BIH CHARITÉ CLINICIAN SCIENTIST PROGRAM
10 Years Clinician Scientist Program
BIH Charité Clinician Scientist Program Scientist Clinician Charité BIH 2021 2021 bihealth.org Content BIH Charité
4 Introduction ( Junior ) ( Digital ) 14 Junior Clinician Scientists Clinician Scientist 48 Junior Clinician Scientist Alumni 89 Clinician Scientists Program Book 147 Clinician Scientist Alumni 233 Junior Digital Clinician Scientists 237 Junior Digital Clinician Scientist Alumni 240 Digital Clinician Scientists 258 Clincian Scientist »Excellence Track« 2021 265 Clincian Scientist »Excellence Track« Alumni 274 BIH Biomedical Innovation Academy Team 276 Clinician Scientist Board 278 Digital Clinician Scientist Board Introduction Introduction 5
In loving memory
Univ.-Prof. Dr. med. Duška Dragun * 12. August 1969 † 28. December 2020
Where there was no way, Duška built one – a visionary and passionate pioneer. 6 Introduction Introduction 7
Between silent mourning and pursuing Duška’s mission: Celebrating the tenth anniversary of the BIH Charité Clinician Scientist Program in honor and memory of Professor Duška Dragun
Introduction by Dr. Nathalie Huber and Dr. Iwan Meij
The date for our international symposium celebrating excellent contributions to the field of renal transplan- training period for the participants as much as possible3. has led to a rethinking of the biomedical research land- the tenth anniversary of the BIH Charité Clinician Scientist tation research. She pursued her goals with extraordinary The guidelines developed by the Berlin Chamber of Phy- scape in Germany and has given rise to a new generation Program (CSP) had been in our calendars for a long time. energy and passion, impressive perseverance and clear sicians and the initiators of the Clinician Scientist Pro- of research-oriented clinicians who are taking on the Due to the far too early death of our program director determination. She will be remembered by us, her gram for recognition of research time as part of the challenges of combining research and clinical practice Professor Duška Dragun in December 2020, this sympo- research group and all the program fellows as a connector training have been continuously optimized and are read- in order to speed up the rate at which scientific findings sium has now taken on an entirely different and, unfor- of people, CSP trailblazer, outstanding physician, excel- justed annually in close consultation with the Chamber. are translated into application and newly identified med- tunately very sad character – namely that of a commem- lent scientist and passionate mentor. Our Junior Clinician Scientist Program, implemented in ical need feeds into new research initiatives. orative event. The same applies to the introduction of 2014 and meant as a booster program, does not include this program book1. Actually, we intended to write exclu- the mandatory structured training and cannot be cred- sively about the program’s achievements of the past ten Duška’S Mission: Clinician Scientist ited as part of the residency training. years and now this anniversary book is overshadowed Programs as Systemic Intervention by the death of Duška, which is still difficult to accept. The Berlin program is not only the largest of its kind in With her tireless effort and vision, she built up the career in University Medicine Germany, it is also considered as a national »best-prac- path for a successful career in science for many physi- tice model« and is recognized internationally for its cians and acted not only as a pioneer but also as a role Until the end, and even from her hospital bed, Duška‘s pioneering role. It has set nationwide standards in terms model for Clinician Scientists. untiring efforts were directed at her life's work: the CSP. of design and quality assurance measures and has served The CSP is a modern career path within academic med- as a model for position papers by the German Research As a physician herself, Duška has always been committed icine that allows physicians to pursue a structured res- Foundation4 (Deutsche Forschungsgemeinschaft, DFG) to research: As managing senior physician and deputy idency with time set aside for clinical and basic research. and the German Science Council5 (Wissenschaftsrat, WR). to the acting director of the Department of Nephrology It is based on a combination of a competence oriented Since an increased focus on Clinician Scientist training and Internal Intensive Care Medicine at Charité – Uni- clinical education with a translational medicine based was set as one of the science policy goals in the current 3. Dragun, Duška and Huber, Nathalie: »Schluss mit versitätsmedizin Berlin and head of a research group on curriculum including clearly defined »protected time« coalition agreement, together with Duška we were in ›Feierabendforschung‹«. In: Berliner Ärzte, 12/2017, pp.29-31. nephrology, she made highly esteemed, internationally for research. Clinician Scientists as researching physi- exchange and consultation with members of the Bund- http://www.berliner-aerzte.net/pdf/bae1712_029.pdf cians are not »clinicians light« or »researchers light«. estag and science policy actors. 