Biologists, chemists, physicists and material scientists in cooperation with clinicians are engaged in the Department for Functional Materials in Medicine and Dentistry in tailoring functional materials for the use in medical products and application in the human body. Research is focused on analyzing the requirements for product placement depending on the location in the body. Material properties are adjusted by modification of the bulk and surface of materials to affect the interface to the biological environment. The workings were funded in the past years by the “Deutsche Forschungsgemeinschaft” with two projects within the priority program “Interface between Material and Bio- system” which was coordinated by the Department as well as in several projects as individual grants. Fig. 1: Nanostructures on stainless steel surface.

108 electrostatic charging of the cement particles due to the adsorption of biocompatible multiple charged anions (cit- rates), whereas the lower water demand of these formulations results in the formation of high strength materials at room temperature with the possibility of an additional organic modification. Current developments are focused on a combination of reactive cements with 3D powder printing as ge- nerative rapid prototyping technology which enables the fabrication of patient individual degradable implants for bone replacement Fig. 2: Porous calcium phosphate structures prepared by 3D powder printing. as well as scaffolds for tissue engineering (Fi- gure 2). The materials are also of interest for the delivery of drugs (e.g. antibiotics or Teaching growth factors) to the hard tissue application site since they provide a controlled re- Teaching activity comprises lectures about lease of pharmaceutical active doses wit- materials designated for use in the human hout systemic side effects. body and mechanisms of their interaction with the surrounding biosystem; lectures concerning quality management system Biological properties of materials and risk analysis of medical products, the application of X-rays on the human body as A prerequisite for the proper integration well as practical measurements for materi- of implant materials is an optimal con- als analysis. The lectures are designed for tact between biosystem and implant. To dental students, graduate students of Bio- improve the understanding of mecha- medicine and, together with the faculty of nisms occurring during tissue integration Physics and Astronomy for students of “Na- U. Gbureck, O. Knappe, L.M. Grover, J.E. cells of different origin (e.g. fibroblasts, nostrukturtechnik”. Barralet: (2005) Antimicrobial properties osteoblasts) were cultured on these sur- of potassium and sodium substituted Cal- faces. Analysed surface parameters of cium Phosphate Cements, Biomaterials the materials include composition, elec- 26: 6880-6886. tronic properties as well as nanostructu- A. Ewald, S. K. Glückermann, R. Thull, U. red surfaces. Cell reaction is analysed by Gbureck: (2006) Antimicrobial Titanium / testing cell attachment, vitality, and pro- Silver PVD coatings on titanium, Biomedi- liferation rate. Tissue specific protein ex- cal Engineering online 5:22. pression and distribution in the cell is also U. Gbureck, E. Vorndran, F.A. Müller, J.E. analysed. Barralet: (2007) Low temperature direct 3D printed bioceramics and biocomposites Serious problems during implant integration as drug release matrices, J Controlled Re- are still caused by infections due to nosco- lease 122: 173-180. mial pathogens. Implant surfaces therefore U. Gbureck, T. Hölzel, C. Doillon, F. A. Mül- should be designed antimicrobial. This can ler, J.E. Barralet: (2007) Direct printing of be achieved by integration of bacteriostatic Bioceramic implants with spatially loca- + metal ions like Ag into the surface layer. SELECTED PUBLICATIONS lised angiogenic factors. Adv. Mater. 19: Silver containing titanium surfaces develo- 795-800. ped in the department showed a clear re- U. Gbureck, T. Hölzel, U. Klammert, K. duction of bacterial growth. Eukaryotic cul- Würzeler, F.A. Müller, J.E. Barralet: (2007) ture cells were not affected by this surface Resorbable dicalcium phosphate bone modification. substitutes made by 3D powder printing, Advanced Functional Materials 17: 3940- 3945. 109 4.4 Department of Oral and Maxillofacial Plastic Surgery

Mission Major Research Professor Dr. med. Dr. med. dent. and Structure Interests Alexander Kübler (Head of the Department) The clinic has got 20 permanent posts and Clinical research team for neoplasia of a further half post which is funded exter- head and neck Pleicherwall 2 nally. The clinic owns 40 permanent beds (T. Reuther, U. Müller-Richter, I. Reuther, A. 97070 Würzburg and covers the whole spectrum of oral and Kübler) Tel.: 09 31 / 201-72720 maxillofacial surgery. Beside the in-patient Fax: 09 31 / 201-72700 care (about 1.200 patients each year), ap- • clinical study concerning neo-adjuvant E-mail: [email protected] proximately 15.000 patients are treated in vs. adjuvant therapy of oral and oropha- www.mkg.uni-wuerzburg.de the outpatient department. Further more ryngeal cancer

CONTACT DETAILS CONTACT the clinic provides a comprehensive con- • in vitro study of oral mucosa exposed to sultant support, particularly for the paedia- carcinogens tric clinic (craniofacial dysplasia and clefts) • satisfaction survey of patients with and within the interdisciplinary emergency transplants from the arm and shoulder treatment and intensive care of traumatised region patients. Together with the adjacent speci- • follow-up of donor-site morbidity of mi- alities, especially orthodontics, neurosurge- crovascular forearm flaps and scapular ry, paediatrics and ENT, the interdisciplinary flaps treatment of patients with complex malfor- • follow-up of patients suffering from os- mations and trauma is ensured. teoradionecrosis

Within the in-patient treatment as well as the consultation hours for outpatients, we Differential diagnosis of oral mucosa le- treat patients with: sions (U. Müller-Richter, T. Reuther) • neoplasia of head and neck (therapy and functional and aesthetical re- The investigations aim to establish new construction including microsurgical tis- markers which improve the estimation of sue transfer) the prognosis of different oral mucosa le- • trauma of jaws and viscerocranium sions. That shall enable the assessment of • craniofacial dysplasia (dysgnathic ano- the dignity and help to establish screening malies, clefts of lip, jaw and palate, cra- methods. niosynostosis) • demand on plastic-aesthetic reconstruction Research team for antigens of oral • dental implants including bone aug- squamous cell carcinoma mentation methods (U. Müller-Richter, A. Kübler) • dentoalveolar disorders (e.g. cysts, abscesses, osteomyelitis) Focus of the research is the characterisa- • disorders of salivary glands tion of the cancer/testis antigen subgroup • TMJ disorders MAGE-A in oral squamous cell carcinoma. • nerv lesions in the facial area Distinct antigens are investigated concerning their clinical relevance for prognosis and therapy.

Clinical research team for imaging methods (U. Müller-Richter, M. Kochel, H. Grimaldi)

Different imaging methods (e.g. based on ionised radiation, ultrasound, magnetic resonance) are evaluated for their applicabi- lity in well-defined interrogations. A further topic is the fusing facility of the various methods.

Clinical research team for bisphospho- nate-associated necrosis of the jaw (A. Kübler, T. Reuther, H. Grimaldi, M. Ko- chel)

110 In collaboration with the pathologic institute and face are presented, including treatment the histological characterization of the af- strategies and reconstructive options. fected bone as well as clinical prospective and retrospective studies concerning risk Within dentistry the fields of oral structure factors and concomitant diseases are con- biology, oral pathology, oral and maxillofa- ducted. cial surgery as well as dental radiology are taught. That includes the local dental anaesthetic techniques. These various fields Research team for tissue regeneration are communicated theoretical as well as in of oral mucosa practical courses and clinical traineeships. (T. Reuther, U. Kriegebaum, C. Klingelhöf- Further more the clinic is involved in the fer, A. Kübler) advanced education for already approbated colleagues due to the organisation of certi- The main focus is the evaluation of various fied meetings and courses, e.g. the Würz- dermal equivalents, i.e. biopolymer matri- burger Herbst-Symposium für Zahnmedi- ces with cultivated fibroblasts on their sur- zin. face. The aim is the tissue engineering of oral mucosa. The comparison of typical co- cultures (dermal equivalents plus keratinocytes) with dermal equivalents alone tends 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 transplant in the oral cavity are emulated and analyzed (mechanotransduction).

Research team for bone regeneration and bone substitution (U. Klammert, T. Reuther, C. Jahn, A. Küb- ler, U. Kriegebaum)

In collaboration with the Department for Functional Materials in Medicine and Den- tistry, novel bone replacement materials with calcium phosphate chemistry fabrica- ted by the rapid prototyping technique of 3D powder printing, are investigated in vitro Gbureck U, Hölzel T, Klammert U, Würzler and in vivo. Further more, bone growth fac- K, Müller FA, Barralet JE (2007): Resorb- tors (BMPs) developed by the department able Dicalcium Phosphate bone substitu- of physiological chemistry II are used for os- tes prepared by 3D powder printing. Adv teoinduction at the implantation site. Ano- Funct Mater 17: 3940-3945. ther topic is the improvement of the integra- Reuther T, Kettmann C, Scheer M, Kochel tion of autologous bone grafts by different M, Iida S, Kübler AC. 82006) modifications at the recipient site. Of parti- Cryopreservation of osteoblast-like cells: cular interest is the volume maintenance of viability and differentiation with replace- the transplant. New methods of cryoconser- ment of fetal calf serum in vitro. Cells Tis- sues Organs. 183:32-40. vation of autologous bone grafts are utilized in the clinical routine. Reuther T, Rohmann D, Scheer M, Kübler AC. (2005) Osteoblast viability and differentiation with Me2SO as cryoprotectant compared to osteoblasts from fresh human iliac cancellous bone. Cryobiology. Teaching 51:311-21.

The clinic ensures theoretical and practical SELECTED PUBLICATIONS Reuther T, A. Kohl, G. Komposch, educational engagements within both the P.Tomakidi. (2003) Morphogenesis and proliferation in mono- and organotypic co- medicine and the dentistry course. cultures of primary human periodontal fi- For medical students the clinic provides op- broblasts and alveolar bone cells. Cell Tis- portunities within multidisciplinary lessons sue Res 312: 189-96. and clinical traineeships. In the context of interdisciplinary oncological lectures typi- Müller-Richter UDA, Dowejko A, Zhou W, Reichert TE, Driemel O. (2007) Different cal tumorous lesions of the oral cavity, jaw expression of MAGE-A-antigens in foetal and adult keratinocyte cell lines. Oral On- 111 col. 2007 Nov 9; [Epub ahead of print]. 4.5 Department of Prosthodontics

Professor Dr. med. dent. Dipl.-Ing. Mission of the “Wuerzburg Post”, which is now Ernst-Jürgen Richter and Structure available for clinical use and is being eva- (Head of the Department) luated in a long term clinical study. It re- The Department of Prosthodontics with its sets on a revolutionary approach – “in- Pleicherwall 2 37 employees is one of five Departments verse conicity” and an annular grove – in 97070 Würzburg at the dental school of Würzburg Univer- which the causes of hardly unavoidable Tel.: 09 31 / 201-73020 sity. Its fields consist of education of both longterm failures (e.g. decementation of Fax: 09 31 / 201-73000 pre-med and med dentistry students and the restoration or radicular fracture) as- E-mail: [email protected] all aspects of prosthetic and restaurati- sociated with conventional post and core www.klinik.uni-wuerzburg.de/deutsch/ ve dentistry for ambulant patients, which systems are eleminated. einrichtungen/kliniken/PoliklinikfrZahnrztli- comprise traditional treatment such as CONTACT DETAILS CONTACT cheProthetik/content.html fixed and removable partial dentures to The construction is designed to permit a contemporary concepts using metal-free wide-based support of the restoration on Prof. Dr. med. dent. Thomas Holste and implant-supported perioprosthethics, the coronal root surface while requiring Tel.: 09 31 / 201-73060 orofacial prosthetics, adhaesive restorati- only a small depth for anchorage, which ons and therapy of patients with myofacial is achieved by means of positve locking Prof. Dr. med. dent. Alfred Renk pain and TMJ-disorders. by a specially designed, spreadable post. Tel.: 09 31 / 201-73080 The apical and middle part of the root are no longer subject to weakening, fracture of the root or decementation of the post are no longer possible. Mascatory forces are transmitted into the dentin through an annular groove and a corresponding fer- Major Research rule. The Wuerzburg Post is available in Interests two versions for FPDs or RPDs.

Clinical and in-vitro studies on dental im- The clinical experience with over 95 in- plantology are prominent subjects in the serted posts reflects excellent results as field of research with focus on improve- the survival rate is in excess of 97% within ment of implant design, e.g. special cor- a maximum period of observation of 24 tical threads in the neck-area of the im- months. plant and their consequences on bone- regeneration and -durability. An additio- An interfaculty task force (Department nal area of research is the debit of in line of Experimental Physics V) supported by standing connected and unconnected im- the industry (Prokuro GmbH, DeguDent- plants. Furthermore, so called “index imp- Dentsply) is engaged with the forward lants” and temporary implants are under looking technology of digital scanning of development. Over the course of the past teeth as well as the production of den- ten years strategic implants in combinati- tures/dental restorations by avoiding the on with removable dentures as well as an- flaw-associated interaction between in- gulated implants have stood in the light of pression taking and tranditional dental clinical interest. techniques. The digital procedures used so far are based on the optical scanning Experimental studies and finite-element of teeth which were prepared by the den- simulations have led to the development tist for in- and onlays, whereat the perpa-

Fig. 1: (a, left) X-Ray of two angulated implants which were inserted under athrophic bone levels without augmentation. (b, right) Fixed partial denture supported by one tooth and an angular implant.

112 Fig. 2: (a, left) Speadable bur for the un- dercut cavity. (b, right) FE-Simulation, ho- rizontal angle of attack. ration margins lie above the gingiva in the enamel. Typically, these prodedures are limited to one tooth. The dental MRT is an alternative to conventional digital methods as it is suitable for all aspects of restorative dentistry under given circum- stances, and exhibits considerable potential for the diagnostic of caries aswell as all other aspects of general dental diagnostics.

Hassel A J, Holste Th. (2007) Improving the Speech Function of Maxillary Complete Dentures: A Pilot Study. Int J Prosthodont; 19: 499-503.

Proff P, Bayerlein T, Rottner K, Mai R, Fanghänel J, Gedrange T. (2008) Effect of bone conditioning on primary stability of FRIALIT-2((R)) implants. Clin Oral Implants Res. 1: 42-7.

Rottner K, Richter EJ, Fanghänel J, Ge- drange T, Kubein-Meesenburg D, Nägerl H, Proff P. (2007) Effects of centric relation prematurities of the frontal teeth. Ann Anat.189:397-403.

Proff P, Richter EJ, Blens T, Fanghänel J, Hützen D, Kordass B, Gedrange T, Rott- ner K. (2007) A michigan-type occlusal

SELECTED PUBLICATIONS splint with spring-loaded mandibular pro- trusion functionality for treatment of anterior disc dislocation with reduction. Ann Anat.189:362-6.

Tymofiyeva O, Proff P, Richter EJ, Jakob, P, Fanghänel J, Gedrange T, Rottner, K. (2007) Correlation of MRT imaging with real-time axiography of TMJ clicks. Ann Anat.189:356-61. 113 4.6 Department of Conservative Dentistry and Periodontology

Professor Dr. med. dent. Bernd Klaiber Mission In patient-care special emphasis is based (Head of the Department) and Structure on minimal-invasive preparation and its adequate supply with adhesive techni- Pleicherwall 2 The Department of Operative Dentistry and ques: Due to the micro-mechanical an- 97070 Würzburg Periodontology (16 dentists – 4 of them in chorage of the restoring materials to the Tel.: 09 31 / 201-72420 the section of periodontology-, 12,5 den- conditioned enamel and dentine, the pre- Fax: 0931 / 201-72400 tal assistants -2.5 of them in the section paration of macro-mechanical cavities - E-mail: [email protected] of periodontology-, 2 dental technicians) with further loss of healthy tooth-sub- www.klinik.uni-wuerzburg.de/deutsch/einrich- is endued with 10 dental chairs - 3 of stance - can be set aside. Further em- tungen/kliniken/PoliklinikfrZahnerhaltungund- them in the section of periodontology-, 2 phasis is based on the Aesthetic Dentistry: Parodontologie/content.html working centres for the dental technicians adjustments of contour-, colour- and po-

CONTACT DETAILS CONTACT and facilities for taking radiographs. For sition-anomalies with non-invasive or mi- the practical part of the students´ edu- nimal-invasive techniques are made pos- cation 24 dental chairs are available, 40 sible through the use of adhesive materi- workings centres for laboratory dentistry als and modern resin-based composites. as well as 40 working centres providing In the majority of cases there is no more phantom-puppets. need to prepare the teeth for veneers or crowns. The conservation of healthy The area of responsibility of the Depart- tooth substance and the renunciation of ment of Operative Dentistry and Periodon- lab-made restorations are obvious advan- tology contains prevention, diagnostics tages in respect of biologic and financial and therapy of diseases to enamel and interests (Fig.1). dentine (caries, abrasion, erosion and trauma) as well as to the pulp (pulpitis, trauma) and to the periodontal ligament (periodontitis) and their sequelae. Each year approximately 4.000 patients are Major Research treated ambulatory. In co-operation with Interests the Department of Paediatrics, the De- partment of Anaesthesiology and the De- Research at the Department of Operati- partment for Oral and Maxillofacial Sur- ve Dentistry and Periodontology is focus- gery patients can be treated in general ed on the evaluation of restorative mate- anaesthesia. rials, appliances and devices required for

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).

114 Fig. 2: Spectral absorbance of photo-initiators compared to the spectral irradiance of different light curing units. conservative restorative therapy. In this The purpose of the current clinical studies context, the interactions between resto- is to compare newly developed restorative rative materials and dental hard tissues materials and appliances with those consi- and among different restorative materials dered to be the gold standard in the past. are studied. In some cases, undergraduate students can be involved in these studies. This lets them A universal testing machine allows the come to know the different tasks of a uni- determination of mechanical properties versity hospital. (compressive strength, flexural strength, tensile bond strength, shear bond Currently, a newly developed restorative strength, extrusion shear bond strength). material is evaluated for margin fidelity in Deformation of teeth under load and du- posterior cavities after four years of clini- ring photo-activated polymerization of re- cal service. Moreover, a newly developed Hofmann N, Markert T, Hugo B, Klaiber sin-based composite restorations can be rubber dam system (appliance for moistu- B. (2003) Effect of high intensity vs. soft- studied using displacement transducers. re control during operative procedures) will start halogen irradiation on light-cured re- Additional experimental setups allow the be compared to the conventional one. Until sin-based composites. Part I. Temperatu- evaluation of the kinetics and the total now, almost 300 patients have been inclu- re rise and polymerization shrinkage. Am J amount of polymerization shrinkage of re- ded in the study. Dent 16: 421-430. storative resin-based composites, as well Hofmann N, Markert T, Hugo B, Klaiber as the spectral irradiance of dental light In collaboration with the Department of B. (2004) Effect of high intensity vs. soft- curing units (Fig. 2). Neurology, interdisciplinary research pro- start halogen irradiation on light-cured re- jects addressing oro-facial pain are being sin-based composites. Part II: Hardness and solubility. Am J Dent 17: 38-42. The marginal seal of restorations is evalu- developed. ated using dye penetration techniques and Hofmann N, Hunecke A. (2006) Influence computer-based image analysis. The mar- of curing methods and matrix type on the gin fidelity of restorations in vivo and in vitro marginal seal of class II resin-based com- is monitored morphologically by the replica posite restorations in vitro. Oper Dent 31: 97-105. technique and a scanning electron microscope, which is used together with other de- Geis C, Feierabend S, Böhner W, Kares H,

partments of the dental school. SELECTED PUBLICATIONS Schirmer P, Busche E, Schindler HJ, Sie- gert J, Hugger S, Türp JC, Hugger A, Som- mer C. (2006) Schemata zur Schmerzein- An atomic force microscope is used in coo- zeichnung bei Patienten mit orofazialen peration with the Department and Chair of Schmerzen. Schmerz 20: 498-508. Functional Materials in Medicine and Den- tistry for studying the interface between Kremeier K, Fasen L, Klaiber B, Hofmann dental hard tissues and restorative mate- N. (2007) Influence of endodontic post type (glass fiber, quartz fiber or gold) and rials. luting material on push-out bond strength to dentin in vitro. Dent Mater (epub ahead 115 of print). 4.6.1. Division of Periodontology

Professor Dr. med. dent. Ulrich Schlagenhauf Mission burg and other national or international in- (Head) and Structure stitutions.

Pleicherwall 2 Besides Prof. Schlagenhauf the staff of the 97070 Würzburg department comprises further four dentists Microbial Recolonization and Inflamma- Tel.: 09 31 / 201-72630 and 3 dental assistents. The Dept of Peri- tion in Aggressive Periodontitis in the Fax: 09 31 / 201-72680 odontology is a clinical center for referrals Wake of Therapeutic Interventions (sup- E-mail: [email protected] of patients suffering from severe periodon- ported by the IZKF Wuerzburg) www-i.klinik.uni-wuerzburg.de/deutsch/ein- tal disease beyond the normal scope of a (U. Schlagenhauf, U. Vogel) richtungen/kliniken/AbteilungfrParodontologie practicing dentist. Especially the therapy of refractory aggressive periodontitis and gin- In patients suffering from aggressive peri-

CONTACT DETAILS CONTACT givoperiodontal manifestations of syste- odontitis the influence of adjunctive sys- mic diseases is at the focus of the special temic antibiotic therapy on the pattern of competence provided by the department to microbial recolonization as well as on the referring dentists and the public. In colla- intensity of clinical signs of inflammation boration with the Institute of Microbiology following periodontal therapy was evalu- and Hygiene of the University of Wuerzburg ated longitudinally over the course of 12 antiinfectious strategies for the therapy of months. It was observed, that the resoluti- aggressive periodontitis and perimplantitis on of clinically visible signs of inflammati- have been devised. Furthermore a therapy on is accompanied by a significant shift of concept for the treatment of oral manifes- microbial colonization patterns. tations of juvenile hypophosphatasia has been developed in close contact with the Pediatric Clinic of the University of Wuerz- Clinical and microbiological aspects of burg. Also guided tissue regeneration of pe- periodontal disease in patients suffe- riodontal lesion using tissue-inductive ena- ring from juvenile hypophosphatasia mel matrix proteins belongs to the clinical (U. Schlagenhauf, H. Girschick, U. Vogel) standard procedures provided by the department. Premature loss of deciduous teeth is a typical early symptom of hereditary juvenile hypophosphatasia. The underlying mechanisms however are only poorly under- Major Research stood. The purpose of the project is to cla- Interests rify whether tooth loss primarily is due to an inflammatory process driven by patho- The main research projects of the Dept. genic microbial biofilms or due to a inhe- of Periodontology are listed below. Some rited malformation of dental cementum. of them are joint efforts in collaboration First results revealed that the oral microflo- with other institutes and clinics in Würz- ra of hypophosphatasia patients is not si-

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

116 Fig. 2: Streptococcus sanguinis biofilm (fluorescence staining). gnificantly different from healthy age-mat- tablished mechanical measures which are ched controls. not sufficiently efficacious in narrow inac- cessible niches, bacterial biofilms may be influenced by chemotherapeutics or the Long-term success of adjunctive antibi- physical or chemical modification of the otic therapy in the treatment of aggres- surfaces to be colonized. In in vivo and in sive periodontitis vitro biofilm models the biofilm inhibiting (U. Schlagenhauf) properties of diverse chemotherapeutics are evaluated as well as the inhibiting ef- Periodontal lesions deeper than 8 mm are fect of some physical and electrochemi- generally regarded as irrational to treat and cal procedures. normally lead to the extraction of the affected tooth. In clinical cases however adjunctive antibiotic therapy combined with meti- colous mechanical biofilm removal resulted in a very pronounced healing even in Teaching deep defects so far regarded as untreatable. Aim of the investigations is to evaluate Dental undergraduate training comprises in a population of more than 100 patients all aspects of periodontology. After tea- Valenza, G., Burgemeister, S., Girschick, suffering from aggressive periodontitis the ching the theoretical base facts of perio- H., Schoen, C., Veihelmann, S., Moter, A., effects of a adjunctive antibiotic interventi- dontology firstly in dummy heads and sub- Haban, V., Vogel, U. & Schlagenhauf, U. on on the long-term healing success over a sequently in patients nonsurgical minimal- (2006). Analysis of the periodontal micro- time period of 3-5 years. ly invasive periodontal therapy procedures biota in childhood-type hypophosphatasia. Int J Med Microbiol, 296, 493-500. are instructed and supervised. Surgical therapy measures are practically instruc- Bokan, I., Bill, J. S. & Schlagenhauf, U. Inhibition of bacterial biofilm formation ted and trained in pig jaws. Postgraduate (2006). Primary flap closure combined by chemical and physical methods training in periodontology following the gui- with Emdogain alone or Emdogain and (U. Schlagenhauf, A. Ewald) delines of the German Society of Periodon- Cerasorb in the treatment of intra-bony defects. tology is available to junior staff members J Clin Periodontol, 33, 885-893. Bacterial biofilms exhibit a far more sus- of the department. tained resistance towards antimicrobi- Hutter, G., Schlagenhauf, U., Valenza, G., al host defense mechanisms than their Horn, M., Burgemeister, S., Claus, H. & Vogel, U. (2003). Molecular analysis of planctonically growing counterparts. The bacteria in periodontitis: evaluation of clo- efficient removal of proinflammatory mine libraries, novel phylotypes and putative crobial biofilms from the tooth surfaces pathogens. Microbiology, 149, 67-75. and the inhibition of bacterial recoloniza- SELECTED PUBLICATIONS tion is at the center of of the preventi- Gripp, V. C. & Schlagenhauf, U. (2002). Prevention of early mutans streptococ- on of periodontal diseases. Besides es- ci transmission in infants by professional tooth cleaning and chlorhexidine varnish 117 treatment of the mother. Caries Res, 36, 366-372. 5 Additional Scientific Units

In this chapter information on scientific insti- Transregios, five Graduate Colleges, and Furthermore, the MD/Ph.D. program, the In- tutions, cooperations and centers will be gi- other joint activities which are performed ternational Graduate School and Research ven which are initiated or partly organized by together with institutions of other faculties, Centers, Research Units and Research Alli- the Medical Faculty. The chapter comprises especially of the Biological Faculty. ances are described which are dealing with information on six Collaborative Research particular scientific problems. Centers (Sonderforschungsbereiche), two

118 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 goal of building a bridge from basic to clini- Fig. 1: Macroga- (Speaker) cal research. Altogether, fourteen individual mete contacting projects are funded, six of which were newly two gametocytes Institut für Virologie und Immunbiologie included in the current funding period. during fertilization Versbacher Str. 7 in the human ma- 97078 Würzburg laria parasite Plas- Tel.: 09 31 / 201-49951 Major Research modium falcipa- Fax: 09 31 / 201-49243 Interests rum. The cells are E-mail: [email protected] connected via fila- www.sfb479.uni-wuerzburg.de The researchers of the SFB 479 are inte- mentous structu- rested in the adaptation of pathogens to res formed by the

CONTACT DETAILS CONTACT Professor Dr. med. Matthias Frosch their hosts both during evolution and in the macrogamete. La- (Vice-Speaker) course of an infection, in the interaction of belling of the ga- Tel.: 09 31 / 201-46160 microorganisms with their target cells, and mete-specific sur- in the interplay between the host’s immune face protein Pfs25 Professor Dr. rer. nat. Roy Gross system and the invaders. The research pro- is shown in red, (Vice-Speaker) gram has been structured into correspon- labelling of the gametocyte protein Pfs230 Tel.: 09 31 / 888-4403 ding project areas, even though during the is shown in green. life of the SFB, these have, in part, been filled with new research topics: mune defense against viruses and bacteria (C6 Hünig/Brombacher; C11 J. Schneider- Project area A: Schaulies; C12 Topp/Einsele; C13 Lutz), Variability of Pathogens but also with the complex immunomodulatory interactions between the immune sys- Here, evolution and adaptation, but also re- tem and measles virus (C4 S. Schneider- gulation of pathogenicity factors in microbial Schaulies) and the fox-tapeworm Echino- pathogens are studied. Besides the bacteri- coccus multilocularis (C10 Brehm). al systems that had been established in the SFB for some time (E. coli: A1 Hacker/Dob- rindt; Bordetellae: A2 Gross; Streptococci: A7 Hammerschmidt; Meningococci: A10 Vo- Teaching gel), we have now included the fungus Can- dida albicans (A9 Morschhäuser), which is The SFB 479 interacts closely with the Gra- an important opportunistic pathogen in im- duate College 520 „Immunomodulation“, mune compromised patients. the Graduate Program of the Centre for Re- search on Infectious Diseases, and with the Graduate School for Life Sciences (GSLS), Project area B: guaranteeing a structured educational pro- Pathomechanisms in the interaction gram to its graduate students. General between microbe and host cells Information How does a pathogen prepare for the inva- Symposia After a successful review in 2006, the SFB sion of a host cell, and how does the cell 479 is now in its fourth and last funding respond to the infection? Such questions Every one to two years, the SFB organizes period (2007-2009). This has allowed the are in the focus of project area B. While an international Symposium with varying to- continuous development of the unifying re- with the retirement of Werner Goebel (Mi- pics derived from the themes of the SFB. search topic, i.e. the interaction of infec- crobiology), the intracellular pathogen Lis- Since the last research report, the following tious pathogens with host cells, but also teria monocytogenes was lost for the final Symposia have been held: with the intact host-organism, over the full funding period from the program of the SFB, 12 years which are the maximum life span we could complement the Meningococcal 2002 Genomics in Infectious Diseases of an SFB. The SFB 479 is composed of (B2 Frosch/Kurzai) and foamy-viral systems 2003 Triggering and Modulation of Natu- research groups of the medical and biolo- (B7 Rethwilm) with the parasite Plasmodi- ral and Acquired Immunity by Pa- gical faculties. The contributing institutions um falciparum, the causative agent of Ma- thogens are the Institute for Virology and Immuno- laria (B8 Pradel). 2005 Microbial Infection: Analysis, Pre- biology, for Hygiene and Medical Microbi- vention, and Use ology, for Molecular Biology of Infectious 2007 Host-Pathogen Co-Evolution: A Tale Diseases, and for Basic Microbiology (in Project area C: of Struggle and Affection the faculty of Biology), the Junior Research Immune response to and immunomodu- Groups of the Centre for Research on Infec- lation by microbial infections tious Diseases, and the Medical Clinic and Policlinic II. By including the Medical Clinic, This project area has grown to be the largest the SFB has realised the long-envisaged one within the SFB. It deals with the im-

119 5.1.2 Collaborative Research Center 487, Regulatory Membrane Proteins: From Molecular Recognition to Drug Targets

Professor Dr. med. Hermann Koepsell General amount (endocytosis, exocytosis) and the (Speaker) Information activity of integral membrane proteins in the plasma membrane. Furthermore, membra- Koellikerstr. 6 The SFB 487 “regulatory membrane prote- ne associated proteins play a critical role in 97070 Würzburg ins” has been founded in 2000 and is in its the regulation of cell metabolism, specific Tel.: 09 31 / 31-2711 third period of funding. The SFB 487 con- cell functions and mitosis because they in- Fax: 09 31 / 31-2087 sists of 15 research groups from the facul- itiate activation cascades. E-mail: [email protected] ties of medicine and biology. The research www.sfb487.uni-wuerzburg.de/ is focussed on molecular mechanisms of Important aims of the SFB 487 are to de- function and regulation of membrane pro- termine structures of physiologicaly and bi- Professor Dr. rer. nat. Roland Benz tein trying to extend our knowledge concer- omedicaly relevant membrane proteins and CONTACT DETAILS CONTACT (Vice-Speaker) ning function of receptors, channels, trans- to identify their functional epitopes. This Tel.: 09 31 / 888-4501 porters and membrane associated regula- includes binding sites for hormones, neu- tory proteins. Therefore a broad spectrum of rotransmitters, substrates and interacting Professor Dr. med. Martin J. Lohse methods is applied ranging from measure- proteins. The structural results will be sup- (Vice-Speaker) ments on isolated proteins to investigations plemented with functional investigations to Tel.: 09 31 / 201-48401 in living animals. Biochemical methods are understand the physiology role of individu- used to identify interaction domains of pro- al proteins. Functional data of membrane Professor Dr. med. Walter Sebald teins and ligand binding sites, and to deter- proteins in vivo are acquired from cultiva- (Vice-Speaker) mine tertiary structures of the proteins. Pro- ted cells, intact organs or living animals. Af- Tel.: 09 31 / 888-4111 tein interactions and protein motion in cells ter the establishment of functional mecha- are analysed using methods of cell biology, nisms of individual membrane proteins the biochemistry, and genetics. Finally the phy- acquired knowledge will be used for the de- siological function of membrane proteins is velopment of novel therapeutic drugs. investigated in intact organs and living animals after knock out or over-expression of certain genes. Thus, the SFB 487 is a me- Research area A: Proteins with several thodological platform that allows access to transmembrane domains a variety of methods for the investigation of membrane proteins. The ultimate goal of A1 Lohse (Pharmacology): Desensitization all efforts is the identification of novel phar- and internalization of G-protein coupled re- maceutical targets in membrane proteins. ceptors This may lead to novel therapies of diseases caused by membrane protein mal-function A4 Koepsell/Gorboulev (Anatomy and Cell- or mal-regulation. biology I): Investigation of the structural basis of substrate recognition, of transport mechanism, and regulation of organic cation transporters

Major Research A5 Benz (Biotechnology): Mechanism and Interests pharmacology of toxin transport on model membranes The common research topic of the SFB 487 are proteins at cell surfaces that regu- A9 Hedrich (Molecular Plant Physiology late cell functions. Cells are surrounded by and Biophysics): Regulation and targeting a phospholipide bilayer membrane, which of tandem pore channels associated with separates them from the environment. In the KCO family these bilayer membrane a multitude of proteins (integral membrane proteins) are A10 Bünemann (Pharmacology): Kinetics embedded. Other proteins are associated and structural aspects of G-protein coupled with the outer or inner leaflet of the plasma signal transduction membrane (membrane associated proteins). Integral membrane proteins are parts of signal transduction pathways (receptors), Research area B: Proteins with a single involved in solute shuttling across the plas- transmembrane domain ma membrane (channels, pores, transporters), or are involved in cell-cell communi- B1 Sebald (Physiological Chemistry II): Mo- cation (cell contact proteins). Membrane lecular recognition and primary activation associated proteins stabilise the plasma steps in BMP/GDF-receptor complexes membrane and mediate contacts of cells with extracellular (i.e. collagen fibers) or B2 Müller (Molecular Plant Physiology and intracellular proteins (i.e. actin filaments). Biophysics): Affinity, specificity and promis- Membrane associated proteins regulate the cuity of cytokine receptors

120 Fig. 1: Demonstration of α2-adrenergic receptor activation on neuronal differentiated PC12-cells by means of fluorescence resonance energy transfer (FRET).

B3 Schartl/Meierjohann (Physiological Che- and Cell Research): Regulation of cell ad- mistry I): Protein interactions at the onco- hesion and the cytoskeleton by p21-activa- genic growth factor receptor Xmrk ted kinases during neuronal differentiation

B5 Drenckhahn (Anatomy and Cellbiology II): Modulation of binding of cadherins Symposia

B7 Wajant (Molekulare Innere Medizin): Internal SFB-Symposia: Mechanisms of TNF-receptor-activation Oktober 2-3, 2003 Oktober 15-16, 2004 B8 Kuhn (Institute for Physiology I): Mecha- Oktober 6-7, 2006 nisms and relevance of the desensitization Oktober 5-6, 2007 of the ANP receptor, the guanylyl cyclase A (GC-A), for the cardiac hypertrophy International Symposia: “Mechanisms of protein activation”, June 10 – 12, 2004 Research area C: Membrane-associa- “Membrane proteins and diseases”, June ted regulatory proteins 7 - 9, 2007

C1 Koepsell Anatomy and Cellbiology I): Functions of Na+-D-glucose cotransporters and their regulation by the regulator protein RS1

C3 Rapp (Institute for Radiation Biology and Cell Research): Dynamics of the recruitment of Raf-multiprotein complexes at cellular membranes upon receptor activation: Role of scaffold proteins and lipid interactions

C4 Sendtner (Klinische Neurobiologie): Pro- tein interactions of receptors for neurotrophic factors

C5 Raabe (Institute for Radiation Biology

121 5.1.3 Collaborative Research Center 567, Mechanisms of Interspecific Interactions of Organisms

Professor Dr. rer. nat. Markus Riederer Major Research Signals in the Interaction Partners (Speaker) Interests The central objects of investigation in this Julius-von-Sachs-Platz 3 In 16 projects scientists are engaged in ap- project area are those signals and result- 97082 Würzburg proaches based on physiology, molecular ing adaptations, which are formed within Tel.: 09 31 / 888-6200 biology, ecology, evolutionary biology and organisms as a response to biotic interac- Fax: 09 31 / 888-6235 biophysics. A broad systematic spectrum of tion. Trans-membrane ion and metabolite E-mail: [email protected] interaction systems is analyzed by applying flows and their functional role in the mo- www.sfb567.uni-wuerzburg.de techniques from infectious biology, phyto- lecular response of a plant upon interac- pathology and analytical chemistry in order tion with microorganisms are investigated. + Professor Dr. rer. nat. Rainer Hedrich to address the following central questions: Here, the molecular basis and role of Ca² CONTACT DETAILS CONTACT (Vice-Speaker) • What are the mechanisms underlying signals, expression and regulation of mass Tel.: 09 31 / 888-6100 interspecies recognition in different in- transport with respect to an infection with teraction systems? Agrobacterium or Pseudomonas are ana- • What kind of information flow is required lyzed. In response to interactions between for the establishment and maintenance microbes and plants the formation of sec- or termination of interactions? ondary plant metabolites, specific molecu- • What is the nature of substantial and lar patterns and the structural and function- energetic resources to be exchanged al characteristics of involved proteins are in- between interaction partners? How is vestigated. this exchange initiated and regulated? What are the genetic and physiological predispositions required to permit inter- Continuity and Evolution action? • How is the flow of information and re- This project area is concerned with the reg- sources generated within the interac- ulation and maintenance of interspecific in- tion partners and how is it finally trans- teractions, investigating a broad spectrum mitted? of tight and obligate symbiotic systems. General • What is the role of the phenotypic plas- Regulatory aspects of even intracellular Information ticity of the partners with respect to es- symbioses (bacteria/ants, microbes/spong- tablishment and maintenance of inter- es) and mutual interactions of more than The Coordinated Research Centre (Sonder- action? two partners (plant/bee/herbivore) are an- forschungsbereich) 567 “Mechanisms of • What are the molecular, morphological alyzed. Moreover, a gynogenetic fish spe- Interspecific Interactions of Organisms” at and behavioural adaptations that can cies serves as a model system to explore the Julius-Maximilians-Universität Würzburg be explained as an evolutionary conse- the evolutionary advantages and/or disad- was established in January 2001 with the quence of interaction? vantages of sexual reproduction. Within the objective to provide a substantial multidis- project area „Continuity and Evolution“ two ciplinary contribution to the investigation of Only the comparative assessment and in- projects of the Medical faculty are included, interactions between organisms belonging tegration of results based on a wide range which are working on the interaction of ma- to different species – symbioses in a broa- of levels of complexity can elucidate com- rine sponges and microorganisms and on der sense. This is achieved by investigating mon principles, characteristics and benefits the interaction of fishes with their hosts: interaction systems from a wide spectrum of symbioses. TP C3: Hentschel/Steinert/Hacker: Analyses of species and over several levels of orga- of the interaction of the sponge Aplysina ae- nization. The Sonderforschungsbereich 567 is subdi- rophoba with associated microorganisms. vided into three project areas: „Recognition TP C5: Schartl: Molecular and cytogenetic This integrative approach combining mole- and Reaction“, „Signals in the Interaction mechanisms of the interaction between the cular and organismic biology is supposed to Partners“ and “Continuity and Evolution”. gynogenetic Amazon molly (Poecilia formo- strengthen and intensify the technical and sa) and his hosts (P. mexicana und P. lati- conceptual exchange between these two pinna). mainstream fields of modern biology rep- Recognition and Reaction resented by various disciplines within three faculties (biology, medicine, chemistry and This project area focuses on signals that pharmacy). lead to the unilateral or mutual recognition of interaction partners and investigates The interdisciplinary structure of the Co- mechanisms involved in the development of ordinated Research Centre greatly facili- compatibility or incompatibility between or- tates the incorporation of multidisciplinary ganisms of different species. This includes aspects into teaching. This helps to famili- the analysis of plant surface characteristics arize undergraduate and postgraduate stu- affecting the recognition of hosts and non- dents with current methods and techniques hosts by obligate biotrophic fungi. Other ap- used in biology and adjacent fields in order proaches investigate pathogen defense re- to improve their qualifications to meet the actions in plant and animal systems on the requirements of the professional world. molecular and cellular scales.

122 5.1.4 Collaborative Research Center 581, Molecular Models for Diseases of the Nervous system

Professor Dr. med. Michael Sendtner General Major Research (Speaker) Information Interests

Institut für Klinische Neurobiologie The “Collaborative Research Centre” SFB The SFB 581 has set the goal to investigate Zinklesweg 10 581 „Molecular models of diseases of the complex course of primary and second- 97078 Würzburg the nervous system“ was established in ary pathophysiological processes in diseas- Tel.: 09 31 / 201-44000 the year 2000 at the University of Würz- es of the nervous system. Diseases of the Fax: 09 31 / 201-49788 burg. It comprises groups from the facul- nervous system follow a complex course of E-mail: [email protected] ties of medicine (clinical and theoretical primary and secondary pathophysiological http://www-i.klinik.uni-wuerzburg.de/deutsch/ institutes), biology and chemistry. The cen- processes leading from a causative cellu- forschunglehre/forschung/sonderforschungs- tral goal is to investigate how gene muta- lar dysfunction to the disease phenotype. CONTACT DETAILS CONTACT bereiche/SFB581/content.html tions ultimatively lead to the specific phe- Despite the fast progress in the last two notypes in these diseases, to identify con- decades in uncovering gene defects, which Professor Dr. med. Klaus Viktor Toyka tributions of reactive cells and neural activ- was particularly made possible due to the (Vice-Speaker) ity in diseases of the nervous system and genome projects for human, mouse, dro- Tel.: 09 31 / 201-23750 thus to contribute to a better understand- sophila and other species, it is often not ing of the underlying disease mechanisms. possible to understand the pathophysiolog- Frau Urveen Oberoi-Lehrieder (Office) For that purpose two main focuses were ical steps from the primary cause of these Tel.: 09 31 / 201-49787 set: the projects of part A focus on mech- diseases, for example a gene defect, to the anisms of inflammatory diseases, whereas specific disease phenotype and from there- the projects in part B deal with molecu- on to development of new therapeutic strat- lar mechanisms of degenerative diseases. egies. This situation calls for a cell biologi- These two project parts are supplement- cally oriented neurobiology, which, in a net- ed by two central projects on morpholo- work with clinical researchers, investigates gy/electron microscopy and modern light the cell biological cascade of disease de- microscopic techniques (confocal micros- velopment using suitable disease models. copy). Thus the main emphasis in the SFB 581 is

Fig. 1: Degeneration of spinal motoneurons (top) in a mouse model for spinal muscular atrophy (bottom).

123 put on mouse, drosophila and zebrafish models, with which not only the direct effect of signal transduction mechanisms on cellular structures and functions in the nervous system can be investigated, but also pathophysiological processes with which the interactions of different cell types can be investigated in neuroimmunological and neurodegen- Fig. 2: Zebra- erative diseases. fish (top) as a model orga- The goal of the SFB is to nism for the connect the molecular cell analysis of biologically oriented funda- axonal chan- mental research to the un- ges during mo- derstanding of the complex toneuronal di- course of disease proc- seases (bot- esses. As this can only tom). be achieved in an interdisciplinary approach, the SFB 581 links groups working with differ- ing a considerable budget for student and ent methods on model systems for neuro- graduate assistants. Members of the SFB degenerative and neuroimmunological dis- 581 are actively involved in courses within ease processes. the training programs for these students. The SFB 581 is also involved in the training This collaborative research centre contrib- of graduate students which is being coor- utes significantly to training programs for dinated in the class “Neuroscience” of the students in the fields of Biology, Biomed- International Graduate School by the Uni- icine as well as Experimental Medicine. versity of Würzburg. Thus the SFB plays a Since the SFB was established, students major role not only in promoting research in that are trained in these fields are enabled neurobiological research groups at the Uni- to participate actively in the projects. For versity of Würzburg, but also in promoting this purpose the Deutsche Forschungsge- young researchers in training programs in meinschaft and the University are provid- the field of neurobiology.

124 5.1.5 Collaborative Research Center 630, Recognition, Preparation and Functional Analysis of Agents against Infectious Diseases

Professor Dr. rer. nat. Dr. h.c. General mechanics, molecular modelling, docking Gerhard Bringmann (Speaker) Information and molecular dynamics simulations allow the design and optimisation of tailor-made Institute for Organic Chemistry The SFB was founded in 2003 to create inhibitors for chemical synthesis. The close Am Hubland an interdisciplinary platform to initiate the collaboration of the groups with their dif- 97074 Würzburg development of novel drugs against infec- ferent expertise and specialised knowledge Tel.: 09 31 / 888-5361 tious diseases. The goal of the SFB is the is the basis and the driving force of the re- Fax: 09 31 / 888-4762 identification of novel agents against infec- search success of the SFB. E-mail: [email protected] tive pathogens, to characterize their mode www.sfb-630.uni-wuerzburg.de of action and to optimise their efficiency. The complexity of this task requires inter- Project division A: Preparation, charac-

CONTACT DETAILS CONTACT Professor Dr. rer. nat. Dr. h.c. mult. Jörg Hacker disciplinary approaches. The 3 project divi- terisation and optimisation of agents (Vice-Speaker) sions of the SFB consist of 17 project parts Tel.: 09 31 / 31-2575 which emanate from four different facul- A1 U. Holzgrabe (Institute for pharmacy ties: the faculty of chemistry and pharma- and food chemistry) Professor Dr. rer. nat. Ulrike Holzgrabe cy, of biology, of medicine and of physics Small molecules for the treatment of in- (Vice-Speaker) and astronomy and, additionally, from the fectious diseases Tel.: 09 31 / 888-5461 Institute of tropical medicine of the Medical Mission Clinic. The three project divisions A2 G. Bringmann (Institute for organic che- are devoted to different duties: projects in mistry) group A prepare, characterize and optimise A new class of active agents against in- the compounds, which are then analysed fectious diseases for their activity in cellular and molecular systems in group B. The dissection of their A3 C. Schmuck (Institute for organic che- mode of action on the molecular level as mistry) well as optimisation predictions are per- Target-oriented combinatorial synthesis formed by projects in group C. of potential new antiinfective lead structures

Major Research A4 T. Schirmeister (Institute for pharmacy Interests and food chemistry) Proteases as targets for agents against Due to the rapid spread, the faster emer- infectious diseases gence and the development of resistances, infectious diseases have an even grow- A5 U. Hentschel (Research Center for In- ing impact on public health today. Efficient fectious Diseases) drugs are especially needed for tropical Novel secondary metabolites from spon- diseases, for which only insufficient thera- ge-associated microbiota pies exist. Hence, the development of novel agents with novel mode of actions is of major global importance. The groups within Project division B: Interaction with cel- the SFB exploit natural sources like plants, lular and molecular systems marine sponges and sponge-associated microbes as well as the versatile possibilities of B1 J. Hacker (Institute for infectious biolo- combinatorial chemistry to generate small gy) effector molecules. The inhibitory activity of Prolylisomerases and serine proteases these compounds is examined for a variety as targets for rational drug develop- of clinically most relevant pathogenic bac- ment teria, fungi and parasites. Modern technologies like transcriptomics, proteomics, me- B2 J. Morschhäuser (Institute for infectious tabolomics and spectroscopy as well as the biology) bioinformatic analysis of cellular networks Inhibition of virulence and resistance enable the characterization of the detailed mechanisms of Candida albicans mode of action of the active agents. The efficiency and effects in vivo are analysed by B3 H. Moll (Institute for infectious biology) NMR imaging of the infections in well-estab- Analysis of the action of naphthylisoqui- lished small animal models. Moreover in an noline alkaloids and cysteine protease additional approach, effector molecules are inhibitors against Leishmania parasites designed on a rational basis against defined well-characterized pathogenicity factors like B5 K. Ohlsen (Institute for infectious biolo- proteases, fatty acid biosynthesis enzymes gy) or efflux pumps. Based on the three dimen- Drug-induced gene expression in sta- sional structure of these targets, quantum phylococci

125 B7 C. Kisker (Rudolf Virchow Center) Joint PhD-student meetings of the SFB 630 Structure-based drug design on essen- and SFB544 tial enzymes from Mycobacterium tu- New Trends in Infectious Disease Research berculosis and other pathogens 10. – 12.11.2004 23. – 25.11.2006

Project division C: Characterization of the molecular mechanism of antiinfectives and predictions for their accelerated optimisation

C1 S. Schlücker (Institute for physical chemistry) CARS microscopy, Raman and IR spectroscopy for the localization and characterization of drugs and their interactions

C2 C. Faber (physical institute) NMR spectroscopy and imaging for in vivo and in vitro characterisation of infections and agents against infectious disease

C3 B. Engels (Institute for organic chemistry) Theoretical studies to characterize inhibition mechanisms and ligand-target complexes

C6 T. Dandekar (Institute for bioinformatics) M. Unger (Institut für Pharmazie und Le- bensmittelchemie) Metabolic and bioinformatical analysis of drug effects on cellular networks ex- emplified in Candida albicans

C7 C. Sotriffer (Institute for pharmacy and food chemistry) Computatinal structure-based drug design for the identification and characterization of new inhibitors of antimicrobial targets

Central project

Z1 T. Ölschläger (Institute for infectious biology) A. Stich (Medical Mission Clinic, Institu- te for tropical medicine) Laboratory for the central evaluation of potential antiinfective agents

Symposia

International Symposium Novel Agents against Infectious Diseases – an Interdisciplinary Approach 12. – 15.02.2006

126 5.1.6 Collaborative Research Center 688, Mechanisms and Imaging of Cell-Cell Interactions in the Cardiovascular System