4. Empfehlungen der Ständigen Senatskommission für Rather, they form the essential link within the compe- 1. The present version is the third edition of our Program Grundsatzfragen in der Klinischen Forschung der Deutschen Book. The first edition was published in 2016 on the occasion tence triad of patient care, student teaching and We participate in national and international working Forschungsgemeinschaft: »Etablierung eines integrierten of the fifth anniversary of the BIH Charité Clinician Scientist research – the combination of these three areas is the groups, such as the meetings of the Medizinischer Forschungs- und Weiterbildungsprogramms für ›Clinician Program and the corresponding Jubilee Symposium in June unique selling point of clinician scientists. Patients in Fakultätentag e.V. (Medical Faculty Association) and the Scientists‹ parallel zur Facharztweiterbildung« (2015): 2016. The second edition of the Program Book was published particular benefit from this (see Dragun et al. 2019)2. Association of Academic Health Centers International http://www.dfg.de/download/pdf/dfg_im_profil/ in June 2018 for the International Symposium on Translational (AAHCI). This has allowed us not only to be informed reden_stellungnahmen/2015/empfehlungen_clinician_ Medicine in Berlin. scientists_0415.pdf The cooperation with the Berlin Chamber of Physicians about national and international debates but also to be
2. Dragun, Duška, Huber, Nathalie, Rösen-Wolff, Angela, was a decisive component for the success of the program involved in setting benchmarks and quality standards 5. Wissenschaftsrat drs. 5663-16: »Perspektiven der Blomberg, Richard. »Clinician Scientists: Ärzte mit Kompetenz- in order to integrate research activities into the further for the structured training and the career pathway of Universitätsmedizin« (2016): http://www.wissenschaftsrat. Trias«. Dtsch Arztebl. 2019;116(50):A-2339 / B-1922 / C-865. residency training and to avoid extending the further Clinician Scientists. The model and success of our CSP de/download/archiv/5663-16.pdf 8 Introduction Introduction 9
Climbing the Career Ladder Step by Step From a Pilot Project to an Advanced Clinician Scientist Institutionally Embedded Program Pilot Program (AdCSP) Our target group specific structured career paths span Based on the program’s fruitful experience of the last the different career stages of the residency (cf. for this ten years, we have adapted our organizational mecha- The CSP was preceded by the »Friedrich C. Luft« Clinical In autumn 2020 we have piloted an Advanced Clinician Figure 1). During clinical specialization, Junior (Digital) nisms to ensure sustainability in a steady state recruit- Scientist Pilot Program, which commenced in Spring 2011 Scientist Program (AdCSP) to close the existing gap in Clinician Scientists and (Digital) Clinician Scientists are ment of approximately 50 new fellows per year. As a through financial support of 1.4 million Euro from Stiftung support for academic career paths after residency. It allotted 20% or 50% of their working hours, respectively, general policy, we actively encourage women to apply Charité and Volkswagen Foundation. It has been awarded aims to support the so far insufficiently considered tar- as »protected time« to exclusively conduct research. The and we have implemented flexible working options in a prize from the »Deutschland – Land der Ideen« initia- get group of scientifically active specialists who have structured curriculum offered (including clinical, scientific, the context of parental leave and part time-employment. tive in 2012. Since 2013, the program has received financial just completed their habilitation and are developing and transferable skills training) is mandatory for (D)CSP Currently, 36% of our (Digital) Clinician Scientists and support directly from the Charité medical faculty as well towards becoming a senior physician or have just fellows and optional for J(D)CSP fellows. The appointment 37% Junior (Digital) Clinician Scientists are female. as funding from Berlin Institute of Health at Charité (BIH) become a senior physician. The primary goals of the of clinical and scientific mentors and, in the case if the and through additional financial support by the Stiftung AdCSP are to create new senior physician positions with D-CSP track a digital mentor, as well as progress and feed- Charité via the Private Excellence Initiative Johanna protected time for research and to strengthen the aca- back meetings, ensure guidance and support both for the Quandt. In its early years the CSP has also taken up demic translational ecosystem to better meet the research project itself and for the career development of several fellows funded through graduate schools funded requirements of today´s highly specialized university 6. DFG bietet Fördermöglichkeiten für »Clinician Scientists« the (Junior) (Digital) Clinician Scientist. New fellows are in integrierten Forschungs- und Weiterbildungsprogrammen within the German Federal Excellence Initiative – namely medicine. Approved candidates will receive either 25% taken up into the programs twice a year following a highly (2015): http://www.dfg.de/foerderung/info_wissenschaft/ the Berlin-Brandenburg School for Regenerative Thera- or 50% protected time for research. competitive two-stage selection procedure. info_wissenschaft_15_25/index.html pies (BSRT), the Berlin School of Integrative Oncology (BSIO) and the Excellence Cluster NeuroCure. In 2015, and based upon the successful cooperation with BIH, the CSP »Excellence Track« program was