Professor Dr. med. Ulrich Walter (Speaker) and scar formation, that strongly influence medicine. Analysis of the functional proteo- heart and brain function, are also investi- me, phosphoproteome and interactome of Institut für Klinische Biochemie und Pathobi- gated. The use of new MR contrast agents human platelets also promises to widen ochemie and high field MR imaging (up to 17.6 Tes- therapeutic options in clinical medicine. Josef-Schneider-Str. 2 la) permits better surveillance of heart and 97080 Würzburg vascular function in the living organism. Investigations in mice harbouring a deletion Tel.: 09 31 / 201-45346 of the p50 subunit of the transcription fac- Fax: 09 31 / 201-45153 tor NF-kappaB exhibited reduced cardiac is- E-mail: [email protected] Project Area A: (Fundamentals and me- chemia-reperfusion damage. Bone marrow www.sfb688.de chanisms of vascular cell-cell interac- transplantation experiments identified atte- tions) nuated activation of NF-kappaB in leukocy-

CONTACT DETAILS CONTACT Professor Dr. med. Georg Ertl (Vice-Speaker) tes as the underlying mechanism. Tel.: 09 31 / 201-36300 This project area investigates the initiation of pathological cell-cell interactions espe- Also with regard to regenerative processes Professor Dr. med. Bernhard Nieswandt cially between platelets, monocytes, leuko- in the vascular wall the SFB 688 made es- (Vice-Speaker) cytes, and endothelial cells in the vascular sential advances: translational studies in Tel.: 09 31 / 201-44063 system. These cells play a central role in mice and patients demonstrated that treat- primary haemostasis, but also in vascular ment with growth hormone via secretion of thromboses leading to organ dysfunction. insulin-like growth factor-1 improved the Adhesion of platelets and other cells to the age-related dysfunction of endothelial pro- vascular wall, together with local activation genitor cells that are essential for vascular of plasma coagulation, constitutes a com- protection and reparation. General plex process leading to pathological throm- Information bus formation. In general, the long-term objective of several SFB research projects is to identify more Cardio- and cerebrovascular diseases ac- Although funded only for the last two years, effective and safer prevention of thrombem- count for most deaths worldwide. The SFB the SFB 688 has already generated seve- bolic events, and to characterize other tar- 688 center grant funded since 2006 crea- ral outstanding results. Unexpected impor- gets for improving therapeutic options for tes a research network involving Würzburg tance of the clotting factor XII (Hagemann patients with arteriosclerosis, myocardial scientists and clinicians from four faculties factor) in stabilisation of arterial thrombi infarction and stroke. and eleven institutes/clinics of the Universi- could be demonstrated. Factor XII deficient ty. It focuses on understanding central pa- mice are protected from vascular throm- thophysiological processes such as thromboses and stroke, but not at the expense Project Area B: Molecular and functio- bosis, as well as secondary processes set of increased bleeding risk. Blockade of the nal imaging of the cardiovascular sys- in motion which lead to subsequent dama- platelet glycoprotein Ib likewise prevented tem and its cell-cell interactions ge and failure of the heart, vascular system secondary infarct growth, without bleeding and brain. New signalling molecules which complications. The use of animal models This project area encompasses imaging mediate cell-cell interactions are investiga- for myocardial infarction and stroke has ser- projects having the long-term goal of visu- ted in order to identifiy suitable candida- ved to link understanding of basic cellular alizing the dynamics of lesion development te targets of innovative concepts for pre- mechanisms to problem solving in clinical in murine models of vascular diseases in vention and treatment of cardiovascular di- vivo. For this purpose, new MR techniques seases. for imaging the vascular system, and for as- Of special importance is the development sessment of cellular infiltration and the ex- of new magnetic resonance (MR) imaging pression of critical signalling molecules, are techniques that allow in-vivo monitoring of developed and applied to disease models disease progression in experimental models generated in Project Area A. The effort invol- and patients with vascular disorders. ves generation of novel MR contrast agents and analytical sequences. In atherosclerosis, the acute infiltration of Major Research T cells and macrophages is regarded as an Interests important indicator of impending plaque destabilisation and increased risk for my- This integrated approach unites comple- Fig. 1: Magnetic resonance imaging of a ocardial infarction or stroke. Thus, in vivo mentary areas of research including mole- beating heart of an ApoE knock-out mouse MR imaging of these processes (see Fig. 1) cular biology, physiology, biophysics, prote- with accelerated arteriosclerosis. (A) Heart and the signalling molecules involved (wit- omics, and bioinformatics, with clinical me- ventricles and aortic arch are shown. (B) hout tissue harvesting) may help to iden- dicine. Molecular and pharmacological mu- Cross section through the aortic root at tify plaques at risk and to monitor preven- rine disease models are generated in the the level of the dashed line in A. After in- tion and therapy of vascular diseases. The SFB and used by clinically-oriented groups jection of MR contrast agent containing experimental results generated using high- to gain new insights into the development iron-particles (C), acute infiltration of ma- field MR imaging will be transferred to clini- of thrombosis, myocardial infarction and crophages at the aortic valve can be visu- cal field strengths for the monitoring of pa- stroke. Certain secondary complications of alized as indicated by the reduction of the tients with atherosclerosis and at high risk cardiovascular disease, such as oedema signal intensity on T2-w MRI (S.I.). for thrombembolic events.

127 5.1.7 Transregio-Collaborative Research Center 17, Ras-dependent Pathways in Human Cancer

Professor Dr. rer. nat. Dr. h.c. Manfred Schartl General Ras pathway is not stereotype, but is dic- (Speaker Würzburg) Information tated by the genetic status of the cell. Hu- mans harbor protective mechanisms that Physiologische Chemie I The Transregio 17 is formed by researchers prevent tumor induction by a single muta- Biozentrum, Am Hubland at the universities of Marburg and Würzburg tion of a proto-oncogene such as Ras. As 97074 Würzburg and is coordinated by Martin Eilers and Man- a result, multiple mutations have to accu- Tel.: 09 31 / 888 -4148 fred Schartl. The Transregio started in 2004 mulate in a single cell before it develops Fax: 09 31 / 888 -4150 / -4242 and will continue its work for a second pe- into a tumor. E-mail: [email protected] riod after a very positive evaluation www.imt.uni-marburg.de/tr17 in February 2008. In total the- Therefore, it is necessary to under- re are about 20 project lea- stand in molecular detail how

CONTACT DETAILS CONTACT Professor Dr. rer. nat. Martin Eilers ders and within each pro- the genetic status (Speaker Marburg) ject there are diploma of a cell affects the and PhD students wor- outcome of deregu- Institut für Molekularbiologie und king on their theses. lated signaling th- Tumorforschung All PhD students are rough the Ras pa- Universität Marburg members of an inte- thway. This does not Emil-Mannkopff-Str. 2 grated Graduate Col- solely apply to cellular 35033 Marburg lege, organized by the phenotypes, but also Tel.: 0 64 21 / 286 -6410 members of the Trans- to the clinical phe- Fax: 0 64 21 / 286 -3114 /-5196 regio. The projects are nomena that we ul- E-mail: [email protected] subdivided into three timately need to un- areas distributed over derstand, like invasi- the two participating union, metastasis and versities, however, there the response to the- is a very close interac- rapy. tion between all areas and projects. A special To approach the- focus of the Transre- se questions, the regio is the integration of clinical and search program con- translational research and the esta- centrates on the elucida- blishment of key technologies through tion of signal transduction central facilities and specific projects. through the Ras pathway (project area A), the analysis of cellular responses to Ras and their genetic control (project area B), Major Research and investigation of Ras-dependent signa- Interests ling in human tumors (project area C). Key technologies supplied by members of the The Transregio aims at understanding how key cellular properties of tumor cells, such as deregulated proliferation, apoptosis, chemoresistance and metastasis emerge from the interaction between deregulated signaling pathways and the genetic status of the tumor cells. Cancer is most often defined as a disease of aberrant cell signaling. While the individual molecules that constitute signal transduction pathways, their biochemical functions and the way they are mutated in human cancers are increasingly well understood, we know very little about how deregulated signal transduction trans- lates into those cellular and clinical pheno- Fig. 1: Medaka fish expressing the Xmrk mena that ultimately dictate the course of transgene under the control of the meda- the disease in the patient. This is particu- ka mitf promoter. Upper: fish with a non- larly true for the Ras pathway, which has malignant hyperpigmentation, a large emerged as a key signal transduction pa- area of the tail fin is covered by melano- thway that contributes to the genesis of a cytes. This type of pigmentation abnor- wide variety of human tumors. mality is a precursor lesion that eventually can develop into melanoma. Lower: The striking observation underlying much of Fish with highly malignant melanoma the work in this Transregio is that the out- showing metastasis and invasion at va- come of deregulated signaling through the rious sites. (by Manfred Schartl).

128 Fig. 2: DeltaNp73 as an inhibitor of the p53 family of tumor suppressors blocks the cell cycle exit and the expression of muscle marker genes when C2C12 myoblasts are induced to differentiate into mature myotubes. This differentiation block enables malignant transformation of myoblasts by Ras-activating oncogenes. Shown are immunofluorescence stainings for S-phase cells (BrdU, green), for myosin as a differentiation marker (red) and for nuclei (DAPI, blue). (by Thorsten Stiewe).

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 Fa- culty of Würzburg include Physiological Che- mistry I (Stefan Gaubatz, Svenja Meierjo- hann, Manfred Schartl), Physiological Che- mistry II (Martin Eilers) and Internal Medici- ne II (Ralf Bargou).

Symposia 2. – 4. April 2007, Rothenburg ob der Tau- ber, 1st Symposium of the Transregio 17: Ras-Dependent pathways in human cancer

129 5.1.8 Transregio-Collaborative Research Center 34, Patho- physiology of Staphylococci in the Post-genomic Era

Professor Dr. rer. nat. Dr. h. c. mult. General comial pathogens, since infections caused Jörg Hacker (Speaker Würzburg) Information by these strains have become difficult to treat. In recent years, S. aureus and S. epi- Institut für Molekulare Infektionsbiologie The aim of this SFB/Transregional collabo- dermidis caused more than 50% of all no- Röntgenring 11 rative research center (TR34) is to take ad- socomial infections. Vancomycin has be- 97070 Würzburg vantage of the great opportunities offered come the drug of choice for treating MRSA Tel.: 09 31 / 31-2575 by the post-genome era to achieve a new infections. However, the emergence of van- Fax: 09 31 / 31-2578 quality of understanding of the life proces- comycin-resistant MRSA strains represents [email protected] ses of the important human pathogen Sta- a great threat for humans, leading to urgent www.uni-greifswald.de/forschen/sonderfor- phylococcus aureus. To reach this ambitious demands for alternative anti-MRSA thera- schungsbereiche/staphylokokken.html aim the expertise of groups in Tübingen and pies and the development of entirely new

CONTACT DETAILS CONTACT Würzburg in cell physiology/biochemistry approaches for antibacterial drug research. Professor Dr. Michael Hecker and infection biology of Staphylococcus au- It is generally accepted that a more holistic (Coordinating Speaker) reus in general is combined with the estab- understanding of the cell physiology of this lished expertise in proteomics of Gram-po- pathogen constitutes an essential step to- Institut für Mikrobiologie und Molekularbiologie sitive bacteria in Greifswald. The research wards the development of new antibacterial Friedrich-Ludwig-Jahn-Straße 15 projects are grouped in three parts: in part approaches to combat S. aureus infections. 17487 Greifswald A (5 projects), the general physiology of S. In the SFB/TR34 projects, the great poten- aureus is considered, dealing with such es- tial of functional genomics will be used to sential chapters as the regulation of meta- accomplish such a new quality in the com- bolism, and the stress and starvation re- prehension of S. aureus physiology and in- sponses with a tight connection to its pa- fection biology, leading finally to a better un- thophysiology, a theme that has frequently derstanding of the entire infection process. been underestimated in the past. The regulation of cell-surface-bound and extracellu- The projects of the groups in Würzburg deal lar virulence factors constitutes the focus of especially with different aspects of host-pa- part B (5 projects). Project area C (4 pro- thogen interactions. Project part A2 studies jects) deals with the behavior of the patho- eukaryotic-type serine/threonine protein ki- gen in the host and will provide new infor- nases (ESTPKs) and protein phosphatases mation on the host-pathogen interaction. that are probably involved in the regulati- Various approaches of functional genomics on of several physiological pathways. The will be applied, such as proteomics, compa- outcome of this work will open a new field rative genomics, transcriptomics, structural in signal transduction. Comparative protein genomics, bioinformatics, and mathemati- expression/mRNA profiling of the wild-type cal modelling. and the corresponding mutants will provide data on the physiological role of both prote- Project leader Würzburg: ins. Furthermore, mutant constructions fol- Dr. K.Ohlsen (A2) lowed by a structural analysis of the kina- Prof. Dr. T. Dandekar (A5) se will explore the structure and function PD Dr. W. Ziebuhr (B4) of these proteins. Moreover, phosphopro- Prof. Dr. Dr. h.c. mult. J. Hacker (C2, C3) teome analysis will be performed to unravel Prof. Dr. A. Szalay (C3) the function of the kinases and corresponding phosphatases in S. aureus to identify putative substrates of kinase and phospha- tase activity. Major Research Interests In the A5 project, modern techniques of bioinformatics are applied for modelling of Staphylococcus aureus is a human patho- metabolic and cellular networks and enzy- gen of increasing importance, mainly as me cascades to describe the physiology of a result of the spread of antibiotic resis- different staphylococcal strains under dif- tances. The pathogenicity of this species is ferent growth conditions. Different functio- very complex and involves the strongly renal genomics and system response data gulated synthesis of cell surface-associated are integrated to model central metabolism and extracellular proteins forming a highly (e.g. central carbon metabolism) and the variable set of virulence factors. Due to the stress and adaptation network during dif- great variety of these proteins, S. aureus ferent stages of the growth cycle in vitro. causes a broad spectrum of infectious di- These models will then be expanded to the seases ranging from superficial abscesses metabolism of S. aureus in general. A new of the skin to endocarditis, osteomyelitis, and emerging field that is becoming the in- toxic shock syndrome, and sepsis. Methi- creasing focus in model bacteria such as E. cillin-resistant S. aureus (MRSA) strains are coli and B. subtilis is the role of small regu- currently predominant and dangerous noso- latory RNAs in cell physiology. These RNAs

130 Fig. 1: Bioluminescence of Staphylococcus aureus in the subdermal infection model. The time course of bioluminescence was monitored for 5 consecutive days (d0 to d5) after subdermal infection of the lower back area of mice with 1x106 CFU S. aureus Xen29 (upper row) or 1x106 CFU S. aureus arl deletion mutant (second row). Signal intensity is indicated by a pseudocolor scale. are significantly involved in stress adaptati- the kinetics of S. aureus infection can be on of bacteria, and it can be expected that directly followed in the host providing new these crucial molecules also play a role in insights into the processes of host-patho- the control of virulence. This novel problem gen interaction. The understanding of the- is being addressed in project part B4. Spe- se mechanisms serves as the basis for the cifically, a sRNA was found that is encoded development of new concepts to combat in- upstream of the ica-operon in S. epidermi- fections caused by staphylococci. dis which is probably involved in the regulation of the ica-expression. This small RNA could thus influence pathogenicity via pro- Symposia duction of PIA (polysaccharide intercellular Summerschool “Pathophysiology of Staphy- adhesin), synthesized by enzymes encoded lococci”, Vilm, 26 – 29 September 2007 by the ica-operon, and therefore constitutes a good starting point for the analysis of the role of regulatory RNAs. In addition, a bioinformatic approach that aims at the prediction of additional small RNAs will be followed. Subsequently, such new small regulatory RNAs can be analyzed for their role in cell physiology, stress adaptation, 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,

131 5.2 Research Centers 5.2.1 Rudolf Virchow Center / DFG Research Center for Experimental Biomedicine

Professor Dr. med. Martin Lohse (Speaker) General search methods. Excellent established sci- Information entists have the possibility to concentrate Versbacher Str. 9 on a five-year, high-risk project as Research 97078 Würzburg In 2001, the University of Würzburg won Professors on the model of American How- Tel.: 09 31 / 201-48400 approval in the context of the first nation- ard Hughes professorships. The Bio-Imag- Fax: 09 31 / 201-48702 wide competition of the German Research ing Center is a new entity and comprises at E-mail: [email protected] Foundation for Research Centers. The con- present two and is planned to hold five re- www.rudolf-virchow-zentrum.de cept of the Rudolf Virchow Center was cho- search groups funded by the State of Bavar- sen among 80 submitted concepts. After ia and the University of Würzburg as basic Professor Dr. Dr. Stefan Engelhardt reconstruction of the temporary accommo- funding. In order to strengthen collabora- (Cardiac Target Proteins) dation, the Center was founded in 2002. tions with researchers in Würzburg the RVZ CONTACT DETAILS CONTACT Tel.: 09 31 / 201-48710 The center extends across several faculties Network program was added. In addition to and is, therefore, organized as a central in- research, the Rudolf Virchow Center was Professor Dr. Gregory Harms stitution of the University. Group leaders, if also involved in conceiving and establish- (Molecular Microscopy) they are professors, belong to the Medical ing the new Bachelor and Masters Program Tel.: 09 31 / 201-48717 Faculty and may have a dual membership in Biomedicine, initiated in the winter term in another faculty. The Rudolf Virchow Cen- 2001/02 at the University of Würzburg and Dr. Heike Hermanns ter is composed of different elements in re- is now coordinating the program. A “Gradu- (Cellular Signal Transduction) search and teaching (Fig. 1). Its interdis- ate School” for Biomedicine has been de- Tel.: 09 31 / 201-48736 ciplinary research focuses on „target pro- veloped that has become the nucleus for a teins“, that are analyzed at several levels large-scale reform of graduate training at the Professor Dr. Caroline Kisker from molecules to disease. University and culminated in the foundation (Structural Biology: DNA-Repair and of the “Graduate School of Life Sciences“. Structure-based Drug-Design) Right from the beginning the Rudolf Virchow This school won approval in the context of Tel.: 09 31 / 201-48300 Center´s intention was to establish inno- the national “Excellence Initiative” in the fall vative structures at the University. An Insti- of 2006. Finally, the “Public Science Center“ Dr. Stephan Kissler tute for Junior Research Groups was estab- offers several courses for pupils. (Immune Tolerance) lished, providing junior scientists the pos- Tel.: 09 31 / 201-44065 sibility to work independently with the option of extension into temporary research Major Research Professor Dr. Bernhard Nieswandt professorships (tenure track) for excellent Interests (Vascular Biology) group leaders. To ensure transfer into in- Tel.: 09 31 / 201-48996 dustry one group is funded by industry and At the time of reporting eleven research the Bavarian Ministry of Economics. The groups and seven projects within the RVZ Prof. Dr. Hermann Schindelin Core Center comprises groups that devel- Network are established at the Rudolf Vir- (Structure Biology: Protein Folding, -Function op and utilize innovative and special re- chow Center. Research groups work on “tar- and -Degradation) Tel.: 09 31 / 201-48320

Professor Dr. Michael Schön (Inflammation and Tumor Biology) Tel.: 09 31 / 201-48977

Professor Dr. Albert Sickmann (Functional Proteomics) Tel.: 09 31 / 201-48730

Professor Dr. Stephan Sigrist (Synapse Architecture) Tel.: 09 31 / 201-44050

Professor Thorsten Stiewe (until 2007) (Molecular Tumor Biology)

Fig. 1: Structure of the Rudolf Virchow Center.

132 get proteins“. Two types of target proteins of Using the family of interleukin-6-type cyto- of people react to self-antigens and devel- particular biomedical importance constitute kines as a model system the laboratory in- op autoimmune diseases. The group seeks the focus of the Center: cell surface recep- vestigates this question. to understand the genetic polymorphisms tors and nucleic acid binding proteins. The- that predispose individuals to autoimmuni- se proteins are analyzed at four levels of ty and the regulatory pathways that fail dur- complexity: molecular structure and func- Structure Biology: DNA-Repair and ing onset of disease. The main approach is tion, biochemical mechanisms, cellular re- Structure-based Drug-Design the genetic manipulation of model organ- sponse, and (patho)physiological roles. (C. Kisker) isms by RNA interference (RNAi). Therefore lentiviral transgenesis is used to generate It has been shown that 80 to 90% of all animals in which target genes are consti- Cardiac Target Proteins human cancers are due to DNA damage. tutively silenced by RNAi. After pioneering (S. Engelhardt) Among the various DNA repair mechanisms this strategy in the model for type 1 dia- available to the cell nucleotide excision re- betes, the group is now refining lentiviral The group investigates cellular signaling pair (NER) stands out because of its broad technology to make its application for the mechanisms in the cardiovascular system substrate specificity. The group aims to un- study of immune tolerance more versatile and aims to prove their relevance in vivo. Its derstand the fundamental mechanisms of and specific. current efforts focus on transcriptional and the bacterial and mammalian NER machin- translational control of cell growth of car- ery. Since damage can accumulate and may diac myocytes, β-adrenergic signaling and not be repaired prior to replication and due Vascular Biology intercellular communication within the my- to the role of DNA polymerases in certain (B. Nieswandt) ocardium. The overall goal is to develop and diseases, the group also analyzes different to test novel therapeutic strategies against DNA polymerases and their role in genetic At sites of vascular injury, blood platelets cardiac disease, namely heart failure. This maintenance. A second focus is structure- come into contact with the subendothelial approach necessitates a broad methodo- based drug design to identify new therapeu- extracellular matrix, which triggers their ac- logical spectrum ranging from optical stu- tics against infectious diseases. tivation and the formation of a hemostatic dies of receptor conformational changes to plug. This process is crucial to limit post- analysis of cardiac function in living mice traumatic blood loss, but may also lead to in vivo. Immune Tolerance pathological thrombus formation, causing (S. Kissler) diseases such as myocardial infarction or stroke. The group uses genetically modified Molecular Microscopy While our immune system is tightly regulat- mouse lines in combination with disease (G. Harms) ed and usually recognizes only harmful anti- models to identify new strategies to inhibit genes like pathogens, a significant number the thrombotic and/or pro-inflammatory ac- The research group studies molecular interactions in cell signaling of membrane proteins and cytosolic messengers like platelet adhesion through the Src kinase family, and growth and development through the Bone Morphogenetic Protein (BMP)/Smad pathway. To this end the group uses techniques like fluorescence resonance energy transfer (FRET) microscopy, single-molecule microscopy and dynamic confocal microscopy. These microscopes allow the detection of low, endogenous levels of proteins in and on living cells. Key objectives are the development of biosensors and imaging techniques.

Cellular Signal Transduction (H. Hermanns)

Deregulated cytokine signaling is involved in the pathogenesis of a large number of diseases including chronic inflammation, autoimmunity and cancer. A large number of cytokines transduces signals via shared cell surface receptors that form multi-molecular complexes. This explains why many of the signaling cascades are common to a number of different cytokines, but leaves Fig. 2: DNA-Repair: Model for the interaction between UvrB (gray) and UvrC (ribbon pre- the question of signaling specificity open. sentation) leading to the successful incision of the damaged DNA strand.

133 tivity of the cells, while preserving their he- tion of mis-folded proteins via the ubiquitin- mostatic function. dependent protein degradation pathway. Second, they are interested in the structure and function of inhibitory neuronal re- Structure Biology: Protein Folding, ceptors and the mechanism of their anchor- -Function and -Degradation ing at the postsynaptic membrane. There- (H. Schindelin) fore the group uses a combination of complementary techniques for the biochemical The group focuses on protein folding in the and biophysical characterization in addition endoplasmic reticulum (ER) and degrada- to X-ray crystallography. Mis-folding and aggregation due to defects in the endoplasmic reticulum associated degradation (ERAD) Fig. 3: STED microscopy uncovers supra- S. Engelhardt Buitrago M, Lorenz K, Maass AH, Ober- pathway, for example, lead to a variety of molecular architectures at synaptic mem- dorf-Maass S, Keller U, Schmitteckert EM, pathophysiological states, such as the neu- branes. Conventional confocal (left) ver- Ivashchenko Y, Lohse MJ, Engelhardt S rodegenerative disorders of Alzheimer’s and sus STED-microscopy (right) of the protein (2005) The transcriptional repressor Nab1 Parkinson’s disease. Bruchpilot (green) in synapses. Scale bar is a specific regulator of pathological car- is 1 µm. diac hypertrophy. Nat Med. 11, 837-44

T. Stiewe Inflammation and Tumor Biology Stiewe T (2007) The p53 family in diffe- (M. Schön) mistry and advanced imaging, like the new rentiation and tumorigenesis. Nature Rev STED technology. This approach allows an Cancer. 7, 165-168 The group is investigating the role of adhe- integrated view on synapse assembly and C. Kisker sion molecules and whether they can be remodeling processes central for learning Truglio JJ, Karakas E, Rhau B, Wang H, exploited as therapeutic target structures and memory, as well as nervous system de- DellaVecchia MJ, Van Houten B, Kisker C in inflammatory disorders. Adhesion mole- velopment and disease. (2006) Structural basis for DNA recogniti- cules mediate tissue-specific recruitment of on and processing by UvrB. Nat Struct Mol Biol. 13, 360-364 leukocytes, a key step in the pathogenesis of inflammatory disorders. In addition, they

SELECTED PUBLICATIONS H. Schindelin focus on how tumors progress, why they are Teaching Tian G, Xiang S, Noiva R, Lennarz WJ, resistant to chemotherapy and how nov- Schindelin H (2006) The crystal structure of yeast protein disulfide isomerase sug- el therapeutic compounds can overcome All groups offer internships and lectures for gests cooperativity between its active sites. mechanisms of resistance. students of the Bachelor and Masters Pro- Cell. 124, 61-73 gram in Biomedicine. Annual symposia and conferences are held for scientists from A. Sickmann Functional Proteomics medicine and the natural sciences. Gradu- Lewandrowski U, Zahedi RP, Moebius J, Walter U, Sickmann A (2007) Enhan- (A. Sickmann) ate students at the Center are members of ced N-glycosylation site analysis of sialo- the graduate program “Virchow Graduate glycopeptides by strong cation exchange Over the last decade, mass spectrometry Program“ that belongs to the Section Bi- prefractionation applied to platelet plas- has not only emerged as the key technolo- omedicine of the “Graduate School of Life ma membranes. Mol Cell Proteomics. 6, 1933-1941 gy for large scale proteomic analysis for the Sciences”. identification and the later functional ana- P. Friedl lysis but also for the elucidation of post- Wolf K, Wu YI, Liu Y, Tam E, Geiger J, Over- translational modifications as well as rela- all C, Stack MS, Friedl P (2007) Multi-step tive quantification of proteins. To provide a pericellular proteolysis controls the transition from individual to collective cancer cell solid basis for functional analysis in cardio- invasion. Nat Cell Biol. 9, 893-904 vascular research, the group established an array of methods for the semi-quantitative B. Nieswandt analysis of phosphorylations and glycosyla- Moser M, Nieswandt B, Ussar S, Pozgajo- va M, Fässler R (2008) Kindlin-3 is essen- tions and in addition, provided the so far tial for integrin activation and platelet ag- largest proteomic survey of platelet plasma gregation. Nat Med. 14, 325-330 membrane proteins.

M. Schön Wienrich BG, Oostingh GJ, Ludwig RJ, En- Synapse Architecture ders S, Harms G, Tauber R, Krahn T, Kra- (S. Sigrist) mer B, Boehncke WH, Schön MP (2006) Efomycine M: an inhibitor of selectins? The group studies the molecular and cel- Nat Med. 12, 873-874 lular mechanisms controlling assembly and S. Sigrist remodeling of synapses. The predominant Kittel RJ, Wichmann C, Rasse TM, Fouquet experimental model of their studies are glu- W, Schmidt M, Schmid A, Wagh DA, Paw- tamatergic synapses of Drosophila, which lu C, Kellner RR, Willig KI, Hell SW, Buch- are particularly suited for combining mo- ner E, Heckmann M, Sigrist SJ (2006) Bruchpilot promotes active zone assembly, dern molecular biology, genetics, bioche- Ca2+ channel clustering, and vesicle release. Science. 19, 1051-4 134 5.2.2 Interdisciplinary Center for Clinical Research (IZKF)

Professor Dr. med. Dr. h.c. General 2004 it is completely funded by the Free Hans Konrad Müller-Hermelink (Speaker) Information State of Bavaria.

Josef-Schneider-Straße 2 The IZKF Würzburg is the internal research 97080 Würzburg funding instrument of the Medical Faculty. Major Research Tel.: 09 31 / 201-47776 Its major goal is to strenghten clincial re- Interests Fax: 09 31 / 201-47505 search on base of interdisciplinary biomedi- Email: [email protected] cal-clinical research. The budget is fixed ap- The IZKF devotes particular interest in of- www.izkf-wuerzburg.de proximately at 5 Mill. Euro per annum. fering research grants within the main research fields of the Medical Faculty. A re- Professor Dr. med. Eva Bettina Bröcker To carry out its mission the IZKF search grant can be used to fund staff, sci- CONTACT DETAILS CONTACT (Vice-Speaker) • supports cooperative research projects entific instrumentation, consumables as Tel.: 0931 201-26350 in the fields of immunology/infectiology, well as most of the other financial require- oncology, cardiac and vasular disease ments of a research project. The decla- Dr. Andrea Thelen-Frölich (Office) as well as neurology; red goal of the programme is to coordinate Tel.: 0931 201-47794 • promotes education and advancement and to improve cooperation between these of young researchers in medicine th- main research fields. A unique feature is the roughout all qualification phases; concept of bringing together the expertise of • improves the scientific infrastructure th- basic and clinical sciences to develop novel rough its core facilities. In addition it of- and effective diagnostics as well as thera- fers special flexible research funding in- peutic approaches. In 2007 the IZKF sup- struments on location. ported a total of 42 research projects including three junior research groups in the fol- The research funding management of the lowing six research fields: IZKF based on peer review process as well as a transparent financial administration. A: Pathological aspects of inflammation The statutory bodies at a glance: • General Assembly (“Zentrumskonfe- B: Tumor-host interactions renz”), • Executive Board D: Transplantation andTissue Engineering • External Scientific Advisory Board. E: Pathogenesis and therapy of vascular The IZKF Wuerzburg was founded in 1996 and myocardial diseases within the federal research funding programme “Health Research 2000” of the F: New diagnostic and imaging techniques Federal Ministry of Education and Research as one of nine centers in Germany. Since N: Clinical and experimental neurobiology

Fig.1: MicroRNA overexpression in cultured neonatal cardiomyocytes (AG T. Thum).

135

Teaching

Supporting young scientists in medicine is a major commitment of the IZKF that involves a wide spectrum of sponsoring activities:

• MD/PhD-Programme is accompanied and funded by the IZKF

• Debut Grants Programme (“Erstantrag- steller-Programm”) is awarded to young researchers of medicine who have completed their doctorate to carry out a clearly defined project. Suppor- ted by mentoring over a period of two years it will help these scientists to receive an external research funding, e.g. DFG.

• Rotation Positions (“Rotationsstellen”) ensure “protected” time for research of young physician scientists through providing positions for physicians who cover for see- ing patients and other medical care.

• Three Junior Research Groups are established to promote excellent young researchers in achieving independence at an early stage of their scientific careers.

Other activities

To advance the scientific infrastructure in clinical research the Center maintains the following Core Facilities: • Microarray-Unit • Central Office for Clinical Trial (ZKS) • Early Clinical Trial Unit

In addition the center offers flexible research funding moduls on location in contrast to major external funding research or- ganisations: • Start-up financing for innovativ research ideas Fig. 2: A: HLA-G expression in ovary carcinomas shows no co-localisation with the tumor • Central budget for rebursements of tra- marker EpCAM. B: HLA-G is expressed in CD68+ cells in ovary carcinomas (AG J. Wisch- vel expenses husen). • Visiting researcher programme for scientists coming from abroad • Organization and funding of symposia, workshops and other mettings in ordert to encourage coooperation between scientists from domestic or international universities.

136 Annual Report (contact: Head office of the IZKF) SELECTED PUBLICATIONS

137 5.2.3 Research Center for Infectious Diseases

Professor Dr. rer. nat. Dr. h.c. mult. General infections including pneumonia, septicae- Jörg Hacker (Speaker) Information mia and meningitis. The function and contribution of important virulence factors, e.g. Institut für Molekulare Infektionsbiologie Infectious diseases still cause global health the capsular polysaccharide, the adhesin Röntgenring 11 problems. In this regard, the ”Research proteins PspC and PavA as well as the eno- 97070 Würzburg Center for Infectious Diseases“ (ZINF) was lase for protection against the host immu- Tel.: 09 31 / 31-2575 already established at the University of ne defense and binding as well as transmi- Fax: 09 31 / 31-2578 Würzburg in 1993. This interdisciplinary re- gration through the extracellular matrix has E-mail: [email protected] search centre includes young investigator been investigated. www.infektionsforschung.uni-wuerzburg.de groups as well as other groups of the Uni- versity of Würzburg working on infectious di-

CONTACT DETAILS CONTACT seases. The Research Centre belongs to the Marine Symbioses- New Antiinfectives Medical Faculty and the Faculty of Biology (U. Hentschel, since 2004) of the University of Würzburg. One of the first objectives of the centre was to repre- Marine sponges have considerable poten- sent a link between these two faculties. An tial for drug discovery. Marine demosponges intensive scientific and organizational rela- are associated with phylogenetically com- tionship has been built to the faculties of plex, yet highly sponge-specific microbial pharmacy, chemistry and physics. The re- consortia that are responsible for the pro- search of the centre aims at the elucidati- duction of many important marine natural on of fundamental aspects of infection pro- product classes, (i.e., polyketides and non- cesses. The young investigator groups are ribosomal peptides). The research goals of associated with the Institute for Molecular the group are to (i) characterize the micro- Infection Biology. bial diversity associated with sponges, (ii) to investigate aspects of symbiosis and function and, (iii) to identify new antimicrobi- Major Research al substan-ces from sponge-associated Interests of the Young microbiota. The overall aim of this research Investigator Groups is to provide a basic understanding of the sponge-microbe association and to use this Pathogen-host communication – Exploi- natural resource for small molecule discov- tation of cellular adhesion molecules by ery. pathogenic bacteria (C. Hauck, 2001-2006) Molecular interactions during fertilizati- A diverse array of cell adhesion molecules on in the human malaria parasite Plas- is exploited by bacterial pathogens to con- modium falciparum tact their eukaryotic host cells. The investi- (G. Pradel, since 2005) gations conducted aimed at a deeper basic understanding of the signal transduction The tropical disease malaria, which is caused capacity and physiologic functions of cel- by the protozoan parasite Plasmodium, is a lular adhesion molecules as well as further major health threat. Currently, there is no insights into the molecular interaction and vaccine in circulation for the treatment of communication between specialized micro- malaria, and pharmaceutical approaches bes and their host cells. Research was fo- are increasingly encountering parasite drug cussed on integrins, the cellular receptors resistance. The main research focus was on for extracellular matrix proteins, and carci- proteins that are involved in sexual stage noembryonic antigen-related cell adhesion differentiation and fertilization. These pro- molecules (CEA-CAMs) that are involved in teins may represent promising candidates cell-cell interactions. The results of these for transmission blocking strategies, which studies not only provide insight into the so- aim to inhibit parasite development in the phisticated adaptations of human-specific mosquito vector and thereby reduce the pathogens, but also point to defense me- spread of the disease. chanisms elaborated by human host cells and tissues. Genetically attenuated malaria liver states as an experimental malaria vac- Pathogenicity of Streptococcus pneu- cine moniae (A.-K. Müller, since 2007) (S. Hammerschmidt, 2003-2007) A major area of interest in the lab is the Streptococcus pneumoniae (the pneumo- characterisation of protective immune re- coccus) cause serious and life-threatening sponses to malaria induced by genetically

138

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. Furthermore, the groups are engaged in the education of graduate students.

Fig. 1: Gliding motility of a Plasmodium sporozoite. Malaria sporozoites (banana shaped) are transmitted via a blood meal of the Anopheles moskito. They are the infectious state and exhibit a characteristic movement pattern (gliding motility) (©A.-K. Müller). attenuated parasites (GAP). Genetically attenuated uis3(-) and uis4(-) parasites that constitute a reproducible and standardized source of potent live-attenuated parasites have been recently generated and characterised. Immunization with GAP elicits steri- lising immunity, but so far the antigenic specificity and the effector mechanisms of this protective immune response have not been carefully characterized. The group com- (Look at the ZINF Annual Report: http:// bines molecular and cell biological research www.uni-wuerzburg.de/ueber/forschung/ on GAP with studies aimed at understand- forschungszentren/zentrum_fuer_infekti- ing the immunological correlates of protec- onsforschung/general_information/annual_ tion elicited by GAP. report_2005-2006/) Scholz, S.M., Simon, N., Lavazec, C., Dude, M.A., Templeton, T.J., und Pradel, Pathogenicity and kryptic sexuality of G. (2007) PfCCp proteins of Plasmodium the human pathogenic fungus Aspergil- falciparum: Gametocyte-specific expressi- lus fumigatus on and role in complement-mediated inhibition of exflagellation. Int J Parasitol. 38: (S. Krappmann, since 2007) 327-340

So far uncharacterized pathogenicity de- Matuschewski, K., and Müller, A.K. (2007) terminants of the mold fungus Aspergillus Vaccines against malaria - an update. fumigatus are within the research focus of Febs J 274: 4680-4687. the group. Different aspects of its sapro- Taylor, M.W., Thacker, R.W., und Hent- phytic life cycle were analyzed in detail, schel, U. (2007) Genetics. Evolutionary in-

e.g. the impact of nitrogen metabolism, SELECTED PUBLICATIONS sights from sponges. Science 316: 1854- the regulation of amino acid homeostasis 1855. on virulence or the function of a conserved Rennemeier, C., Hammerschmidt, S., Nie- regulator of fruiting body development. In mann, S., Inamura, S., Zähringer, U., und addition, the group works on the further Kehrel, B.E. (2007) Thrombospondin-1 development of molecular biological meth- promotes cellular adherence of gram-posi- ods for targeted manipulation of the fun- tive pathogens via recognition of peptido- glycan. Faseb J 21: 3118-3132. gal genome, in order to get insights into the A. fumigatus virulome by functional ge- Hauck, C.R., Agerer, F., Münzner, P., und nomics. Schmitter, T. (2006) Cellular adhesion molecules as targets for bacterial infection. 139 Eur J Cell Biol 85: 235-242. 5.2.4 Interdisciplinary Cancer Center

Professor Dr. med. Michael Flentje (Speaker) General • cares for education and training of the Information health care staff Josef-Schneider-Str. 6 • coordinates outreach programs 97080 Wuerzburg Plannning and carrying out of diagnostics, • informs the public about several aspects Tel.: 09 31 / 201-28890 treatment and research of cancer diseas- of the cancer disease Fax: 09 31 / 201-35952 es are objectives of the Medical Faculty Tel.: 09 31 / 201-35150 of the University of Wuerzburg. To provide The catchment area of the University hos- E-mail: [email protected] optimal standards of care, corresponding pital, which is Lower Franconia and adja- www.tumorzentrum.uni-wuerzburg.de to the actual state of knowledge, it is recent regions, contains about 2.5 million in- quired that all institutions which are in- habitants. Since the passing of the federal Professor Dr. med. Hermann Einsele volved in treatment cooperate interdisci- law for cancer registries the cancer registry CONTACT DETAILS CONTACT (Vice-Speaker) plinary. is of crucial importance for epidemiologicl Tel.: 09 31 / 201-70000 cancer registration in Germany. In Bavaria, Bodies of the cancer centre are the mem- the law obliges the cancer centres to imple- Professor Dr. med. Ulf R. Rapp (Vice-Speaker) bers, the advisory board and the executive ment population based cancer registration. Tel.: 09 31 / 20145140 board with the chairman. The activities of the centre are coordinated and managed PD Dr. rer. biol. hum. Jutta Riese (Office) by an administrator. Tel.: 09 31 / 201-35151 Major Research The Interdisciplinary Cancer Centre was Interests founded in 1983 within the Medical Fac- ulty. For a long time there are scientific col- National and international multicentre tri- laborations with the Rudolf-Virchow Zen- als and study groups in pediatric brain tu- trum and other scientific institutions of the mors, multiple myeloma, melanoma, cu- University Wuerzburg. Likewise, there are taneous lymphoma, advanced lung can- close cooperations with the teaching hos- cer, and thyroid cancer have been initiated pitals of the University, rural hospitals and and are being chaired by clinical scientists resident doctors. from Wuerzburg. The Institute of Pathology serves as a reference centre for many na- To realise its aims the Cancer Centre tional and international studies, namely in • periodically works out and implements the field of lymphatic diseases. standardised clinical pathways for diagnostics and treatment for different tu- In Wuerzburg, basic research in oncology mour entities in collaboration with the focuses on questions of tumour origin and involved experts of the interdisciplinary molecular mechanisms of malignant trans- teams formations and their consequences for di- • supports the basic and clinical oncologi- agnostics and treatment. Another research cal research, and specific health service topic is tumour immunology which aims to research identify molecular targets for the develop- • collects and analyses data of tumour ment of novel therapies. The projects of patients these topics are notably funded by grants

Fig. 1: Simple structure of the Interdisciplinary cancer centre.

140 of non public resources (DFG, BMBF, Wil- helm Sander-Stiftung, Mildred Scheel-Stif- tung, Deutsche Krebshilfe).

In Wuerzburg, oncological research also benefits from several core facilities. These include the Early Clinical Development Unit (ECDU) and the clinical trial office which are set up at the University Hospital Würzburg to support the development and clinical investigation of novel compounds and therapies.

141 5.2.5 Interdisciplinary Centre for Addiction Research (ICAW)

Professor Dr. med. Jobst Böning (Chair) General Molecular mechanisms of alcohol tole- Information rance at Drosophila melanogaster Füchsleinstrasse 15 (A. Scholz, Institute for Genetics and Neu- 97080 Würzburg ICAW has developed in 2000 from the in- robiology) Tel.: 09 31 / 49545 terdisciplinary BMBF addiction research Fax: 09 31 / 201-77840 network (1996-2001) focusing neurobio- With molecular genetic, genetic and ana- E-mail: [email protected] logical and behavioral foundations on alco- tomical methods we investigate ethanol in- hol-addiction. The objectives are enduring duced behaviors in the genetic model orga- Dr. med. C. Jacob (Vice-Chair) development and encouragement of clini- nism Drosophila melanogaster. With our be- Tel.: 09 31 / 77-810 cal and neurobiological research on ad- havioral assays we analyze the influence of diction. Advancement of traineeship, tea- learned behavior and/or alcohol preference

CONTACT DETAILS CONTACT ching, qualification in addiction associated on the development of alcohol tolerance topics, inpatient and outpatient interventi- and alcoholism. We are interested in iden- ons and political decision guidance are ad- tifying networks that mediate these beha- ditional topics. viors. In addition we try to understand how ethanol affects the brain on cellular level. Previously we have identified a new cellular mechanism that is important for the deve- Major Research lopment of ethanol tolerance. This mecha- Interests nism is similar to a cellular stress response. The hangover gene plays an important pro- Neurophysiological assessment of ce- cess in this process and the human homo- rebral cue reactivity in substance de- logue of this gene can be associated with pendence clinical alcohol dependence (DFG-Einzelför- (A. Fallgatter, M.M. Richter, derung und Graduiertenkolleg, Thyssen Stif- M. Schecklmann, Dept. of Psychiatry) tung).

Event-related potentials (ERP), functional Magnetic Resonance Imaging (fMRI) and Functional and structural cerebral neu- Near-Infrared Spectroscopy (NIRS) are rodegeneration in alcohol dependency used to investigate addiction memory as (A. Bartsch, Department of Neuroradiology) well as topographical aspects of emotional and cognitive processes in alcohol Chronic alcohol abuse results in morpho- and tobacco dependency. Other areas of logical, metabolic, and functional brain da- research are the reversibility of distur- mage which may, to some extent, be re- bances in brain function in alcohol-de- versible with early effects upon abstinence. pendent patients and the application of We investigated global and local brain volu- repetitive Transcranial Magnetic Stimu- me changes in a longitudinal two-time point lation (rTMS) in tobacco dependent pa- study with T1-weighted MRI at admission tients. and after short-term (6-7 weeks) sobrie- ty follow-up in 15 uncomplicated, recently detoxified alcoholics. Volumetric brain gain Biopsychological mechanisms of nicoti- was related to metabolic and neuropsy- ne craving chological recovery. On admission and af- (P. Pauli, R. Mucha, M. Winkler, Department ter short-term abstinence, structural image of Psychology) evaluation using normalization of atrophy (SIENA), its voxelwise statistical extension Within the DFG funded research group (Fo to multiple subjects, proton MR spectrosco- rschergruppe) “Emotion and Behavior“we py (1H-MRS), and neuropsychological tests examine the addiction specific question were applied. The increase of concentration how emotional learning processes mo- of choline was proved as a matter of a de- dulate the significance of environmen- tectable increase of the brain volume. The tal cues for craving to smoke. We ex- increase of NAA, a product of the metabo- pect that some environmental cues, es- lism of the white matter and the neurons, pecially those associated with the be- is directly connected with an increased con- ginning of the smoking ritual, increa- centrativeness. se craving while others, especially those associated with the end of the smoking ritual, inhibit craving. An understand of Genetic of alcohol addiction the latter process seems especially im- (K.P. Lesch, Psychiatry, Psychobiology) portant since it may help to create envi- ronments in which smokers have only litt- Neurobiological and psychobiological pro- le urge to smoke. cesses such as reward-related behavior,

142 Fig. 1: Molecular imaging of complex behavior and psychopathology.

cognitive-executive dysfunction, stress ADHD as a risk factor of the develop- coping or anxiety that are involved in the ment of addition development of alcohol addiction are (J. Böning, C. Jacob, A. Schmidtke, Dept. presumably under the influence of gene- of Psychiatry) tic variation. Traits, e.g. impulsivity, sen- sation seeking, or aggressive behavior, as 60%-80% of the childhood manifestations well as dysfunctional cognitive styles, an- of ADHD persist into adulthood. There is xiety, emotional lability, and stress vulne- a variety of co-morbid disorders including rability are directly or indirectly related to substance use disorders. The treatment of morbidity. As evidenced by a plethora of ADHD with stimulants is protective against research, most of these psychobiological substance use disorders. The clinical re- domains are modulated by a functional search group ADHD which is supported by serotonin transporter polymorphism. The- the DFG performs a multilayered evaluati- se findings demonstrate the increasing re- on of the endophenotypes working memory levance of translational research and mo- and response inhibition. lecular-functional imaging studies in order to describe neurobiological founded endophenotypes, thereby bridging the gap Bartsch AJ, Homola G, Biller A, Smith SM, between molecular variation and clinical Teaching Weijers HG, Wiesbeck GA, Jenkinson M, diagnoses. De Stefano N, Solymosi L, Bendszus M The seminary “neurobiology of addiction“is (2007). Manifestations of early brain reco- an advanced training for young scientists very associated with abstinence from alco- The endogenous neurotoxine TaClo and students of medicine, psychology and holism. Brain. 130, 36-47. (C. Bringmann, D. Feineis, Institute for Or- biology. The annual basic and advanced Bringmann G, Feineis D, Münchbach M, ganic Chemistry) training convention of addiction medicine God R, Peters K, Peters E-M, Mössner R, and teaching of modules of the qualificati- Lesch K-P (2006). Toxicity and metabo- Chemical reactive compounds that peo- on addiction medicine are additionally acti- lism of the chloral-derived mammalian al- kaloid 1-trichloromethyl-1,2,3,4-tetrahy- ple are in contact with due to environmen- vities. Research projects are presented on dro-beta-carboline (TaClo) in PC12 cells. tal pollution, drug abuse, medical treat- the annual meetings of the ICAW. Z. Naturforsch. 61c, 601-610. ment or workplace conditions are sus- pected to be involved in the etiology of Lesch KP (2005). Alcohol dependence neurodegenerative processes. The inves- and gene x environment interaction in emotion regulation: Is serotonin the link? tigations focus upon highly chlorinated te- Eur J Pharmacol. 5, 13-24. trahydro-beta-carbolines such as “TaClo”

that originates in man from endogenous SELECTED PUBLICATIONS Schecklmann M, Ehlis AC, Plichta MM, tryptamine (“Ta”) and chloral (“Clo”), e.g., Boutter HK, Metzger FG, Fallgatter AJ (2007). Altered frontal brain oxygenati- after intake of the hypnotic chloral hydra- on in detoxified alcohol dependent pati- te, or, due to addiction, after occupational ents with unaffected verbal fluency perfor- exposure to the industrial solvent trichlo- mance. Psychiatry Res. 15, 129-38. roethylene (TRI), or as a consequence of solvent abuse (“sniffing”). Scholz H, Franz M, Heberlein U (2005). The hangover gene defines a stress pathway required for ethanol tolerance. Na- 143 ture 436, 845-847. 5.2.6 Interdisciplinary Center for Familial Breast and Ovarian Cancer

Professor Dr. med. Tiemo Grimm (Speaker) General developed the concept of interdisciplina- Information ry care units which includes counselling, Division of Medical Genetics diagnosis, follow-up, and prevention. So Theodor-Boveri-Weg 11 Since 1996, women at risk for famili- far, more than 10, 000 families received 97074 Würzburg al breast and ovarian cancer are offered counselling, and over 5,000 families were Tel.: 09 31 / 888-4076 specialized counselling in Germany. There included in the joint follow-up project, Fax: 09 31 / 888-4434 are twelve interdisciplinary centres for fa- 574 of these families were followed in E-mail: [email protected] milial breast and ovarian cancer (Zentren the Würzburg centre. Mutations in either http://www.humgen.biozentrum.uni-wuerzburg. für Familiären Brust- und Eierstockkrebs - BRCA1 or BRCA2 were identified in more de/krebszentrum/ Deutsche Krebshilfe). These centres offer than 1,000 families (around 100 in Würz- http://www.frauenklinik.uni-wuerzburg.de/ a structured approach by which women burg). The affected women were offered a CONTACT DETAILS CONTACT brustzentrum/familiaerer_brustkrebs.htm not only receive an answer to their con- comprehensive care package. BRCA-as- cerns about personal and familial cancer sociated breast and ovarian cancers have Professor Dr. med. Johannes Dietl (Speaker) risk, but also receive counselling and as- different characteristics such that effec- Department of Obestetrics and Gynecology sistance of how to deal with an increa- tive prevention must be adjusted to the Josef-Schneider-Str. 4 sed risk. The Würzburg centre is known individual patient. As a rule, BRCA1 and 97080 Würzburg as “Interdisciplinary Centre for familial BRCA2 related breast cancers are early Tel.: 09 31 / 201-25251 breast and ovarian cancer” and includes onset cancers, with an average age of on- Fax: 09 31 / 201-25406 the following institutions: Division of Me- set of around 43 years - some 20 years E-mail: [email protected] dical Genetics: Prof. Dr. Grimm; University prior to the age of onset in the general www.frauenklinik.uni-wuerzburg.de Women’s Hospital: Prof. Dr. Dietl; Depart- population. Thus, primary and seconda- ment of Psychotherapy and Medical Psy- ry prevention represents a major chal- chology: Prof. Dr. Dr. Faller, Institute of Di- lenge. International and national data of agnostic Radiology: Prof. Dr. Hahn. the joint project show that mutation carriers can reduce their breast and ovari- The results of the national pilot testing an cancer risks by prophylactic bilateral and evaluation phase were so positive mastectomy, in combination with bilate- that the statutory health insurance com- ral salpingo-oophorectomy, to below five panies (in 2005) and the majority of pri- percent. 0ophorectomy alone has been vate insurers (in 2007) agreed to include shown to reduce the risk of breast cancer the hereditary breast cancer comprehen- by at least 50%. Currently, only 1 in 10 sive care package as part of their regular carrier women in Germany opt for prophyl- coverage. The services provided are inter- actic mastectomy, but an increasing num- disciplinary – i.e. genetics, gynaecology, ber of women undergo oophorectomy. As diagnostic radiology, and psycho oncolo- an alternative to radical breast removal, gy. Genetics includes computer-assisted within the framework of the joint project risk estimates and quality-assured mole- 80 percent of women participate in the cular genetic analysis of the BRCA and programme of intensive early detection. other susceptibility genes. Optimal use of In regular intervals, these women utilize a resources and assurance of high quality combination of mammography, magnetic care has been achieved through close co- resonance imaging and sonography. The operation within the local centre. question of how successful such a conservative strategy will finally turn out to be Breast cancer is the most common can- cannot be answered at this time. In order cer for women in Germany. Approximately to evaluate the performance of the twelve ten to twelve percent are affected during hereditary breast centres, a database was their lifetime, with an average age of 63 established at the University of Leipzig. years. For the small group of women with Each centre contributes all relevant data a hereditary predisposition, risk is consi- to this anonymous database financed by derably higher: the lifetime probability of the Cancer Society. The hope is that the these women amounts to 80 percent for final analysis of this dataset will permit a breast cancer and 20 to 50 percent for comparison between the different strate- ovarian cancer. It is currently estimated gies of primary and secondary preventi- that at least five percent of breast canon. So far, there is a clear benefit of pro- cers and up to ten percent of ovarian can- phylactic mastectomy in primary preven- cers are due to mutations in single ge- tion, but acceptance of this procedure is nes. BRCA1 and BRCA2 figure most pro- comparatively low. More data are needed minently among the high-risk genes. Fol- for the evaluation of enhanced early de- lowing the discovery of these genes 1994 tection using sonography, mammography and 1995, the joint project “Familial bre- and complementary magnetic resonance ast and ovarian cancer” was launched by imaging (MRI). A major goal of early de- the German Cancer Aid Society. Funded tection is to reduce mortality caused by by the Society, twelve university hospitals breast and ovarian cancer.