integrated within the BIH Biomedical Inno- vation Academy (BIA), ensuring long-term structural and Since several program participants of the (Junior) Clinician institutional support. Through third party funding by the Scientist Program have applied successfully for excellent German Research Foundation6 (DFG), in 2019 the CSP could junior research group programs (such as ERC Starting be expanded by a new »digital« branch – the »Digital Grants Program, DFG Emmy Noether Program, Freigeist Clinician Scientist Program« (D-CSP) forming an addi- Fellowships or Lichtenberg Professorship of the Volkswa- Sustainability Since 2020 tional career track to prepare academic clinicians for the gen Foundation, BMBF Research Goup or Max-Eder challenges of the emerging technological transformation Research Group), the idea of an »Excellence Track« was Advanced Clinician of medicine (see below). born in 2018. Fellows of the »Excellence Track« do not Scientist Pilot Program Consolidation have to go through the official two-stage selection pro- cess of the CSP as they have already prevailed in a highly Clinician Scientist Since 2019 Program Keeping Abreast of the Times: Digital competitive external selection process. Fellows of the Boosting Digital (J)CSP 25 – 50% »protected time« for research »Excellence Track« have the same rights and obligations Clinician Scientist Program (D-CSP) Recognition by Berlin Chamber as regular program participants. The only difference is Junior Clinician of Physicians Scientist Program 5 5 – 6 years As academic medicine undergoes unprecedented tech- that they are not financed through program funds. Cur- nological change, many »classical« prospective Clinician rently, we have 8 members in the CSP »Excellence Track«. 50% »protected time« Research for research Scientists are not adequately prepared for technological stipends Recognition by Berlin challenges associated with advanced computational sci- Chamber of Physicians 20% »protected time« 3 years entific approaches. To address this, we have successfully for research secured additional funding from the German Research 12 months 2 years Foundation (DFG) in 2018. The DFG initially funds the proj- ect for three years with over three million euros and allows applying for a two-year extension in conjunction with a grant of two million euros. The D-CSP aims to strengthen Specialist Senior physician Medical studies Specialist training the »classical« CSP and take it to the »next level« by certification maturity integrating the new structural element of digital science Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 training within the regular structured program. The first call for proposals for the D-CSP was published in March 2019, and funding for the first program participants, also Gold Standard including a Junior track, begun in August 2019.
Figure 1. Structured career paths for Junior (Digital) Clinician Scientists and (Digital) Clinician Scientists spanning different stages of career beginning from medical school. 10 Introduction Introduction 11
Inter-Clinic Community Building » In my discipline of psychiatry,
The CSP serves as an important model for building a there is a lot of room for scientific community of early career researchers with an open mind progress. That's why I feel to translational and innovative biomedical research. Fel- lows in the BIH Charité (Junior) (Digital) Clinician Scientist the urge to conduct research. Program come from the wide variety of clinical and diag- The program has provided me nostic disciplines creating a new translational ecosystem and nurturing transdisciplinary collaboration (see Dra- with the protected time for gun/Huber 2017). The number of participants has research I need to do this and increased impressively from eight participants in 2011 2016 to 141 active participants in 04/2021 (90 (Digital) Clinician helped me to define myself as Scientists and 51 Junior (Digital) Clinician Scientists). The a Clinician Scientist. « Clinician CSP’s success within Charité has steadily increased and Retreat atS cientist GCenshagenCastle approximately 8-10% of all senior Charité residents and Dr. med. Katharina Schmack linician Scientist Retreat at 5% of all junior Charité residents receive protected time CSP Alumna C G astle for research through the program. Figure 2 depicts a Currently postdoctoral fellow enshagen graphic representation of all program participants as at Cold Spring Harbor Laboratory 2020 distributed across disciplines. (translated from (3)) 2017
2018
2019
60 Figure 3: Foto collection of CSP Retreats at Genshagen Castle 51 Currently active JCSP members » ... the CSP allowed us an intense (including 5 JDCSP members) from 2016 to 2020 90 Currently active CSP members and so far never experienced (including 17 DCSP members) interdisciplinary scientific 45 66 JCSP Alumni Interdisciplinary Networking 84 CSP Alumni discussion and way of working, Interdisciplinary is not just a phrase but actually lived that still connects us today. « through different community building measurements: A 30 PD Dr. med. Peter Bobbert monthly Jour Fixe is held for (Junior) (Digital) Clinician Alumnus Clinician Scientist Pilot Program Scientists to present their research projects to other President of Berlin Chamber of Physicians fellows and to the program director. Every year, a two- (translated from (3)) day retreat