144 Another focus of the work of the German consortium is on the field of molecular genetics. In about half of the families in whom breast and ovarian cancer appears to follow a monogenic pattern, no predis- posing mutations in the BRCA genes are found. This could be due to undetected mutations or mutations in other genes known to be associated with breast cancer, including p53, ATM, BRIP1, etc. Some of these lower penetrance genes are studied in parallel in the Fanconi anemia research laboratory of the Division of Medical Genetics. Another possibility which needs to be explored is the interaction of several low-penetrance susceptibility genes. The differentiation between these alternatives is subject of current research efforts. Fur- thermore, modifying factors need to be investigated since there are obvious inter- and intrafamilial differences in the clinical presentation of BRCA1-/BRCA2-mutation families which may be caused by environmental factors and/or by modifier genes. Within the international breast cancer research consortium (CIMBA), more than 10.000-BRCA1 and 5.000 BRCA2 mutation carriers will be examined for variants in various genes in order to identify potential modifier genes.

Meindl A; (2002) German Consortium for Hereditary Breast and Ovarian Cancer. Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population. Int J Cancer. 97: 472-480.

Gadzicki D, Wingen LU, Teige B, Horn D, Bosse K, Kreuz F, Goecke T, Schäfer D, Voigtländer T, Fischer B, Froster U, Welling B, Debatin I, Weber BH, Schönbuchner I, Nippert I, Schlegelberger B; (2006) Ger- man Cancer Aid Consortium on Hereditary Breast and Ovarian Cancer. Communica- ting BRCA1 and BRCA2 genetic test results. J Clin Oncol. 24: 2969-2970.

Preisler-Adams S, Schönbuchner I, Fiebig B, Welling B, Dworniczak B, Weber BH.

SELECTED PUBLICATIONS (2006) Gross rearrangements in BRCA1 but not BRCA2 play a notable role in predisposition to breast and ovarian cancer in high-risk families of German origin. Cancer Genet Cytogenet. 168:44-49.

White K, Held KR, Weber BH. (2001) A BRCA2 germ-line mutation in familial pancreatic carcinoma. Int J Cancer. 91: 742- 744.

Levran O, Attwooll C, Henry RT, Milton KL, Neveling K, Rio P, Batish SD, Kalb R, Vel- leuer E, Barral S, Ott J, Petrini J, Schind- ler D, Hanenberg H, Auerbach AD. (2005) The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia. Nat Genet. 145 37: 931-933. 5.2.7 Transplant Center (TPZ)

Professor Dr. med. Arnulf Thiede (Speaker) General mice models can be performed in a well Information equipped modern laboratory for microsur- Josef-Schneider-Str. 11 gery. All departments took part in different Tel.: 09 31 / 201-31001 The Transplant Centre Würzburg (TPZ) is one multi-centre studies during this reporting 97080 Würzburg of several German transplant centres. The period. The clinical and experimental wor- E-mail: [email protected] centre was reorganized to fulfil the require- king groups have had numerous disserta- ments of the new German transplantation tions and publications published. Close co- Professor Dr. med. Georg Ertl (Vice-Speaker) act (Transplantationsgesetz). The new nati- operations exist with the universities in Ox- Tel.: 09 31 / 201-36300 onal standard waiting list for heart and liver ford/England, Boston/USA, Rochester/USA, organs has led to fewer organs from Euro- Sydney/Australia and the Ludwig Maximilian transplant (Leiden, Netherlands). Conse- University in Munich.

CONTACT DETAILS CONTACT quently, the number of liver transplantations has dropped significantly since Au- gust 2001 and there has been an increase Further Activities in patients that die on waiting lists. Würz- burg has been able to ease this situation Every two years the Transplant Centre or- slightly through interdisciplinary cooperati- ganizes a local transplantation workshop ons. Kidneys from living donors have hel- (Franconian Transplant Workshop) focu- ped to alleviate the shortage of kidney or- sing on the operative and conservative gans. So far, 63 kidneys from living donors aspects of kidney transplantation. This have been transplanted. Since Würzburg meeting will take place in 2008 for the started transplanting in 1984, 690 kid- 10th time. Seminars for patients and phy- neys have been transplanted in the Clinic sicians also take place on a regular ba- for Urology and Pediatric Urology, 71 livers sis. A very successful international sympo- in the Clinic for Surgery I, and 26 hearts sium on chronic rejection of transplanted in the Clinic for Heart and Thorax Surgery. organs was held in March 2001. In June One liver/kidney transplant and 13 kidney/ 2002 a workshop on experimental and cli- pancreas transplantations were performed nical liver transplantation and hepatology by the Clinic for Surgery I and the Clinic for was organized. Urology together. The aftercare was provided by the Medical Clinic I. Also, children and adults received stem cell transplantations and AAA facial bones were transferred to repair defects around the mouth and jaw (AAA = allogneic, autolysed, antigen extracted). The German Foundation of Or- gan Transplantation (DSO) educates physicians, health care workers and the general public on brain death and organ explanta- tion. With the support of the hospitals in Aschaffenburg, Schweinfurt, Coburg and other hospitals in the region, the registration of potential organ donors has been successfully optimized and more people in the lower Franconia area are willing to do- nate organs. The aftercare of transplanted patients has improved greatly. Besides the university medical clinics and policlinics, the Clinic of Dermatology also contributes to aftercare by offering a dermatologic surgery for patients.

Experimental and Clinical Transplanta- tion Research

Würzburg is one of the few places in Ger- many supporting experimental transplantation research, including xenotransplantati- on. This research is coordinated by a W2 professor for experimental transplantation immunology. Transplantation of nearly all vascularised organs in both rat and

146 5.2.8 Cardiovascular Center

Professor Dr. med. Georg Ertl (Speaker) General The cardiovascular center has also an im- Information portant role in continuing medical edu- Herz-Kreislaufzentrum cation. Interdisciplinary student educa- Josef-Schneider-Str. 2 Cardiovascular and cerebrovascular dition and meetings have been organized 97080 Würzburg seases are the major cause of death in including lectures for experimental me- Tel.: 09 31 / 201-36301 Germany. Thus, cardiovascular research dicine, cardiologic-cardiovascular surge- is one of the most important scientific ry seminars, cardiovascular imaging se- Professor Dr. med. Rainer Leyh (Vice-Speaker) as well as clinical topics at the Medical minars, cardiologic-paediatric seminars, Tel.: 09 31 / 201-3301 University of Würzburg. In the cardio- and medical patholo- vascular center of Würzburg University gy conferences. Nu- Professor Dr. med. Martin Lohse (Vice-Speaker) the medical faculty and the university merous meetings have CONTACT DETAILS CONTACT Tel.: 09 31 / 201-48401 hospital unites the clinical and scien- taken place discussing tific competence of dif- for example acquired PD Dr. med. Stefan Frantz (Office) ferent institutions diseases of the aor- Tel.: 09 31 / 201-36120 regarding preventi- tic valve, cardiovascu- on and treatment of lar healing, quality ma- cardiovascular diseases, its risk factors, nagement in the cath and complications. It uses existing struc- lab, and the Mainfran- tures for this interdisciplinary approach of ken Heart Attack Net. Physician-patient- cardiovascular disease management and seminars have been organized in collabo- establishes new collaborations with local ration with the Deutsche Herzstiftung. physicians and national institutes. Due to the multifactorial etiology and treatment of cardiovascular diseases this interdisci- National competence net „heart failure“ plinary approach for scientific questions is mandatory. Treatment of cardiovascular Prof. Ertl is the co-chair of the national diseases also benefits from interdiscipli- competence net „heart failure“. The car- nary networks (“comprehensive medical diovascular center contributes 5 out of 20 management”). Innovative diagnostics projects, as for example SP6a “New dia- and therapeutics can promptly be trans- gnostic strategies – Cardiac imaging and ferred in patient care. This increases at- serum-/plasmamarkers”, C. Angermann/G. tractiveness for patients, scientists, and Ertl, SP6b “Etiology and prognostic rele- physicians. vance of beta1-receptor autoantibodies in human myocardial diseases”, R. Jahns/C. The central interest of the cardiovascular Angermann, SP15 „Dieases manifestation center lies in the prevention and treat- and management in chronic heart failure“ ment of heart failure and its complicati- (INH-Study), C. Angermann/G. Ertl. Over ons. Over 12 years mechanisms of heart 2000 patients have been included in regis- failure development have been investiga- tries and studies to test effecitvity and ef- ted in the SFB 355 “Pathophysiology of ficiency of disease management including Heart Failure”. Results have been trans- cardiologic as well as psycho-educative in- ferred into clinical trials (see below). Ho- terventions to monitor and educate patients wever, while mortality of coronary artery with systolic heart failure. The translation in disease is decreasing, mortality of con- patient care is being developed. Associa- gestive heart failure is increasing. Thus, ted to the competence net is the Mood-HF- to investigate basic mechanisms and new study (funded by the BMBF). In this study therapeutic options for heart failure nu- the effect of a serotonin reuptake inhibitor merous projects have been funded by the on morbidity and mortality of patients with DFG, IZKF, SFB 688 and by the Rudolf- heart failure and depression is tested in as- Virchow-Zentrum. Molecular, genetic, as sociation with the psychiatry department. well as physical results are transferred Furthermore, the connection of rheumatic into clinical research and practice. It is and cardiac diseases is tested in collabora- our goal to integrate basic science and tion with the Medizinische Klinik II. clinical research (cardiology, endocrinology, nephrology, psychiatry, neurology, psychology) to improve patient care. This led Mainfranken Heart Attack Net to the “Interdisciplinary HeartFailure Net- work” as well as the “Mainfranken Heart The Mainfranken Heart Attack Net was fun- Attack Net” fostering interdisciplinary re- ded in 2007 to connect emergency physi- search, teaching and patient care and the cians with cardiologists and cardiothoracic initiative for the “Integriertes Forschungs- surgeons to minimize the time for cardiac und Behandlungszentrum (IFB) Herzinsuf- interventional therapy. Should a coronary fizienz”. artery intervention not be feasible or useful

147 the department of thoracic and cardiovas- new procedures. In close cooperation with cular surgery offers emergency operations the departments of anesthesiology and car- 24 hours a day. The Mainfranken Heart At- diology the cardiovascular surgery depart- tack net has diminished the time to corona- ment helps to transfer patients in cardio- ry interventions within a few months and al- genic shock with the life-bridge-system (a miniaturized and portable heart-lung support system).

Furthermore a cardiac transplantation program has been reinstituted. Minimally invasive surgery techniques for mitral and aro- tivc valve surgery are currently beeing established. lows 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 the according chapter). Besides the SFB there are numerous interdisciplinary collaborations demonstrated by a large number of publication. Many of them are supported by the IZKF (see separate chapter). Faller H, Störk S, Schowalter M, Steinbü- chel T, Wollner V, Ertl G, Angermann CE. (2007) Is health-related quality of life an independent predictor of survival in chro- Department of Thoracic and Cardiovas- nic heart failure? Journal of Psychosomatic cular Surgery Research 63: 533-538 Güder G, Bauersachs J, Frantz S, Weis- mann D, Allolio B, Ertl G, Angermann CE, Störk S,. (2007) Complementary and in- cremental mortality risk prediction by corti- sol and aldosterone in chronic heart failure. Circulation 115:1754-1761

Jahns R, Boivin V, Hein L, Triebel S, Anger- mann CE, Ertl G, Lohse MJ. (2004) Direct evidence for a beta-1-adrenergic receptor directed autoimmune attack as a cause of idiopathic dilated cardiomyopathy. J Clin Invest 113: 1419-1429 SELECTED PUBLICATIONS Solomon S D, Zelenkofske S, McMurray J J V, Finn P V, Velazquez E, Ertl G, Harsa- nyi A, Rouleau J L, Maggioni A, Kober L, White H, Van de Werf F, Pieper K, Califff R M, Pfeffer M A, for the Valsartan in Acute Prof. Rainer G. Leyh was appointed as the Myocardial Infarction Trial (VALIANT) Inves- new director on April 1 2007. Apart from a tigators. (2005) Sudden death in patients with Myocardial Infarction and left ventri- dramatic increase in the number of open cular dysfunction, heart failure, or both. heart cases various operative procedures The New England Journal of Medicine have been introduced in Würzburg: Complex 352:2581-2588 aortic procedures like Ross, David and Ya- Thum Th, Hoeber S, Froese S, Klink I, coub operations and emergency operations Stichtenoth D O, Galuppo P, Jakob M, Tsi- of aortic dissections. In addition, the de- kas D, Anker St D, Poole-Wilson P A, Bor- partment offers help with operative techni- lak J, Ertl G, Bauersachs J. (2007) Age- ques e.g. for bi-ventricular pacing devices to dependent impairment of endothelial pro- surrounding hospitals who embark on these genitor cells is corrected by growth hormone mediated increase of Insulin-like growth factor-1: Circulation Research 100: 148 434-443 5.2.9 Center for Experimental and Molecular Medicine (ZEMM)

Dr. med. vet. Heike Wagner General In 2001 the construction of the ZEMM (Direction Animal Facility) Information building was begun and late in 2006 the Tel.: 09 31 / 201-44077 building was largely finished. The lab- The ZEMM is a facility of the Medical Fa- oratories covering a total of 710 square Dr. med. vet. Bettina Holtmann culty to provide a basis for experimental meters were taken into use in 2007 and (Direction Transgenic Technology) research in the field of Molecular Medi- currently harbour the Institute of Clinical Tel.: 09 31 / 201-44078 cine. The labzone and the animal facility Neurobiology (Prof. Dr. M. Sendtner) and are available for defined time periods to two groups of the Rudolf Virchow-Center Professor Dr. med. Michael Sendtner research groups engaged in clearly defined (Prof. Dr. B. Nieswandt und Dr. S. Kiss- (Chair Advisory Board) research activities. The animal facility is in ler). Tel.: 09 31 / 201-44001 charge of the central breeding, husbandry

CONTACT DETAILS CONTACT and supply of uninfectious laboratory ani- The animal facility offers about 1000 Zinklesweg 10 mals used by research institutions from square meters of animal husbandry se- 97078 Würzburg the area of medicine and biomedicine. parated into three areas: the open animal facility, the breeding station and the The ZEMM is organized in two parts: the so called SPF area for breeding and hou- animal facility and the laboratories. Step sing of transgenic animals. In total, the by step, the animal facility of the ZEMM animal facility has a capacity to keep up should assume the tasks of the local un- to 49 000 mice. Connected to the animal infectious animal facilities, unless special facility is an extensive supply area and the experimental approaches do not call for facility is equipped with a complex venti- the housing of animals in a local facili- lation and air conditioning system which ty. Upon request, well-equipped labora- assures the highest hygienic standards for tories can be provided temporarily within animal husbandry. The whole animal fa- the labzone. Furthermore, several opera- cility is currently disinfected and animals ting rooms for small and large animals are will start to be moved into the building in available. the first half of 2008.

Fig. 1: The labzone from outside (Picture: Johannes Marburg, Berlin, Genf).

149 Major Research Interests

The animal facility of the ZEMM is in charge of the central breeding, maintenance and supply of uninfectious laboratory animals for research units from medicine and biomedicine. Being available for all interested scientists, the ZEMM does not conduct own research programmes. How- ever, the unit “Transgenic Technology“ will provide an up-to-date facility offering modern methods for the generation of transgenic animals, the restoration of transgenic mouse strains and the cryoconserva- tion of mouse embryos. Thus, the medical faculty expects a massive scientific support and stimulation of respective research activities.

Fig. 2: Within the animal facility – sterilisation (Picture: Johannes Marburg, Berlin, Genf).

150 5.3 Graduate Colleges 5.3.1 Graduate College 520, Immunomodulation

General logy and medicine, and clinical depart- Professor Dr. rer. nat. Thomas Hünig (Speaker) Information ments participate in the graduate college. Institute for Virology and Immunobiology The Graduate College gives students of Versbacher Str. 7 medicine and biology the opportunity 97078 Würzburg to perform a high level experimental re- Tel.: 09 31 / 201-49951 search project within an interdisciplinary Teaching Fax: 09 31 / 201-49243 training programme, usually aiming at an E-mail: [email protected] MD or a Ph.D. The Graduate College “Im- The most important teaching activity of www.gk-520.uni-wuerzburg.de/ munomodulation” was initiated in Janua- the graduate college is the weekly “Jour ry 2000, and is currently in its third and Fixe”, consisting of progress reports, spe-

CONTACT DETAILS CONTACT last funding period (2006-2008) after a cial lectures and journal clubs. The pro- third successful evaluation. Besides gra- gramme is organized in a three year cy- duates funded directly by the DFG through cle, and is continuously adjusted to the the Graduate College, an equal number of progress of the current cohort of gradua- graduate students financed through other tes. In addition, the graduates participate sources have joined the programme. Sin- in the regular seminars, practical courses ce 2006, the Graduate College “Immu- and lectures of the participating institutes nomodulation” is one of several training and clinics. programmes which jointly form the class “Infection and Immunity” of the Graduate The annual highlight of our scientific activi- School for Life Sciences (GSLS) in Würz- ties is a joint retreat with two other gradua- burg. te colleges, the GRK 592 “Lymphocyte Ac- tivation” (Erlangen), and the GRK 794 “Cell Biology of immune-associated Processes” Major Research (Tübingen). Interests

The graduates can choose a project from three research areas: “Regulation and Dysregulation of the Immune Response”, “Modulation of the Immune Response by Microorganisms and Parasites”, and “Ex- perimental Approaches to the Develop- ment of Immunomodulatory Therapies”. The projects offered encompass a broad range from basic research into the cell biology of the immune system to clinical-experimental studies. Accordingly, both theoretical institutes of the faculties of bio-

151 5.3.2 Graduate College 1048, Molecular Basis of Organ Development in Vertebrates

Professor Dr. rer. nat. Dr. h.c. Manfred General Major Research Schartl (Speaker) Information Interests Tel.: 09 31 / 888-4148 Developmental Biology is one of the most The focus of this initiative is on vertebra- Professor Dr. rer. nat. Thomas Brand exciting and fast moving fields of modern te organogenesis, which allows the use of (Speaker) biology. Its research aims at under- related model organisms by all parti- Tel.: 09 31 / 888-4259 standing the principles of mor- cipants. The restriction to verte- phogenesis and pattern for- brates is also of advantage for GRK 1048 mation leading to the esta- education and training as Biozentrum blishment of a fully func- students have more clo- Am Hubland tional, healthy organism. sely related scientific pro- CONTACT DETAILS CONTACT 97074 Würzburg A similarly important goal jects, which will foster the Fax: 0931-888 4150 is, by studying normal de- exchange of ideas, rea- E-mail: [email protected] velopment, to contribute gents and technical proto- www.gk-1048.uni-wuerzburg.de to the elucidation of me- cols. The research program chanisms that lead to pa- focuses on the role of key thological development and molecules or molecular com- disease. Transgenic mouse tech- plexes (signaling molecules, tran- nology has broadened the study field scription factors, splicing factors, mic- for developmental biologists and serves ro RNAs) in organogenesis of vertebrates. the above-mentioned goals as do the Major topics include neurogenesis, cardio- other recently emerging study objects, the vascular development and sex determinati- small aquarium fish models zebrafish and on. Experiments are done in five model or- medaka. The coordination of research in ganisms (mouse, frog, zebrafish, medaka, the field of Developmental Biology with a and chick) and cover a wide range of techni- special emphasis on organogenesis pro- ques. An important methodological aspect vides the crystallization point for collabo- of the GRK 1048 is the inclusion of modern rations that without this graduate college imaging techniques such as confocal mic- would not have taken place. roscopy and SPIM.

Teaching

The participating research groups represent various fields ranging from stem cell biology to single molecule microscopy. This has its impact on the breadth of the teaching program, which in the past was very successful and will be further improved in the coming years by establishing novel teaching initiati- ves to broaden and deepen the understanding of organogenetic processes. This research training group is part of the “Gradua- te School of Life Science (GSLS)”. Structu- res of supervision have been built such that each student has a Thesis Advisory Com- mittee that mentors her/him during the entire period of his training. On an annual basis the project of each student is evaluated and restructured as necessary to guaran- tee a successful completion. The teaching program of this initiative comprises lectures and seminars, an annual retreat, workshops and “soft skill” training. The participants are also exposed to selected topics of Fig. 1: Immunohistochemical visualization clinically oriented research that is ongoing of sensory neurons in the neural tube of in the medical faculty of Würzburg with the zebrafish embryos after gain (upper half) aim to broaden the scope of young scien- or knock down (lower half) of Midkine-b tist. Together with the strong international function (Published online as Liedtke et al links this program ensures that students will “DD ArtPix” in Dev Dyn, Vol.237, Issue 2, be well equipped for an independent and 21.Jan.2008). successful scientific carreer.

152 5.3.3 Graduate College 1141, Signal Transduction: Where Cancer and Infection Converge

Professor Dr. med. Ulf R. Rapp Würzburg and Nice is bringing together les such as the RAF kinases or identical (Speaker Würzburg) preeminent researchers in immunology, pathways such as those leading to apo- microbiology and can- ptosis play a decisi- Institut für Medizinische Strahlenkunde und cer research and has ve role in both classes Zellforschung two major goals: (1) of diseases. Research Versbacher Straße 5 Tear down the bounda- performed by the RTG 97078 Würzburg ries between the fields 1141 is addressing pri- Tel.: 09 31 / 201-45141 of oncology and infec- marily three questions. Fax: 09 31 / 201-45835 tion in order to create (1) How is the MAP ki- E-mail: [email protected] synergies for the deve- nase pathway regula- www.gcwn.de lopment of novel ap- ted under physiologi-

CONTACT DETAILS CONTACT proaches to combat cal and disease con- Professor Dr. Emmanuel Lemichez infection and cancer. ditions? (2) How do (Speaker Nice) (2) Educate an elite bacterial pathogenici- Tel.: (+33) 4 93 / 377709 group of students un- ty factors affect signal der the premise that transduction mecha- cancer and infection share many common nisms in mammalian cells? (3) How can principles, provide those students with a we exploit bacteria as Trojan horses inter- comprehensive scientific and technologi- fering with tumor cell signaling pathways cal view of both fields and enable them or stimulating an anti-tumor immune re- to perform creative research in an inter- sponse? A wide range of methods inclu- national spirit. The RTG 1141 also recei- ding those of biochemistry, microbiology, ves funds by the Franco-German Univer- cell biology, immunology and genetics are sity (http://www.dfh-ufa.org), which are used to identify and characterize in de- used for exchange programs, lab visits tail targets and mechanisms that may be and workshops. used for the development of novel therapies against infections and cancer.

Major Research Interests Teaching Targeting the signaling machinery in eukaryotic host cells is a common denominator At the “Jour Fixe”, which takes place for the pathogenic action of bacteria and each week on Tuesdays, students are parasites during infection as well for on- presenting their research progress and cogenic transformation during tumor for- novel scientific publications or textbook mation. Often the same signaling molecu- chapters related to the research focus of the RTG 1141. The students are also in charge to invite and take care of external scientists speaking at the Jour Fixe. Annual retreats at Nice or Würzburg are used to intensify the cooperation between the German and French scientists. The students participate in lab ex- changes and have a German-French thesis committee. Additional skills are im- parted by annual workshops lasting several days. Topics included so far: (1) En- trepreneurship and intellectual property management, (2) Epistemology, history and ethics of science and (3) Scientific General writing. RTG 1141 students also bene- Information fit from courses and other events that are offered by the International Graduate The DFG International Research Training School of Life Sciences Würzburg. Some Group 1141 (RTG 1141) started in Feb- events are also performed together with ruary 2005 and will be initially funded un- the BioMedTec International Graduate til July 2009. Currently 12 PhD students School of Science (BIGSS), which is a financed by the RTG 1141 and a varying joint endeavor of the Universities of Bay- number of associated students financed reuth, Erlangen-Nürnberg and Würzburg by other sources are participating. The Fig. 1: Poster for the Workshop of the GRK and which is funded by the Bavarian Eli- joint program between the universities of 1141/BIGSS: How Sience Works. tenetwork.

153 5.3.4 Graduate College 1156, From Synaptic Plasticity to Behavioural Modulation in Genetic Model Organisms

Professor Dr. rer. nat. Martin Heisenberg by a broad interdisciplinary approach go- (Speaker) ing beyond faculty frontiers in Würzburg and including international cooperations Biozentrum with the groups at the Chinese Academy Am Hubland of Science. 97074 Würzburg Tel.: 09 31 / 888 4451 Fax: 09 31 / 888 4452 E-mail: [email protected] wuerzburg.de Teaching http://www.biozentrum.uni-wuerzburg.de/ CONTACT DETAILS CONTACT genetics/ Fig. 1: Brain of an adult fly (red; in yel- Central courses of the Graduate College low the mushroom bodies, the associative are methodological courses to the gene- center for odour learning). ration and analysis of model organisms, introduction into modern microscopy (Life Immaging, confocal and STED microscopy), introduction into modern cell cultu- Major Research re techniques, special classes and annual Interests symposia in which the students from the groups from Würzburg and the chinese Based on the research foci of the facul- partners participate. The PhD program will ties of biology and medicine in the field of extent over three years and will be adap- neuroscience which are funded and orga- ted to the current level of education and nized via the “Collaborative Research Cen- the progress in the experimental work of ter 554, Behavior of Arthropods” and the the graduate students. The concomitant “Collaborative Research Center 581, Mo- educational programme of the Graduate lecular Models for Diseases of the Nervous College is an integral part of the educati- System” as well as the “Clinical Research on of graduate students in the class “Neu- Unit 125, Attention-Deficit/Hyperactivi- roscience” of the International Graduate General ty Disorder - Translational Research Fo- School of Life Science at the University Information cus on Molecular Pathogenesis and Treat- of Würzburg. ment across the Life The Graduate College 1156 was set up in Cycle”, the students 2005 as a combined interdisiplinary educa- should work on basic tional programme by the University of Würz- topics concerning sy- burg, the Institute of Neuroscience, Shang- naptic plasticity in the hai, and the Institute of Biophysics, Beijing. nervous system. All Highly skilled students from both countries projects address the in the disciplines of biology and medicine main question, how will be offered an interdisciplinary educati- synaptic plasticity on onal programme aimed to study the gene- the molecular, synaptic and cellular basis of synaptic plasticity tic and cellular level using a methodologically broad approach. modulates the func- The Graduate College provides funding for tion of the nervous 12 students from biology and medicine system and forms at the University of Würzburg and additio- behaviour. From the nal 15 students from the partner institu- methodological point tes in China. An integral part of the educa- of view, model orga- tional programme is a stay of at least 3-6 nisms like Drosophi- months at the respective partner institutes, la and mouse models allowing the students from Würzburg to be- with mutations in mo- come familiar with the research structures lecules relevant for of both chinese elite institutes and to use the regulation of syn- the methods established there in their own aptic plasticity, are in research projects. The first round of fun- the center of interest. ding will end in 2009 and the majority of The analysis of the re- Fig. 2: Disruption of the presynaptic clustering of N-type Ca- the PhD-students from biology and medici- lation of structural al- channels in growth cones of isolated mouse motoneurons from ne are expected to finish their theses. Sin- terations to behaviou- a mouse model of spinal muscle atrophy (Smn-/-SMN2tg in ce 2007, the students of this Internatio- ral modulations is one contrast to controls (Smn+/+SMN2tg). While control moto- nal Graduate College are also members of of the biggest challen- neurons (A,C) form clusters of Ca-channels with other compo- the class “Neuroscience” of the Internati- ges in current neuros- nents of the active zone (piccolo), this process is distorted in onal Graduate School at the University of cience. This challen- motoneurons from a mouse model for the spinal muscle atro- Würzburg. ge can only be met phy (B,D).

154 5.3.5 Graduate College 1253, Emotions

Professor Dr. rer. soc. Paul Pauli (Speaker) General le interdisciplinary research opportunities Information for doctoral students within the Affective Department of Psychology I Sciences. The projects of the GK conver- Marcusstr. 9-11 The GK is part of the International Gradua- ge on four levels, each addressed by hu- 97070 Würzburg te School of the University of Würzburg and man or animal research: the neurobiologi- Tel.: 09 31 / 31-2843 follows its rules for the supervision of doc- cal and molecular basis for the processing Fax: 09 31 / 31-2733 toral students. An interdisciplinary supervi- of affective stimuli, the morphology and E-mail: [email protected] sion is ensured by doctoral committees for anatomy of the involved neural systems, www.gk-emotions.uni-wuerzburg.de each student with members from different normal and pathological emotional beha- research groups. The three year curriculum vior on a cognitive, behavioral and physi- Professor Dr. med. Klaus-Peter Lesch is organized to allow an intensive interdis- ological level, and modulating self-regula- CONTACT DETAILS CONTACT (Vice-Speaker) ciplinary training on theories and methods tion processes and contexts. Special inte- Tel.: 09 31 / 201-77600 of the Affective Sciences and to provide re- rests of the GK are to evaluate the role of search experiences in different laboratories. the serotonin system and the amygdala in Independence of students and professional the processing of affective stimuli on se- academic skills will be ensured by special veral work levels and to identify interac- workshops. The integration in international tions between levels. The philosophy pro- networks of scientists working in the Affec- ject provides a theoretical framework for tive Sciences will be advanced by guest sci- the empirical-experimental projects, and entists, summer-schools with international itself focuses on the epistemological, an- scholars and the mandatory presentation of thropological and ethical dimension of re- results at international meetings. search on emotion.

Major Research Interests Teaching

The present Graduiertenkolleg (GK) aims Internet: http://www.gk-emotions.uni-wu- at identifying important mediators and mo- erzburg.de/teaching/ derators influencing the processing of af- Jour Fixe – Journal Club fective stimuli. To reach this goal, nine re- Seminars and lectures search groups from philosophy, psycho- Invited Guests logy, psychiatry, neurology, anatomy, and Lab Rotation physiology closely collaborate in order to Soft Skills develop excellent and internationally visib- External Events

155 5.4 MD/PhD-Program

Professor Dr. med. Axel Rethwilm Purpose and Objective The MD/PhD study (Speaker Medical Faculty) of the Program program includes

Institut für Virologie und Immunbiologie The MD/PhD program is a joint training Lectures, seminars, and practical courses in Versbacher Str. 7 program of the Medical Faculty and the research labs. It lasts for approx. 6 months 97078 Würzburg Faculty for Biology of the University of and is followed by an oral examination. The Tel.: 09 31 / 201-49554 Würzburg. The MD/ PhD program is open graduate work starts after finishing the stu- Fax: 09 31 / 201-47505 for medical students who have finished dy program. E-mail: [email protected] their MD thesis and have passed success- www.uni-wuerzburg.de/izkf fully the ”3. Staatsexamen”. Goal of the The MD/PhD program started in summer program is to earn the degree of ”Dr. rer. 1997 and until now 35 students were en-

CONTACT DETAILS CONTACT Professor Dr. rer. nat. Jörg Schultz nat.” (Ph.D.) according to the graduation rolled. Of these, 15 have received their (Speaker Faculty of Biology) rules of the Faculty for Biology or the In- PhD, 6 obtained a medical specialization ternational Graduate School of Life Sci- (“Facharztanerkennung”), 3 are in the USA Lehrstuhl für Bioinformatik ences (since 2007), respectively, of the as postdocs, 4 obtained their “Habilitati- Am Hubland/Biozentrum University of Würzburg. The MD/PhD pro- on” and 1 received a call for professorship. 97074 Würzburg gram consists of lab practica, a general We expect 5 further PhDs to be obtained Tel.: 09 31 / 888-4552 (specializing) study and seminar program, in 2008. Although not very large, the MD/ Fax: 09 31 / 888-4552 graduate work with thesis and a graduate PhD-program of the Medical Faculty can be E-mail: [email protected] defense with exam. regarded to be a great success. wuerzburg.de

MD/PhD Committee The Faculties of Medicine and Biology ap- point one chairman to the permanent joined committee. The committee evaluates the sui- tability of the applicants and makes the final decision for acceptance. Chairmen of the committee are:

Professor Dr. Axel Rethwilm (Medical Faculty) Professor Dr. Jörg Schultz (Faculty for Biology)

156 5.5 Research Units 5.5.1 Clinical Research Unit 103, Osteogenic Stem Cell Differentiation and Therapy of Bone Loss

Professor Dr. med. Jochen Eulert (Speaker) General therapeutic strategies. During the ongo- Information ing second term of funding the main topics Orthopedic Center for Musculoskeletal are differentiation pathways of mesenchy- Research The Clinical Research Unit „Osteogenic mal stem cells and the characterization of König-Ludwig-Haus Stem Cell Differentiation and Therapy of key transcription factors for differentiation. Brettreichstr. 11 Bone Loss“ We focus on the phosphatonins FGF23 and 97074 Würzburg sFRP4 in context with vitamin D3, on the Tel.: 09 31 / 803-1102 (KFG 103) is being funded by the German members of the CCN family of matricellular Fax: 09 31 / 803-1109 Research Society DFG since 2001, to foster signalling proteins and the action of bone E-mail: [email protected] research at the Orthopedic Department. A morphogenetic proteins (BMP). We analyse www.orthopaedie.uni-wuerzburg.de full research professorship for Experimental subpopulations of Mesenchymal stem cells

CONTACT DETAILS CONTACT and Clinical Osteology was established at using genome wide array analysis to enhan- Professor Dr. med. Franz Jakob (Head) the same time and was taken over by Prof. ce our knowledge about the basis of rege- Tel.: 09 31 / 803-1580 Franz Jakob. Presently 5 individual projects nerative therapeutic strategies. KFG 103 and one central project are funded within was tightly linked to KFG 102 at the Center this Research Unit, two of which are ex- for Musculoskeletal Surgery of the Charité ternally localised. One takes place at the Berlin to establish animal models for tissue chair for Biophysical Chemistry of Würzburg engineering and bone healing and to analy- University (Prof. em. Dr. W. Sebald), a se- se the effects of intervention using growth cond is run at the Charité, Berlin (Clinical and differentiation factors for bone healing Research unit 102 Prof. Dr. G. Duda). The in small and large animal models. main part of funding is performed according to the funding model of Clinical Research Units, which requires the identical amount Key Issues in Research of funding to be given from the budget for • Biology of mesenchymal stem cells, research and teaching of the state of Bava- phosphatonins and osteogenic cell dif- ria. The district of Unterfranken generous- ferentiation (F. Jakob, R. Ebert, T. Schil- ly provides the infrastructure and overhead ling, P. Benisch) costs for this Clinical Research Unit (KFG). • Molecular orthopedics and cell biolo- From the beginning the KFG could be built gy, The matricellular signalling molecu- up in a 500 sq. m. environment with wor- le CYR61/CCN1 during osteogenic dif- king and laboratory space, equipped for S1, ferentiation (N. Schütze, T. Schilling, R. S2 and radioactivity working procedures. Schenk, K. Schlegelmilch) The DFG Reviewer Group strongly recom- • Physiologic BMP signals in osteogenic mended that KFG 103 should be a seed stem cells. Ligands, receptor cascades, crystal to establish a Center for Musculos- modulators and signalling proteins (W. keletal Research, and should expand by as- Sebald) sociating other basic and translational science projects. It should further develop Ex- perimental and Clinical Osteology and represent all these issues in Research and Teaching at both the national and international level. During the period under report the KFG is in its second term of funding and it will be finished by 2008. An Orthopedic Center for Musculoskeletal Research has meanwhile been successfully established and Research Capacity has been substan- tially developed. Based on this and other steps taken during this time the Medical Fa- culty has decided to advance Research on Musculoskeletal Diseases as an Emerging Field at the Research Campus Würzburg with the perspective of the development of a new research focus for this university.

Fig. 1: Fibrous Dysplasia Major Research in McCune Albright Synd- Interests rome causing additional hypophosphatemic rickets KFG 103 is an interactive platform connec- due to FGF23 overpro- ting basic science, translational science duction in affected osteo- and clinical implementation of innovative blast precursors.

157 • Regenerative Medici- ne/Tissue Engineering (U. Nöth, L. Rackwitz, M. Weber, A. Heymer) • Fracture healing after trauma (KFO 103 in cooperation with KFO 102 Berlin) • Special outpatient clinic in osteology with a focus on osteoporosis and rare metabolic bone diseases (F. Ja- kob, L. Seefried, S. Go- ebel) Fig. 2: Immunohistochemical staining of bone chip derived mesenchymal stem cells (antibodies against the cell membrane associated adhesion molecule L1CAM).

Teaching

• Course in clinical examination techniques for operative and conservative orthopedics • Lectures in Basics of Orthopedics (also accompanying the practical course) • Practical Course in Orthopedics (bedside teaching in small groups, demonst- rations in physiotherapy, plaster techniques and orthopedic technical devices and corselets) Li Y, Schilling T, Benisch P, Zeck S, Meiss- • Clinical ward Rounds, x-ray discussions, ner-Weigl J, Schneider D, Limbert C, Seu- orthopedic colloquia fert J, Kassem M, Schutze N, Jakob F, • Molecular Aspects of Bone Diseases – Ebert R. (2007) Effects of high glucose Genes and Cell Biology on mesenchymal stem cell proliferation • Molecular Methods for osteology in and differentiation. Biophys Biochem Res Comm 363: 209-15. basic science • Integrated Seminar on the Molecular Nöth U, Rackwitz L, Heymer A, Weber M, Basis of Musculoskeletal Diseases Baumann B, Steinert A, Schütze N, Jakob F, Eulert J. (2007) Chondrogenic differentiation of human mesenchymal stem cells in a collagen type I hydrogel for articular cartilage repair. J Biomed Mat Res-A 83A: 626-635.

Schütze N, Wagemanns R, Fiedler J, Mat- tes T, Jakob F, Brenner RE. (2007) CYR61/ CCN1 and WISP3/CCN6 are chemoattrac- tive ligands for human multipotent mes-

SELECTED PUBLICATIONS enchymal stroma cells. BMC Cell Biology 2007, 8:45, (in press).

Cooper C, Jakob F, Chinn C, Martin-Mola E, Fardellone P, Adami S, Thalassinos NC, Melo-Gomes J, Torgerson D, Gibson A, Marin F. (2008) Fracture incidence and changes in quality of life in women with an inadequate clinical outcome from osteoporosis therapy: the Observational Study of Severe Osteoporosis (OSSO). Osteopo- ros Int. 19: 493-501.

Crockett JC*, Schütze N*, Tosh D, Jatzke S, Duthie A, Jakob F, Rogers MJ. (2007) The matricellular protein CYR61 inhibits osteoclastogenesis by a mechanism independent of alphavbeta3. Endocrinology 158 148: 5761-8. 5.5.2 Clinical Research Unit 124, The Tumor Microenvironment: Target Structure and Modulator of Immune Responses

Professor Dr. med. Eva-Bettina Bröcker General Within the scope of the KFO124 anti-tu- (Speaker) Information mor immune responses ongoing in situ in the context of the tumor microenviron- Josef-Schneider-Str. 2 The Clinical Research Group 124 (KFO124) ment are analysed. The goal is to obtain 97080 Wuerzburg was founded in 2004 under the guidance a comprehensive understanding of the Tel.: 09 31 / 201-2635 of Prof. Broecker and Prof. Becker at the immunological relevant processes, which Fax: 09 31 / 201-26462 Department of Dermatology. Other subpro- determine the result of immune response E-mail: [email protected] jects (SP) are localized at the gynecologi- to solid tumors. Moreover, the tumor mi- www.tumor-microenvironment.de cal hospital, the Medical clinic II and the croenvironment may serve as an additio- Virchow Centre. In September 2007, sin- nal source for targets of therapeutic im- Professor Dr. med. Jürgen C. Becker (Head) ce the prolongation of its term, 3 further mune responses. Hence, the subprojects CONTACT DETAILS CONTACT Tel.: 09 31 /201-26396 subprojects at the Dermatology, Neurolo- of the KFO 124 focus on different cell ty- gy, and the Medical clinic I were added to pes and interaction aspects in the tumor the KFO124. micromilieu.

The KFO124 attends to fundamental research and clinical orientated problems SP Becker concerning tumor-stroma interactions. The obtained knowledge should allow to better In this subproject stroma-associated anti- understand immune responses in solid tu- gens are preclinically and clinically evalu- mors. Subsequently, this information can ated concerning their usage in anti cancer be transferred to clinical aspects to impro- therapy. Immunogenic peptides of tumor- ve the efficacy of immune therapies for ma- stroma-associated antigens are identi- lignant diseases and to establish new anti- fied. By using such peptides in a vaccina- cancer vaccines targeting the tumor mic- tion setting, an immune response should romilieu. be elicited which by attacking the tumor- Stroma inhibits tumor progression.

SP Fassnacht/Reichardt

The role of tumor-induced immunosuppression in adrenocortical carcinoma is charac- Major Research terised in this project. In particular the ef- Interests fect of glycocorticoids on regulatory T cells is examined. Malignant tumors are complex tissues composed of cellular and structural components interacting with and influencing SP Friedl each other. Indeed, many steps in cance- rogenesis, e.g. proliferation, invasion, an- The subproject Friedl addresses cell-cell giogenesis, remodeling of the extracellar and cell-matrix interactions in 3D colla- matrix and metastasis depend on micro- gen gels and in vivo in a mouse model. environmental factors that are produced Focussed on dynamic imaging of cell-cell by stroma cells, e.g. fibroblasts, endo- interactions the group analyses CTL mig- thelial cells and infiltrating inflammatory ration, binding to target cells and killing. cells. In addition, the tumor microenvi- The aim is to identify tumor escape me- ronment is an important modulator of on- chanisms that prevent CTL migration in going tumor-specific immune responses. the microenvironment and CTL-target cell The modulation is both direct, i.e. inflic- interaction. ting the activity of tumor infiltrating lymphocytes, as indirect, e.g. changing the function of antigen presenting cells. Inte- SP Kaemmerer restingly, very similar mechanisms seem to be involved in several physiologic si- The placenta could be regarded as a na- tuations such as maintaining peripheral tural model system for invasive tumours. tolerance to self antigens or avoiding im- In this project the interaction of the tu- mune reactions to the semiallogenic fe- mour-like invasive fetal trophoblasts with tus during pregnancy. Therefore, analyses maternal immune cells are studied focus- of immune evasion mechanisms in preg- sing on mechanisms which lead to the in- nant women may help to better under- duction of tolerance and allow the cyto- stand immune reactions in cancer pati- trophoblasts to escape the maternal im- ents and vice versa. mune system.

159 Fig. 1: Cellular components of the tumor stroma and analysis of different aspects in the Blank C., Kuball J., Voelkl S., Wiendl H.; KFO124 subprojects. Becker B.; Walter B.; Majdic O., Gajewski T.F., Theobald M., Andreesen R., Macken- sen A. (2006). Blockade of PD-L1 (B7- H1) augments human tumor-specific T cell responses in vitro. Int J Cancer 119, 317-327. SP Wiendl Teaching Engert S., Rieger L., Kapp M., Becker The main emphasis of the project is on J.C., Dietl J., Kammerer U. (2007). Pro- the detailed characterization of membra- The groups participating in the KFO124 su- filing chemokines, cytokines and growth factors in human early pregnancy decidua ne transfer of immune-tolerogenic molecu- pervise medical and biological dissertati- by protein array. Am J Reprod Immunol les, such as the non-classical MHC mole- ons, as well as biomedical master theses 58, 129-137. cule HLA-G or the coinhibitory B7 molecule in fundamental and clinical research. The B7-H1, using trogocytosis as a mechanism supervision of dissertations partly is done Hofmeister V., Vetter C., Schrama D., Bro- of immune-modulation in the milieu of the within the Graduate School of Life Sci- cker E.B., Becker, J.C. (2006). Tumor stroma-associated antigens for anti-cancer tumor. ences. In addition, the group leaders par- immunotherapy. Cancer Immunol Immu- ticipate in lectures for the students of dif- nother 55, 481-494.

ferent specialisations (medicine, biomedici- SELECTED PUBLICATIONS SP Schrama ne, and biology). Schrama D., Voigt H., Eggert A.O., Xiang R., Reisfeld R.A., Becker J.C. (2006). The- rapeutic efficacy of tumor-targeted IL2 in In this subproject the influence of the na- LTalpha(-/-) mice depends on conditioned ture of the antigen on the development of T cells. Cancer Immunol Immunother 55, effector and memory immune responses is 861-866. analysed. The specific immune responses Wobser M., Voigt H., Houben R., Eggert are directed against antigens which differ in A.O., Freiwald M., Kaemmerer U., Kaemp- their expression and regulation: a) ubiquita- gen E., Schrama D., Becker J.C. (2007). ry b) localized, and c) after induction prima- Dendritic cell based antitumor vaccination: rily on stroma-associated fibroblasts. impact of functional indoleamine 2,3-dio- xygenase expression. Cancer Immunol Im- munother 56, 1017-1024. 160 5.5.3 Clinical Research Unit 125, Attention-Deficit/Hyperactivity Disorder – Translational Research Focus on Molecular Pathogenesis and Treatment across the Life Cycle

Professor Dr. med. Klaus-Peter Lesch The primary goals are based on the follo- 50%. Affective disorders and alcohol/drug (Speaker and Coordinator) wing concept: By joining preclinical and cli- dependence also display a remarkable fre- Tel.: 09 31 / 201-77600 nically oriented research groups, who work quency (Fig. 1). A co-morbidity with anti- Fax: 09 31 / 201-77620 on ADHD-specific molecular mechanisms social personality disorder was reported to E-mail: [email protected] of nerve cell function as well as molecular be increased in several clinical cohorts. The genetic and developmental biological es- burden of disease cannot be overestimated Professor Dr. med. Andreas Warnke sentials of brain function, and on struc- by accounts of social and economic pro- (Coordinator) tural-functional basis of the complex be- blems as well as impaired academic achie- Tel.: 09 31 / 201-78000 havior of ADHD, predictors and differential vement and work performance. Particularly, Fax: 09 31 / 201-78040 strategies for therapy during the long-term disruptive family environment may harm off- E-mail: [email protected] course of illness are being developed. Mo- spring development.