is held at Genshagen Castle southwest of 15 Berlin to which all (Junior) (Digital) Clinician Scientists and their mentors and clinic directors are invited. The retreat aims at creating a communication platform for discussing both scientific and strategic topics relevant 0 to Charité and BIH and beyond. In addition, every two years, a two-day Clinician Scientist Symposium on Trans- Urology NeurologyPsychiatry Pathology Radiology lational Medicine is organized in Berlin, to which fellows Nephrology Cardiology Orthopedics Dermatology Neonatology Neurosurgery Endocrinology Rheumatology Cardiac Surgery OphthalmologyAnesthesiology Neuropathology can invite internationally renowned scientists as speak- Gastroenterology Radiation therapy Pediatric Neurology Maxillofacial Surgery Pediatric Cardiology Hematology/Oncology Ped. Gastroenterology Pediatric Pneumology Pediatric Endocrinology ers. This gives (Junior) (Digital) Clinician Scientists the General/Visceral Surgery Obstetrics/Gynaecology Ped. Hematology/Oncology Medical and Human Genetics opportunity to discuss their project in person with lead- Pneumology/Infectious Diseases Radiooncology/Radiation therapy ing personalities from the field of their own research and to take a big step in expanding their own scientific Figure 2: Broad distribution of (J)(D)CSP fellows and alumni over the clinical disciplines at Charité. and professional network. 122 Introduction Introduction 13
Never Stand Still – Continuous Adaptation and Optimization
StartStart ofof projectproject »structural»structural effectseffects ofof CSCS Programs«Programs«
ImplementationImplementation ofof semi-automaticsemi-automatic tracktrack recordrecord analysis,analysis, extendedextended CSPCSP celebratescelebrates itsits projectproject reviewreview andand feedbackfeedback inin 100th100th AlumnusAlumnus Start of Pilot CSP Symposium 2012 Consolidation of Integration in BIA (J)CSP open FirstFirst awardaward ceremonyceremony Hearing at Bundestag selectionselection processesprocesses Funding of the fi rst 8 fellows the program to »returnees« (Federal(Federal Parliament)Parliament) IntegrationIntegration ofof dentaldental medicinemedicine Measures to increase family friendliness ImplementationImplementation ofof QUESTQUEST CriteriaCriteria StartStart ofof PilotPilot AdvancedAdvanced CSPCSP BIHBIH andand BIA,BIA, aa fifi rstrst callcall forfor AdvancedAdvanced
2011 2012 2013 2014 2015 2016 2016 2017 2018 2019 2020 2021
Start Junior ParticipationParticipation inin MFTMFT StartStart ofof CSPCSP ImplementationImplementation ofof »CSP-Button«»CSP-Button« Prize »Deutschland Clinician Scientist Participation at GAIN conference »UAG»UAG ClinicianClinician Scientists«Scientists« »Excellence»Excellence Land der Ideen« Program (JCSP) Track«Track«
StartStart ofof externalexternal ProgramProgram EvaluationEvaluation DeathDeath ofof Prof.Prof. DuskaDuska DragunDragun 5 5 StartStart ofof (Junior)(Junior) DigitalDigital CSPCSP First (J)CSP Retreat StartStart ofof 100th100th ClinicianClinician ScientistScientist FellowFellow
PublicationPublication ofof externalexternal ProgramProgram EvaluationEvaluation resultsresults 14 Introduction Introduction 15
Charité J(D)CSP Fellow External Program Evaluation Résumé and Outlook Translational (D)CSP Fellow Research Centers JCSP Alumni On the occasion of the tenth anniversary of the CSP, in Within a relatively short period of time Duška has made cooperation with the German Centre for Higher Education a very significant contribution to the development of a Industry CSP Alumni Research and Science Studies (DZHW), we have conducted new generation of junior medical staff – the impact of BIH a comprehensive and social science-based program eval- her programs will last for a long time, through promising uation (project duration: June 2019 -March 2021). The individual careers as well as through the programmatic Technology Transfer 21,5 Million € study uses a mixed-method approach in which qualitative strengthening of patient-oriented science. Few individ- 50 Million € EU and quantitative methods systematically complement uals have managed to make such a positive and lasting each other (interviews, online survey and bibliometric difference to Charité and the lives of many residents BMBF-BMWi/Federal analysis). Our evaluation is based on the experiences there. She demanded full performance and set challeng-
Foundations and perspectives of a total of 90 active and former ing goals. Those who made it into the one of the CSP (J)CSP fellows and, comparatively, a control group at tracks had their further development closely monitored. DFG Charité which is not funded by the program. The findings At the same time, she showed an almost endless com-
0 5 10 15 20 give multifaceted empirical insights into the program, mitment to the program fellows and their projects. She identify opportunities and challenges and provide the knew each fellow by name and their projects through basis for general recommendations for action for the the selection process, target-agreement meetings, Jour development and expansion of Clinician Scientist Pro- Fixes, Retreats and Symposia. We feel, thus, like a big Figure 4: Estimated third-party funding raised in k€ by BIH Charité (Junior) (Digital) Clinician Scientists up to 03/2021 grams in the context of German university medicine7. »Clinician Scientist Family«.