CONTACT DETAILS CONTACT reover, evolutionary conserved ADHD-rele- Clinic of Psychiatry, Psychosomatics and vant principles of structure and function of By integrating the concepts of molecular Psychotherapy the brain as well as syndrome-typical be- genetics, neurobiology, and cognitive psy- Clinic of Child and Adolescent Psychiatry, havior (e.g., hyperactivity, attention-defi- chology, the psychiatric neurosciences have Psychosomatics and Psychotherapy cit, impulsivity, aggression, substance use) witnessed remarkable progress in the under- Füchsleinstr. 15 are being defined by comparative investi- standing of the relationship between neuro- 97080 Würzburg gations of different species (humans, non- development, neural function, and behavior www.psychobiologie.uni-wuerzburg.de/ human primates, mice). Finally, the pree- related to ADHD. In this context particular- xisting areas of convergence between the ly animal models such as genetically modi- fields of neuropsychology, psychobiology fied mice or nonhuman primates contribut- as well as child and adolescent, and adult ed important insight. On the other hand im- psychiatry will strengthen the connections provement of methodological tools in psy- between the individual disciplines by esta- chology and psychiatry permitted the accu- blishing new research groups, who will in- mulation of new information on the psycho- vestigate common topics. In that, new op- and neurobiological basis of behavior and portunities for the study of the molecular its alteration in ADHD. The human genome foundations in the etiopathogenesis and project and the sequencing of mouse and long-term course of ADHD have been put rhesus macaque genomes shifted the fo- into practice. cus also to investigations of gene function in psychiatry. This development will allow better understanding of both the molecular Major Research and cellular foundation of ADHD and the Interests relevance of genetic variation for disease- related behavior such as hyperactivity, at- ADHD (MIM 143465) is the most common tentional and cognitive deficits, emotional behavioral disorder in childhood with a pre- dysregulation, and drug use. Finally, the de- valence of 4-8% and with substantial heri- sign of novel therapeutic strategies requires tability which is likely due to multiple genes translational approaches with interdiscipli- of small effect size. Longitudinal studies de- nary cooperation of basic research and cli- monstrated persistence into adulthood with nical medicine. General a lifetime prevalence estimated at approxi- Information mately 2-4%. Epidemiological studies sug- The KFO 125 is divided into ten tightly gested high co-morbidity with other psychi- interconnected subprojects (Fig. 2): Two The molecular pathogenesis of Attention- atric disorders; lifetime prevalence rates of subprojects (SP 1 and 2) focus on clinical Deficit/Hyperactivity Disorder (ADHD) and anxiety disorders in adult ADHD approach aspects including diagnostic evaluation of the significance of its endophenotypes and ADHD and co-morbid dis- comorbid disorders, such as substance orders across the life cy- abuse, affective disorders, and antisocial cle as well as ascertain- personality disorders, for the course of ill- ment of patients and their ness is both clinically and health politically families for genetic stu- a highly relevant but largely unsolved pro- dy. In addition, these two blem. The Clinical Research Program (KFO subprojects assess etio- 125), as a joint facility of the Departments logical heterogeneity, cli- of Child and Adolescent Psychiatry, Psycho- nical symptoms of subty- somatics and Psychotherapy (KJPPP) and pes and outcome, as well Psychiatry, Psychosomatics and Psychothe- as psychosocial impact of rapy (PPP), deals with the interdependent ADHD within the frame- relationships between the molecular and work of a family-centered functional-structural mechanisms of the outpatient unit. In cont- pathogenesis of ADHD and its significance rast to previous longitudi- for its long-term course using interdiscipli- nal studies, a multi-layer nary and translational research strategies. Fig. 1: ADHD subtypes and co-morbidity. analysis facilitates a novel

161 approach in follow-up research which is likely to provide a more profound under- Teaching standing of the interaction between genetic disposition and environmental influ- The unique configuration ences on the course of juvenile and adult of competence for transla- ADHD. In synergy to SP 1 and 2 a BMBF- tional research of the KFO supported study entitled “Effects and Me- 125 together with the SFB chanisms of Psychotherapy in the Treat- 581 and Graduate Pro- ment of ADHD in Children and Adults – grams within the Interna- The First Randomized Multicentre Study” tional Graduate School of exclusively focuses on the treatment of Life Sciences (GSLS) pro- ADHD across the life cycle. vides an excellent platform for competent education Three subprojects (SP 3-5) represent an and training of a wide va- integrated approach toward elucidation riety of junior researchers Fig. 2: Overview of KFO 125 subproject interactions indi- of specific molecular genetic and neuro- including Bachelor and cating the respective main research focus and principle in- biological mechanisms of complex beha- Master students, M.D. and vestigators. vior related to ADHD. Genome-wide linka- Ph.D. students as well as ge scans using 50K SNP arrays are being Postdocs from the Facul- performed on extended multigenerational ties of Medicine, Biology, Physics, and Hu- families with high density of ADHD and a manities. The enhancement of the interdis- sample of affected sib pairs. In addition, ciplinarity of teaching in the psychiatric neu- application of a 500K SNP array in ge- rosciences is therefore an ultimate goal of nome-wide association (GWA) studies will the KFO 125. Complex approaches to neu- provide a profound basis for subsequent robiological questions and the joint use of studies on genetically modified mouse techniques and methods derived from mo- models of ADHD. Furthermore, three sub- lecular biology, genetics, and imaging are projects (SP 6-8) attempt to define en- the hallmarks of modern psychobiological dophenotypes of ADHD by electrophysio- research, making psychiatric neurosciences Walitza S, Renner TJ, Dempfle A, Kon- logical and neuropsychological paradigms interdisciplinary by definition. rad K, Wewetzer Ch, Halbach A, Herpertz- as well as functional magnetic resonance Dahlmann B, Remschmidt H, Smidt J, Lin- imaging (fMRI). Finally, all aspects of the der M, Flierl L, Knölker U, Friedel S, Schä- clinical and neurobiological research pro- fer H, Gross C, Hebebrand J, Warnke A, Lesch KP (2005) Transmission disequilib- gram are integrated by a subproject on rium of polymorphic variants in the trypto- genetic epidemiology/biostatistics (SP 9) phan hydroxylase-2 gene in attention-de- and by a junior research group on ima- ficit/hyperactivity disorder. Mol Psychiat- ging of genetic variation (SP 10 - JRG). ry10:1126-32. The primary goal of the JRG is the eluci- Jacob CP, Romanos J, Dempfle A, Heine dation of the effects of genetic variation M, Windemuth-Kieselbach C, Kruse A, Reif on the functional neuroanatomy of atten- A, Walitza S, Romanos M, Strobel A, Bro- tion, impulsivity as well as emotion and its cke B, Schäfer H, Schmidtke A, Böning J, relevance for ADHD using different brain Lesch KP (2007) Co-morbidity of adult attention-deficit/hyperactivity disorder with imaging techniques like EEG, NIRS, fMRI focus on personality traits and related dis- and PET. orders in a tertiary referral center. Eur Arch Psychiatry Clin Neurosci 257:309-317.

The basis for the pursuit of these concepts SELECTED PUBLICATIONS and goals is the interdisciplinary compo- Canli T, Lesch KP (2007) Long story short: the serotonin transporter in emotion regu- sition of KFO 125 and its integration into lation and social cognition. Nature Neu- the research structures of the University of rosci 10:1103-1109. Wuerzburg (e.g. SFB 581, GRK 1156, GRK 1263, GSLS, IZKF) as well as into a wide Herrmann MJ, Huter T, Müller F, Mühlber- ger A, Pauli P, Reif A, Canli T, Fallgatter A, spectrum of national (e.g. BMBF Multicen- Lesch KP (2007) Additive effects of sero- tre Study, Nationales Schwerpunktnetzwerk tonin transporter and tryptophan hydroxy- ADHS, MPI für Molekulare Genetik) and in- lase-2 gene variation on emotional pro- ternational collaborations (e.g. EU New- cessing. Cerebral Cortex 17:1160-1163. mood Network, NIMH, NHGRI, NIDA, NI- Romanos M, Freitag C, Jacob CP, Craig AAA, Tgen Research Institute). This resul- DW, Dempfle A, Nguyen T, Halperin R, Wa- ted in a specific and long-term configura- litza S, Renner TJ, Seitz C, Romanos J, tion of competence at the Clinical Institute Palmason H, Reif A, Heine M, Windemuth- of the University of Wuerzburg with focus on Kieselbach C, Vogler C, Sigmund J, Warn- ke A, Schäfer H, Meyer J, Stephan DA, future-oriented translational research of eti- Lesch KP (2008) Genome-wide linkage opathogenetic mechanisms and novel the- analysis of ADHD using high-density SNP rapeutic options of ADHD. arrays: novel loci at 5q13.1 and 14q12. Molecular Psychiatry (13:522-530. 162 5.6 Research Alliances 5.6.1 Rehabilitation Research Network of Bavaria

Professor Dr. med. Dr. phil. Hermann Faller General ting factors in the rehabilitation process (Speaker) Information (Prof. Dr. R. F. Wagner). Several studies that were performed outside the Univer- Institut für Psychotherapie und Medizinische The Rehabilitation Research Network of sity of Würzburg provided information for Psychologie/Arbeitsbereich Rehabilitations- Bavaria (RFB) was founded in 1998 with the development of a questionnaire for wissenschaften funding from the “Rehabilitation Sciences” the fear of progressive disease, ICF-Core- Marcusstr. 9-11 program of the German Ministry of Educa- Sets for selected disorders, and a con- 97070 Würzburg tion and Research and the German Statu- cept for the monetary evaluation of health Tel.: 09 31 / 31-2070 tory Pension Insurance. As chronic disor- outcomes in rehabilitation. Furthermore, Fax: 09 31 / 31-2078 ders have gained increasing medical and gender-specific predictors of rehabilitati- E-mail: [email protected] economical importance, medical rehabili- on successes in patients with myocardial CONTACT DETAILS CONTACT www.rehawissenschaft.uni-wuerzburg.de tation should be more scientifically orien- infarction were identified. ted. The RFB provides well-coordinated and high-quality rehabilitation research, contributes to the transfer of research re- Project Area B – Evaluation of Treat- sults into practice, and improves the re- ment Programs gional research infrastructure on a long- term basis. The central institutions, such Patient education programs are a central as the coordination center, methods coun- feature of medical rehabilitation. Their seling center (Prof. Dr. Dr. H. Faller, Würz- successes depend, among others, on the burg), and health economics counseling patients’ own motivational factors. In a center (Prof. Dr. G. Stucki, Munich), provi- multi-center study, interventions for the de support for research methods and co- enhancement of motivation in developing ordinate the 25 network projects. A clo- healthy lifestyles were evaluated (Prof. Dr. se cooperation of university departments, H. Ellgring). In a multi-network project, rehabilitation clinics, and regional pension in-depth analyses of the predictors of suc- insurance institutes characterizes the net- cesses in patient education were identi- work structure. fied and recommendations for the evaluation of patient education were published (Dr. H. Vogel, A. Reusch). Several other Major Research projects of rehabilitation clinics aimed to Interests develop and evaluate disease-specific interventions of chronic back pain, kidney The theme of the network is “Patients in diseases, chronic obstructive pulmonary Rehabilitation: Disease-specific and Over- disease, somatoform disorders, and lesi- lapping Approaches to Motivation, Co- ons of the brain. Based on studies of ping, Intervention and Evaluation”. Du- Area A, both a treatment program for the ring two separate stages of funding, re- fear of progressive disease and a gender- search questions organized into three to- specific intervention for cardiological re- pics were examined with a patient-orien- habilitation were also developed and eva- ted perspective (see below). Transfer pro- luated. jects are currently being executed in the areas of patient education and occupational rehabilitation. Project Area C – Interface Problems in Rehabilitative Care

Project Area A – Diagnostic and Predic- In two successive projects, the social me- tor Studies dicine evaluation process and the selection of patients for medical rehabilitation In a multi-center study, several patient- were explored in cooperation with the sta- based questionnaires for the assessment tutory pension insurance. Different stra- of rehabilitation effects (SF-36, IRES, tegies for evaluating rehabilitation needs SCL-90-R) were examined regarding their were examined regarding their prognostic sensitivity to change (Prof. Dr. Dr. H. Fall- validity, and an algorithm for a systematic, er). The German version of the Short Mu- stepwise decision-making strategy in so- sculoskeletal Function Assessment Ques- cial medicine was developed and assessed tionnaire (SMFA-D), which is suitable for (Dr. H. Vogel, Dr. A. Holderied). Two other the assessment of functional capacity du- consecutive studies were designed to eva- ring routine orthopedic care, was deve- luate working-capacity tests in psychoso- loped and validated (Prof. Dr. A. König). matic rehabilitation and to optimize work- The subjective illness theories of patients related treatment measures. A model pro- with chronic back pain were explored re- ject aimed to improve the care of diabetes garding their role as facilitating or inhibi- mellitus patients in a specific region by es-

163 Consolidating and extending the departmental section of Rehabilitati- on Sciences at the above-mentioned institute has improved the research infrastructure. A major input was a professorship for rehabilitation sciences (Prof. Dr. Dr. H. Faller), which was initially granted by third-party Fig. 1: Aims and roles of the Center of Patient Education. payers and is now implemented into the university tablishing a network between a diabetes budget. Additionally, the center and general practitioners. Lastly, a Network of Rehabilitation Research of Ba- project that combined both philosophical varia (NRFB) aims to sustain the regional reasoning and empirical research attemp- cooperation of research, clinics, and insu- ted to answer questions of efficiency and rance institutes. justice in the rehabilitation system.

Transfer Projects Teaching

The goals of the project “Center for Pati- The institute’s departmental section of ent Education” (Prof. Dr. Dr. H. Faller, A. Rehabilitation Sciences is responsible for Reusch, Dr. H. Vogel) include the optimi- the education in the cross-sectional sub- zation of patient education and the disse- ject area 12, “Rehabilitation, Physical Me- mination of research results into rehabili- dicine, Naturopathy”, and offers an optio- tation clinics (see Fig. 1). Criteria for de- nal seminar on Rehabilitation Science. In scribing and evaluating patient education addition, it contributes to the cross-sectio- programs that may be applied to a wide nal areas 3, “Health Economy, Health Care range of diseases were developed. Exis- System, Public Health”, and 10, “Preventi- ting educational programs were surveyed on, Health Promotion”. on a nation-wide basis, and this information was systematically assessed and presented in an online database. In a successive project, one of the focuses will be on quality assurance (training of trai- Faller H, Reusch A, Vogel H, Ehlebracht- ners, among others). The focus of ano- König I, Petermann F (2005) Patienten- ther transfer project is on occupational re- schulung. Rehabilitation 44:277-286. habilitation. A generic screening instrument for the identification of occupational Igl W, Zwingmann C, Faller H (2006) Än- problems and the assessment of job-rela- derungssensitivität von Fragebogen zur Er- fassung der subjektiven Gesundheit - Er- ted rehabilitation needs is currently being gebnisse einer prospektiven vergleichen- developed (Dr. H. Vogel). A second pro- den Studie. Rehabilitation 45: 232-242. ject performs a survey of all occupational interventions currently being applied in re- Meng K, Zdrahal-Urbanek J, Frank S, Hol- deried A, Vogel H (2006) Patients‘ expec- habilitation clinics in order to determine tancies, motivation, and multidimensional which interventions are most appropria- subjective and sociomedical objective suc- te (Dr. S. Neuderth). An education mo- cess in medical rehabilitation measures. dule covering occupational rehabilitation International Journal of Rehabilitation Re- topics suitable for various disorders and search 29:65-69. easily accessible is developed and evalu- Wollmerstedt N, Kirschner S, Faller H, Kö- ated as part of a multi-center cooperati- nig A (2006) Reliability, validity and re-

on project. SELECTED PUBLICATIONS sponsiveness of the German Short Mus- culoskeletal Function Assessment Questi- onnaire in patients undergoing surgical or In the recent funding program, “Patient Ori- conservative inpatient treatment. Qual Life entation and Chronic Diseases” (BMBF, Res 15:1233-1241. among others), five additional rehabilitation research projects have been accepted. Faller H, Reusch A, Ströbl V, Vogel H (2008) Patientenorientierung und Patien- tenschulung. Rehabilitation 47: 77-83. Improvement of Research Infrastructure 164 5.6.2 BMBF-Network PathoGenoMik-Plus

Professor Dr. med. Matthias Frosch (Speaker) General Information Institute for Hygiene and Microbiology Josef Schneider Str. 2; Bau E1 The „PathoGenoMik-Plus“ network is part of 97080 Würzburg the funding and research initiative “Genome Tel.: 09 31 / 201-46160 research on microorganisms” which was in- Fax: 09 31 / 201-46445 itiated by the German Federal Ministery of E-mail: [email protected] Education and Research (Bundesministeri- www.genomik.uni-wuerzburg.de/pathogeno- um für Bildung und Forschung, BMBF). mik-plus_2006_-_2009/ During the funding period from 2006 to

CONTACT DETAILS CONTACT Dr. rer. nat. Gabriele Gerlach (Office) 2009 the participating groups of the “Pa- Tel.: 09 31 / 201-46901 thoGenoMik-Plus” network focus on human pathogenic bacteria that are of high soci- oeconomic relevance for the public health system in Germany due to their wide dissemination in, e. g., hospitals or that pose a particular threat for the health system due to their high rate of antibiotic resistance or their high virulence potential. Fig. 1: Locations of the research groups of the “PathoGenoMik-Plus” network. While the “PathoGenoMik” initiative (2001- 2006) focused on the sequencing of entire genomes from a number of medically important bacterial pathogens the functional (the meningococcus) and Streptococcus analysis of the sequenced genomes with re- pneumoniae (the pneumococcus) which spect to potential applications in the diag- are both responsible for the vast majority of nosis, therapy as well as prophylaxis of in- cases of acute bacterial meningitis worldwi- fectious diseases is the main focus of the de, especially in young children. “PathoGenoMik-Plus” funding initiative. The research activities of the other two clus- The PathoGenoMik-Plus network is coordi- ters focus on the causative agent of tuber- nated by Prof. Dr. M. Frosch from the In- culosis in humans Mycobacterium tubercu- stitute for Hygiene and Microbiology from losis and on periodontitis as a model for the University of Würzburg. Besides se- polymicrobial disease. veral research groups of the University of Würzburg further German research groups from eight different Universities, the Max- Planck-Institute of Infection Biology (Ber- lin), the Robert-Koch Institute and the Re- search Center Borstel are members of the network (Fig. 1). Schoen C, Blom J, Claus H, Schramm- Glück A, Brandt P, Müller T, Goesmann A, Joseph B, Konietzny S, Kurzai O, Schmitt Major Research C, Friedrich T, Linke B, Vogel U, Frosch Interests M. 2008. Whole genome comparison of disease and carriage strains provides insights into virulence evolution in Neisseria According to the wide spectrum of infec- meningitidis, Proceedings of the National tious diseases investigated in the network Academy of Sciences U.S.A. 105: 3473- the reasearch groups collaborate in four 3478. clusters. Batzilla CF, Rachid S, Engelmann S, He- cker M, Hacker J, Ziebuhr W. 2006. Im- Cluster 1 is coordinated by Prof. Dr. Dr. h.c. pact of the Accessory Gene Regulato- J. Hacker from the Institute for Moleculare ry System (Agr) on Extracellular Proteins, Infection Biology at the University of Würz- codY Expression and Amino Acid Metabo- burg and is focussed on nosocomial infec- lism in Staphylococcus epidermidis. Prote- omics 6(12): 3602-13 tions with special emphasis on the hospital- acquired bacterial species Staphylococcus A detailed overview about the projects

aureus, Staphylococcus epidermidis and SELECTED PUBLICATIONS of the former “PathoGenoMik” network Pseudomonas aeruginosa. (2001-2006) is given in the special issue of the International Journal of Medical Mi- crobiology; Volume 297; November 2007; Cluster 2 is coordinated by Prof. Dr. M. pp. 479-642; ISSN 1438-4221. Frosch and works on Neisseria meningitidis

165 5.6.3 Network of Excellence EuroPathoGenomics

Professor Dr. rer. nat. Dr. h.c. mult. General Comparative genomics/Biodiversity Jörg Hacker (Speaker) Information Comparative genomics has been used to Institut für Molekulare Infektionsbiologie Bacterial infections remain a major contribute to a better understanding of Bayerische Julius-Maximilians-Universität cause of disease and mortality in hu- genome content and evolution of bacte- Würzburg mans and animals throughout the world. rial pathogens. Therefore, DNA-DNA hy- Röntgenring 11 Only the detailed understanding of their bridizations, sequencing as well as ana- 97070 Würzburg pathogenic processes will provide us lysis of genes and complete genomes of Tel.: 09 31 / 31-2575 with innovative tools for their preventi- different bacteria (e.g. Vibrio, Rickettsia, Fax: 09 31 / 31-2578 on and treatment. The study of infec- Chlamydia, Listeria, Salmonella, Legio- E-mail: [email protected] tious disease needs a multidisciplinary nella, Bartonella, Escherichia, Staphylo- CONTACT DETAILS CONTACT www.noe-epg.uni-wuerzburg.de approach that brings together the differ- coccus, Helicobacter) were performed in ent disciplines of molecular biology, im- the NoE EPG. Broad comparative genome Dr. rer. nat. Andreas Demuth (Office) munology, cell biology and structur- analysis of different Vibrio genomes for Dr. rer. nat. Gabriele Blum-Oehler (Office) al biology. Although scien- example allowed the establish- Tel.: 09 31 / 31-2126 tific collaborations within ment of a map of the overall Europe have been es- genome plasticity in this tablished to some bacterial group. Fur- extent, there is a thermore, preliminary pressing need for results of the com- more permanent parison of patho- links and struc- genic Legionella tures between species indica- the different dis- te major diffe- ciplines. rences in the virulence gene re- This task is accom- pertoire and in secre- plished by the Net- tion systems. Moreover, work of Excellence “Eu- the genome sequence of Sta- roPathoGenomics” (NoE phylococcus carnosus, a non- EPG) that is supported by the pathogenic Staphylococcus spe- European Union with 6.7 million Euro cies has been completed and the genome for the duration of five years (July 2005 has been annotated. Comparative genome – June 2010). The NoE EPG, comprising analysis with the pathogenic S. aureus will 38 top level laboratories from 13 different give new insight into the core-genome of nations, is co-ordinated by the University the species and new accessory genes that of Würzburg under the direction of Profes- might contribute to the virulence of S. au- sor Jörg Hacker. reus. These data provide the basis for the application of new genomic approaches allowing the specific combat of pathogenic bacteria. Major Research Interests Antibiotic resistance

One of the major objectives in the field of Lateral gene transfer through its impli- research is to organise the mass of geno- cation in the development and spread of mic information that has become avail- antibiotic resistance genes among bac- able, regarding both microorganisms and terial pathogens is also a topic of major their hosts, into schemes allowing one concern in the EPG network. Using Gram- to decipher the cross talks between pa- negative and Gram-positive model sys- thogens and commensals and their host tems, different aspects of the evolution cell and tissue targets. Innovation in di- and spread of antibiotic resistances were agnostic techniques and therapy, as well analysed by comparative genomics and as the development of vaccines against functional studies. Furthermore, bacteri- pathogenic microorganisms, are expec- al gene expression in response to expo- ted to come out of the joint research ac- sure to antibiotics was investigated in or- tivities of these top-level European re- der to get a deeper insight into the effect search groups in the field of genomic re- of antibiotics on gene regulation. These search. approaches will result in an improved understanding of the molecular mecha- Accordingly, several topics are in the focus nisms contributing to the development of the EPG project: and spread of antibiotic resistances and

166 cluster) and surface proteins is important for biofilm formation of Pseudomonas aeruginosa.

Pathogen-host cell interactions

Microbial diseases are the result of the interaction of the parasite and its host. Therefore, analysis of the interactions between bacterial pathogens and eukaryotic cells were accomplished in various cell culture and animal models and corresponding adhesion assays as well as screening tests were established. For ex- Fig.1: Comparison of different E. coli ge- ample, a library of small organic molecu- nomes. Circles represent complete E. les was screened for their inhibitory capa- coli genomes. From inside to outside: E. cities on microbial specific structures that coli K-12 strain MG1655, uropathogenic induce Toll-like receptor activated sig- E. coli strain 536, uropathogenic E. coli nal transduction cascades. This screen strain CFT073, enterohemorrhagic E. coli resulted in 20 substances classified as strain EDL 933. inhibitors that could not only help to understand the stimulation of cascades but also serve as therapeutic agents.

to the discovery of novel anti-infectious Teaching agents and their targets. One of the main activities of the EPG project is related to the education and trai- Cellular microbiology ning of students in the field of pathogenomics. Therefore, the so-called “EuroPatho- The analysis of factors influencing the viru- Genomics Graduate Academy” (EGA) has lence of bacterial pathogens is one of the been established. The EGA provides young cornerstones of experimental infection bi- scientists a broad-based interdisciplinary ology. Therefore, extensive analysis of regu- study programme with a wide range of semi- latory networks involved in the production of nars, summer schools and practical work- virulence factors and survival of pathogens shops. Furthermore, participants of the im- (e.g. Mycobacteria, Pseudomonas, Listeria, plemented exchange programme have the Brzuszkiewicz E, Brüggemann H, Liese- Legionella, Salmonella, Neisseria) in vitro opportunity to visit the laboratory of project gang H, Emmerth M, Olschläger T, Nagy and within the host was carried out in the partners in order to exchange expertise and G, Albermann K, Wagner C, Buchrieser C, EPG project. Whole genome expression and to gain new insights into particular areas Emody L, Gottschalk G, Hacker J, Dob- comparative gene profiling were performed of interest. rindt U. (2006) How to become a uro- to allow the identification and quantitative pathogen: comparative genomic analysis of extraintestinal pathogenic Escheri- analysis of network components that are chia coli strains. Proc Natl Acad Sci U S A. parts of signalling pathways. 103:12879-84.

Nougayrède JP, Homburg S, Taieb F, Boury M, Brzuszkiewicz E, Gottschalk G, Buch- Microbe-microbe interaction rieser C, Hacker J, Dobrindt U, Oswald E. (2006) Escherichia coli induces DNA Microbial communities such as biofilms are double-strand breaks in eukaryotic cells. involved in many infections in humans often Science 313:848-51. resulting in chronic states that are very dif- Fournier PE, Vallenet D, Barbe V, Au- ficult to combat. Therefore, to develop new dic S, Ogata H, Poirel L, Richet H, Ro- strategies for diagnosis, prevention and bert C, Mangenot S, Abergel C, Nordmann

control of microbial infections it is aimed SELECTED PUBLICATIONS P, Weissenbach J, Raoult D, Claverie JM. to identify specific factors expressed within (2006) Comparative genomics of multid- rug resistance in Acinetobacter baumannii. biofilms (e.g. Escherichia, Legionella, Pseu- PLoS Genet. 2:e7. domonas, Staphylococcus). The collaboration of some EPG network partners already Josenhans C, Beier D, Linz B, Meyer TF, showed that the presence of specific ge- Suerbaum S. (2007) Pathogenomics of nes (e.g. cupB/cupC and flp/tad/rcp gene helicobacter. Int J Med Microbiol. 297: 589-600. 167 5.6.4 Research Program of the BMBF: Effects and Mechanisms of Psychotherapy in the Treatment of Attention Deficit Hyperactivity Disorder (ADHD) in Children and Adults

Professor Dr. med. Andreas Warnke (Speaker) General and monitoring will be provided by the Information Centre for Clinical Trials in Freiburg. An Klinik und Poliklinik für Kinder- und advisory board is supervising the projects. Jugendpsychiatrie, Psychosomatik und This national network is part of a research Treatment integrity is assured by randomi- Psychotherapie program on psychotherapy in the treat- zed videotaping and external supervision. Füchsleinstr.15 ment of psychiatric disorders founded by The consideration of scientific and ethical 97080 Würzburg the German Ministry of Education and Re- criteria based on the GCP document of Tel.: 09 31 / 201-78000 search. The need for a more intense stu- the International Conference on Harmoni- Fax: 09 31 / 201-78040 dy of psychotherapy in Germany had been zation (ICH) is supervised by a Data Mo- E-mail: [email protected] stressed by the advisory committee for evi- nitoring Committee (DMC). Our research www.klinik.uni-wuerzburg.de/kjp dence based psychotherapy (Wissenschaft- program is strengthened by the coope- CONTACT DETAILS CONTACT www-i.klinik.uni-wuerzburg.de/deutsch/ licher Beirat Psychotherapie) of the German ration with the Clinical Research Group einrichtungen/kliniken/kjp/forschung/ADHD/ Psychotherapeutic Association (Bundespsy- ADHD (KFG 125, funded by the German ForschungsverbundPsychotherapieADHS/ chotherapeutenkammer) and the German Research Association, DFG) in Würzburg content.html Medical Association (Bundesärztekammer). and international cooperations. Our network focuses on the treatment of ADHD. ADHD in adults has long been unre- In cooperation with the Clinical Research cognized and underestimated. Randomized Group ADHD (KFG 125) the “1st Inter- controlled clinical trials including morpholo- national Congress on ADHD” was held in gical and genetic variables are still missing Würzburg. More than 1300 experts and worldwide. among them the representatives of all leading research groups on ADHD out of The aims of the present network are: 5 continents participated in the congress. • to evaluate the effects of a structured Within this framework the „World Associa- disorder specific psychotherapy (group tion on ADHD“ (president: Prof. Dr. Warn- setting) in adult ADHD in a randomized, ke) and the „International Journal ADHD“ placebo-controlled multi-centre study; (chief editor: Prof. Dr. Gerlach) had been • to compare the efficacy of this psycho- founded. More than 300 patients and re- therapeutic program to pharmacologi- latives participated in a “patient’s day” cal treatment (methylphenidate) alone and had the opportunity to be informed and a combination of both; on new developments in ADHD research • to analyse whether the developed psy- and treatment. chotherapy manual can be successfully transferred to the setting of child and adolescent psychiatry: does ADHD pa- Major Research rent (i.e. adult) treatment reinforce pa- Interests rent (i.e. mother) training outcome in the treatment of ADHD children; Main issue of the child psychiatric stu- • to examine whether there are specific dy groups (principal investigator: Prof. Dr. neurobiological markers (e.g. cerebral A. Warnke, CAPP Würzburg) is the project morphology, neurochemistry and gene- “Does the treatment of maternal ADHD tic variations), which can differentially enhance the effectiveness of parent predict therapeutic response to phar- management training for children’s macotherapy, psychotherapy or a com- ADHD?”. (M. Gerlach, T. Jans, T. Renner, bination of both. M. Romanos, A. Warnke) The therapy of mothers includes a structured group-psy- The structure of the national network is in- chotherapy-program for adult ADHD in terdisciplinary and multicentre. 4 projects combination with medication (methyl- are established in 10 study centres: rec- phenidate). The control intervention is ruiting and manualized therapy are provi- psychiatric counselling without the imp- ded by Departments for Adult Psychiatry lementation of specific therapeutic stra- and Psychotherapy (APP) and Department tegies (randomized trial). After 13 weeks for Child and Adolescent Psychiatry and all mothers and children receive parent Psychotherapy (CAPP) in Würzburg (APP, management training for children’s ADHD CAPP), in Freiburg (APP, CAPP), Mann- carried out on a one-to-one basis. Each heim Central Institute (APP, CAPP), Hom- of the 4 study centres is going to screen burg (forensic psychiatry, CAPP) and Ber- 40 mother-child-pairs for eligibility, 36 will lin (APP). The multimodal imaging studies be randomized. Other research questions will be conducted by the recently establis- to be addressed by the study are: To what hed South German Brain Imaging Center extent do treatment effects generalize on (APP Freiburg). Genetic data will be col- co-morbid symptoms, family functioning lected and analyzed in Würzburg (EPP). and quality of life areas? Are the diffe- Data management, statistical analysis rences between the ratings of child, mo-

168 ther or therapist? Does the sole treatment of maternal ADHD already have influences on the child’s symptoms? Are the effects of treatment stable over settings (school, family environment) and time? Is there an association between the child’s co-morbidity and treatment outcome?

The project “Evaluation of the efficacy and effectiveness of a structured disorder specific psychotherapy in ADHD in adults” (principal investigator: Dr. A. Phi- lipsen, APP Freiburg) is a randomized controlled multicentre clinical trial including 4 conditions: “group psychotherapy + placebo“, “group psychotherapy + medication (methylphenidate)“, “clinical management + medication” and “clinical management + placebo“.

Both of these clinical studies are linked with other projects. The project “Molecu- lar imaging might predict therapeutic response in adult patients with ADHD. A pilot multimodal neuroimaging study” (principal investigator: Prof. Dr. L. Tebarzt van Elst, APP Freiburg) is designed to investigate morphological and functional bio- Friedel S, Horro FF, Wermter AK, Geller F, logical brain markers of treatment response Dempfle A, Reichwald K, Smidt J, Bronner using MR spectroscopy. G, Konrad K, Herpertz-Dahlmann B, Warn- ke A, Hemminger U, Linder M, Kiefl H, The moleculargenetic project is entitled Goldschmidt HP, Siegfried W, Remschmidt “The association of genetic variation H, Hinney A, Hebebrand J. (2005). Muta- tion screen of the brain derived neurotro- with molecular imaging and the effica- phic factor gene (BDNF): identification of cy of cognitive behavioural therapy in several genetic variants and association adult ADHS” (principal investigator: Prof. studies in patients with obesity, eating dis- Dr. K. P. Lesch, APP Würzburg). Main stu- orders, and attention-deficit/hyperactivity disorder. Am J Med Genet B Neuropsychi- dy questions are: Which genetic variati- atr Genet, 132, 96-99. ons are risk factors for the persistence of ADHD in adulthood and which different al- Hesslinger B, Tebartz van Elst L, Nyberg E lele distributions are present in treatment et al. (2002) Psychotherapy of attention non-responders as compared to respon- deficit hyperactivity disorder in adults - a pilot study using a structured skills training ders and allow for a prediction of treat- program. Eur Arch Psychiatry Clin Neuros- ment response? Which specific morpho- ci, 252,177-184

logical or neurochemical abnormalities SELECTED PUBLICATIONS are associated with specific genetic va- Hesslinger B, Philipsen A, Richter H, Ebert D (2003) Zur Psychotherapie der Auf- riants? Genotyping and statistical analy- merksamkeitsdefizit-Hyperaktivitätsstörung sis will be performed in national (Institu- (ADHS) bei Erwachsenen. Verhaltensthera- te of Human Genetics, Würzburg; Institu- pie, 13, 276-282. te of Medical Biometry and Epidemiology, University of Marburg) and international Tebartz van Elst L, Hesslinger B, Thiel T, Geiger E, Haegele K, Lemieux L, Lieb K, (amongst others the National Human Ge- Bohus M, Hennig J, Ebert D (2003) Fron- nome Research Institute, NIH, Bethesda) tolimbic brain abnormalities in patients cooperation. with borderline personality disorder: a volumetric magnetic resonance imaging study. Biol Psychiatry, 54, 163-71.

Walitza S, Renner TJ, Dempfle A, Kon- rad K, Wewetzer Ch, Halbach A, Herpertz- Dahlmann B, Remschmidt H, Smidt J, Lin- der M, Flierl L, Knolker U, Friedel S, Scha- fer H, Gross C, Hebebrand J, Warnke A, Lesch KP (2005). Transmission disequilib- rium of polymorphic variants in the tryptophan hydroxylase-2 gene in attention-deficit/hyperactivity disorder.. Mol Psychiatry, 169 10, 1126-1132. 5.7. International Graduate School – Graduate School of Life Sciences

Professor Dr. med. Martin Lohse (Director) General tional GK587 “Gene regulation in and Information by microbial pathogens”, GK639 “Mo- Versbacher Str.9 lecular and structural basis of tumor in- 97078 Würzburg For many years the Faculties of Biology and stability”, and GK1048 “Molecular ba- Tel.: 09 31 / 201-48400 Medicine have offered high-level structured sis of organ development in vertebra- Fax: 09 31 / 201-48702 graduate training. Early experiences with tes”) E-mail: [email protected] structured graduate training at the Univer- www.graduateschools.uni-wuerzburg.de/ sity of Würzburg were achieved most no- These programs came together to find and life_sciences/ tably in the context of several DFG-funded develop common structures and curricula, graduate programs (Graduiertenkollegs). A to share activities and to set common stan- prime example of graduate training is also dards (see box). In 2006, the first graduate

CONTACT DETAILS CONTACT the MD/PhD-program, which was initiated students received their PhD from this com- by the Faculties of Biology and of Medicine mon program. in 1996/7 as the first such program in Ger- many. These programs with several gene- rations of basic and clinical scientists have The growing Graduate School shown the effectiveness of such structured training programs and came together Increases in size and scope resulting from to found the Section Biomedicine in the In- the progressive integration of further pro- ternational Graduate School in 2003. This grams and the discussions in the con- section has not only built up new structu- text of the national “Excellence Initiative” res and developed key elements but also called for a number of changes within the served as a nucleus for the foundation of International Graduate School in 2006. the “Graduate School of Life Sciences”. These changes concerned both the inter- The last years, and in particular 2006, have nal structure and the formal status. The seen major steps towards this goal, in par- IGS transformed into a holding structure ticular the foundation of separate graduate of the independent Graduate Schools by schools and the funding of the “Graduate 2006. These Graduate Schools now cater School for Life Sciences” in the “Excellence for the needs of different broad fields of Initiative of the Federal and State Govern- science, uniting research in the Life Sci- ments”. ences, the Humanities and Natural Sci- ences (see Fig. 1). A fourth School in the area of Social Sciences is under way. Each Foundation of the International Gradua- of these schools will independently handle te School (2003-2005) their specific affairs.

Discussions in the entire university on mo- The holding, the IGS, assures adherence dern forms of graduate training culminated to, and development along common rules. in the foundation of the “International Gra- It also provides general services to the in- duate School” (IGS) by the University Se- dividual schools. In this context, gradu- nate in December 2003. This “Internatio- ation regulations (“Promotionsordnung”) nal Graduate School” was initiated to en- were developed and passed by the Uni- compass the whole university, with separa- versity Senate in 2006. These regulations te sections (“Klassen”) to cover the specific contain a set of common articles along scientific and training needs and cultures of with specific regulations of the individu- their diverse disciplines. al schools. The core principles laid down in the graduation regulations remain those that were originally established in the Section of Biomedicine Section of Biomedicine, including a mentoring system as well as rules for admis- As a first step, a Section of Biomedicine sions and formal standards (see box). A was formed in the IGS in 2003 by unifying common charter for the IGS and all the several programs and their graduate stu- individual Graduate Schools was passed dents: by the Senate in August 2007, regulating issues of membership and operating • The graduate program “Target Proteins” procedures. The IGS has also developed of the Rudolf Virchow Center a standard regulation for doctoral study • The graduate program of the Research programs that is easily adaptable to the Center for Infectious Diseases needs of the individual Graduate Schools. • The MD/PhD-program of the Interdisci- The Study programs “Life Science” and plinary Center for Clinical Research “Humanities” were approved by the Ba- • Four DFG-funded graduate programs varian State Ministry of Sciences at the (GK520 “Immunomodulation”, interna- end of 2007.

170 During 2007, the number of formal members of the GSLS rose to 103 principal investigators from all participating faculties. 127 young researchers were enrolled in the newly established doctoral study program “Life Sciences”.

Fig. 1: Structure of the International Graduate School.

Recent developments in the Graduate developed process, and interviews with School of Life Sciences more than 150 candidates were performed by the admission board or are cur- The Graduate School of Life Sciences rently scheduled in Würzburg, abroad and (GSLS) is now the most advanced Gradua- by means of video conferencing. Sixteen te School in Würzburg. It is putting to work of the 27 fellows that started their thesis the plans that were set forth in the suc- in 2007 are from 9 different countries, cessful application within the Excellence underscoring the international character Initiative. of the GSLS.

The GSLS now houses graduate students of all collaborative research programs – such as the DFG-funded collaborative research Key elements of training in the Graduate Schools centers (“Sonderforschungsbereiche”), • The traditional single advisor (“Doktorvater“) is replaced by a three-person com- research training groups (“Graduierten- mittee. kollegs”) and clinical research groups (Kli- • A panel of training activities is offered, from which an individual program is tailored nische Forschergruppen), as well as also to each graduate student. other collaborative programs funded by • Graduate students actively participate in the program by offering and organizing the Federal Ministry of Education and Re- courses and symposia. search (BMBF), the European Union and •� A set of requirements has to be met to warrant a common quality standard. other sources. This will be a total of more than 300 graduate students. The school is Mentoring System therefore currently divided into five separa- Each student has an individual supervisory committee, which meets with the doctoral te Sections. In addition to the Section “Bi- student at regular intervals to monitor progress and adjust the research and training omedicine”, the Sections “Infection and activities. Additionally, the graduate students report the status of their project within Immunity”, “Neurosciences” and “Integra- the research groups and programs, exchanging ideas and obtaining feedback within tive Biology” were established in addition their peer-group. to the MD/PhD-program. A section usually comprises different programs of about 15 Training activities to 25 graduate students. These programs The training activities total a minimum of 150 hours per year and consist of laboratory are the scientific as well as social “home” seminars, journal clubs, program-seminars, methods courses and transferable skills of the graduate students. workshops as well as retreats and international conferences.

A special fellowship program of the GSLS Common Graduation Commission is the core element of funding by the Ex- The participating faculties form a new common Graduation Commission within the cellence Initiative. The third round of in- Graduate School. The Commission is responsible for the conferral of all doctoral de- ternational recruitment was already un- grees within the Graduate School. This enforces common standards across disciplines derway at the end of 2007. More than and fosters interdisciplinary cooperation in graduate training. 1000 standardized written applications have been evaluated so far in a newly

171 6. The Medical Faculty: Basic Data

1. Collaborative Research Centers, Graduate Colleges, Clinical Research Units (in 2007)

Collaborative Research Centers: Transregio-Collaborative Research Center Clinical Research Units: 17, Ras-dependent Pathways in Human Collaborative Research Center 479, Vari- Cancer Clinical Research Unit 103, Osteogenic ability of Pathogens and Host Reactions in Stem Cell Differentiation and Therapy of Infectious Diseases Transregio-Collaborative Research Center Bone Loss 34, Pathophysiology of Staphylococci in the Collaborative Research Center 487, Regu- Post-genomic Era Clinical Research Unit 124, Clinical Re- latory Membrane Proteins: From Molecular search Group 124, The Tumor Microenvi- Recognition to Drug Targets ronment: Target Structure and Modulator of Immune Responses Collaborative Research Center 567, Me- Graduate Colleges: chanisms of Interspecific Interactions of Clinical Research Unit 125, Attention-Defi- Organisms Graduate College 520, Immunomodulation cit/Hyperactivity Disorder - Translational Re- search Focus on Molecular Pathogenesis Collaborative Research Center 581, Mole- Graduate College 1048, Molecular Basis of and Treatment across the Life Cycle cular Models for Diseases of the Nervous Organ Development in Vertebrates system Graduate College 1141, Signal Transduc- Collaborative Research Center 630, Recog- tion: Where Cancer and Infection Converge nition, Preparation and Functional Analysis of Agents against Infectious Diseases Graduate College 1156, From Synaptic Plasticity to Behavioural Modulation in Ge- Collaborative Research Center 688, Mech- netic Model Organisms anisms and Imaging of Cell-Cell Interac- tions in the Cardiovascular System Graduate College 1253, Emotions

2. Honorary doctorates awarded by the medical faculty

1948 Dr. Albert Knoll 1982 Dr. Johannes von Elmenau 1997 Professor Dr. Hans Thoenen Ludwigshafen München München 1952 Professor Dr. Georg Hohmann 1982 Professor Dr. Wilhelm Feldberg 2000 Professor Dr. Hermann Bujard München London, England Heidelberg 1956 Dr. G. Wahl 1991 Professor Dr. Arno G. Motulsky 2001 Professor Dr. Hermann Wagner Würzburg Seattle, USA München 1961 Professor Dr. Ernst Freudenberger 1995 Professor Dr. Peter Vogt 2005 Professor Dr. Volkmar Braun Basel, Schweiz La Jolla, USA Tübingen 1963 Professor Dr. Franz Büchner 1995 Professor Alan E.H. Emery 2007 Professor Dr. G. Fritz Melchers Freiburg Budleigh Salterton, England Basel/Berlin

172 3. Rinecker- Medals awarded by the medical faculty

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

4. Virchow-Lectures

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

5. Winners of the Albert Koelliker-Award for excellent teaching

Semester Winners Autumn 2003 Doctors of the Department of Anaesthesia and Critical Care 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, Director of Department of Internal Medicine II Autumn 2004 Professor Dr. D. Patzelt, Head of the Institute of Forensic Medicine Spring 2005 Professor Dr. A. Warnke, Director of the Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy Autumn 2005 University lecturers of the Institute for Anatomy and Cell Biology II: Professor Dr. D. Drenckhahn, Professor Dr. E. Asan, Professor Dr. P. Kugler, Dr. J. Waschke Spring 2006 Professor Dr. M. Gekle, Institute of Physiology Autumn 2006 Professor Dr. M. Frosch, Head of the Institute for Hygiene and Microbiology Spring 2007 Professor Dr. M. Böck, Director of the Institute for 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

173 6. Habilitations

2005 Dr. Enno Schmidt Dermatology and Venerology Clinical Dr. Martin Gasser Surgery Dr. Ulrich Oppitz Radiation Therapy Dr. Hans-Thomas Renné Clinical Biochemistry Dr. Peter Flachenecker Neurology Dr. Anil Martin Sinha Internal Medicine Dr. Jürgen Zielasek Neurology Dr. Thorsten Stiewe Biochemistry and Molecular Dr. Christiane Schneider-Gold, Neurology Biology Dr. Richard Kellersmann Surgery Dr. August Stich Internal Medicine Dr. Kay Double Neurochemistry Dr. Norbert Hofmann Dental-, Oral- and Maxillofacial Preclinical Medicine, especially Operative Dr. Wolfgang Völkel Toxikology and Pharmakology Dentistry and Periodontology Dr. Christoph Sauvant Physiology Dr. Volker Kunzmann Internal Medicine Dr. Jean-Nicolas Volff Biochemistry and Molecular Dr. Frank Weidemann Internal Medicine Genetics Dr. Peter Reimer Internal Medicine Dr. Bernhard Schmitt, Anatomy and Cell Biology Dr. Sebastian Maier Internal Medicine Dr. Moritz Bünemann Pharmacology Dr. Wolf Bertram Illert Surgery Dr. Dominik Brors Otorhinolaryngology Dr. Sibylle Jablonka Neurogenetics Dr. Uwe Gbureck Experimental Dentistry Dr. Thomas Meigen Biophysics of Visual Perception Dr. Christiane Völter Otorhinolaryngology 2007 Dr. Burkhard Jabs Psychiatry and Psychotherapy Clinical Dr. Oliver Ritter Internal Medicine Dr. Andreas Eggert Dermatology and Venerology Dr. Kai Schuh Clinical Biochemistry, focus Dr. Marcus Koller Internal Medicine Molecular Biology Dr. Stefan Rutkowski Pediatrics Dr. Christiane Waller Internal Medicine Dr. Arnd Hönig Obstetrics and Gynecology Dr. Brigitte Buchwald-Lancaster Neurology Dr. Ulrich Dietz Surgery Dr. Herbert Kuhnigk Anaesthesiology and Intensive Dr. Oliver Al-Taie Internal Medicine Care Dr. Jochen Weber Neurosurgery Dr. Thomas Dirk Böhm Orthopedics Dr. Ulrich Schwemmer Anaesthesiology Dr. Jonas Gehr Surgery Dr. Susanne Grunewald Dermatology and Venerology Dr. Susanne Schwedler Internal Medicine Preclinical Dr. Thomas Meyer Surgery Dr. Andreas Rosenwald Pathology Dr. Susanne Walitza Child and Adolescent Psychiatry Dr. Gerald Schwerdt Physiology and Psychotherapy Dr. Stefan Engelhardt Pharmacology Dr. Jörg Bederlau Anaesthesiology and Intensive Dr. Philipp Ströbel Pathology and Pathological Care Anatomy Dr. Winfried Göbel Ophthalmology Dr. Wolfram Brune Virology Dr. Anna Tycholpon Djuzenova Clinical Radiation Biology Dr. Carsten Scheller Virology Dr. Steffen Kunzmann Pediatrics Dr. Thomas Bohrer Surgery Dr. Martin Fassnacht-Capeller Internal Medicine Dr. Dr. Tobias Reuther Dental-, Oral- and Maxillofacial Medicine, especially Oral and Maxillofacial Surgery Dr. Thomas Klink Ophthalmology 2006 Dr. Stefan Störk Internal Medicine Clinical Dr. Stefan Radke Orthopedics Dr. Annette Kolb-Mäurer Dermatology and Venerology Dr. Ulrich Nöth Orthopedics Dr. Axel Larena-Avellaneda Surgery Dr. Bernd Baumann Orthopedics Dr. Claudia Mehler-Wex Child and Adolescent Psychiatry and Psychotherapy Dr. Markus Luster Nuclear Medicine Dr. Christian Wunder Anaesthesiology Preclinical Dr. Boris Kramer Pediatrics Dr. Andreas Zettel Pathology and Pathological Dr. Stefan Frantz Internal Medicine Anatomy Dr. Lorenz Rieger Obstetrics and Gynecology Dr. Jens Waschke Anatomy and Cell Biology Dr. Matthias Eyrich Pediatrics Dr. Carola Förster Histology and Cell Biology

174 7. Statistics

Registration numbers

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

WS 2004/05 135 / 79 50 / 32 26 / 18 16 / 14

SS 2005 139 / 71 52 / 29 - -

WS 2005/06 139 / 85 50 / 29 33 /28 13 / 10

SS 2006 144 / 65 53 / 25 2 / 2 -

WS 2006/07 150 / 108 61 / 41 27 / 25 25 / 16

SS 2007 162 / 87 63 / 39 - -

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

Graduations (Abschlüsse)

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

Spring 2005 144 / 76 32 / k. A. - -

Autumn 2005 133 / 64 42 / k. A. 17 / 12 -

Spring 2006 146 / 81 34 / k. A. - -

Autumn 2006 142 / 83 34 / k. A. 28 / 19 14 / 12

Spring 2007 138 / 76 38 / k. A. - -

Autumn 2007 96 / 64 40 / k. A. 21 / 12 14 / 11

Doctorates (without doctorates in natural sciences)

Year preclinical clinical total

2005 54 179 233

2006 58 214 272

2007 57 202 259

Habilitations

Year preclinical clinical total

2005 6 25 31

2006 5 14 19

2007 3 25 28

175 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 Martin Lohse

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

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

176 University of Würzburg University of Würzburg Universitätsklinikum Würzburg Medical Faculty

Medical Faculty

Josef-Schneider-Str. 2 · 97080 Würzburg 2008 Report – Research University of Würzburg Medical Faculty http://www.uni-wuerzburg.de/ueber/fakultaeten/ Research Report 2008 medizin/startseite/