We do not rest on the success of the BIH Charité Clinician Research Project »Structural Effects Scientist Program during the last ten years. Rather we of Clinician Scientist Programs on feel obligated to implement Duška's impulses, which she even set last year (like the Advanced Clinician Scientist Outcome Career Tracking the Biomedical Research Landscape« Program or the integration of dental medicine in the (D)CSP). We will honor Duška’s memory and continue her An outcome analysis of our CSP alumni (04/2021) shows What started as a project to generate a reliable, unbiased, How are CSPs set up at different locations and what are mission of training Clinical Scientists in her spirit. excellent outcomes: 94% percent have become special- semi-automated track record analysis system to support the similarities and differences in the context of the ists, 65% have completed their habilitation and 60% have the selection processes of the different Clinician Scientist structural framework conditions? How can different arrived at leading positions. All alumni are not only suc- Programs, has by now grown into the beginnings of a experiences with the implementation and establishment cessful Clinician Scientists by themselves, they are also full-blown career tracking tool, which may be used in of CSPs and the associated challenges be analytically raising a new generation of fellows by acting as mentors Meta Research analysis. With it, we hope to be able to described? In cooperation with the Institute of Medical and supervisors. A significant proportion of our fellows better map typical career paths and especially the hur- Sociology and Rehabilitation Science (IMSR) at Charité obtain professorships – some of them already during dles that need to be overcome by our fellows. It will allow we conducted a research project (duration: January – their (J)(D)CSP funding. Overall, we currently boast 11 the analysis of correlations between the careers of young October 2020) to carry out a systematic review of relevant professors among our fellows and alumni (seven W2- and academics at Charité and specifically the investigation organizational framework conditions of Clinician Scientist four W3-Professorships). of correlations that lead to successful careers in aca- Programs in German university medicine. Based on the demic medicine. It is also possible to find out when, for empirical results, the location factors in which the CSPs Another impressive statistic is the cumulative amount example, young scientists most frequently leave the are embedded can be probed for the first time, relevant of third-party funding raised by alumni and (Junior) (Dig- academic career path. With this in-depth understanding strategies in dealing with differently situated challenges ital) Clinician Scientists of 50 million Euro (see figure 3). of the different archetypes of Clinician Scientist career can be presented, and common themes and future tasks This represents roughly a two to one »return on invest- pathways, on the one hand the individual tracks may be can be identified and passed on to science policy in the ment« which underlines once more the effectiveness of even further refined. On the other hand, we will also form of synthesized implications. the program and the excellence of its fellows. have a scientific basis for recommendations to politics and funding agencies for the development of innovative career support structures.
7. Hendriks, Barbara; Schendzielorz, Cornelia; Heger, Christophe; Reinhart, Martin (2021): Kritische Bestandsaufnahme des BIH Charité (Junior) Clinician Scientist Programms: Untersuchungen einer integrierten Forschungs- und Facharztweiterbildung in der Universitätsmedizin. Ergebnisse der Programmevaluation 2019/20. Deutsches Zentrum für Hochschul- und Wissenschaftsforschung GmbH (DZHW). https://www.dzhw.eu/pdf/ab_folder_26/ KritischeBestandsaufnahme.pdf Junior Clinician Scientists Junior Clinician Scientists 17
Dr. med. Dipl. phys. Christopher Maximilian Arends
In Program From – to Fields of Research 01.2021–12.2022 › Clonal hematopoiesis › Myeloid Malignancies Contact › Tumor Genetics [email protected] › Vascular Biomedicine Clinic Charité – Universitätsmedizin Berlin Department of Hematology, Oncology and Cancer Immunology Junior Director Clinician Univ.-Prof. Dr. med. Lars Bullinger Scientists Clinical Implications of Clonal Hematopoiesis Under Different Stress Scenarios
Ageing is strongly associated with an increasing risk of emic stroke and its functional outcome after brain injury. cardiovascular disease and cancer. Recently, an inter- However, despite its indisputable relevance on epide- esting common driver of these two age-associated dis- miologic scales, the role of CH in the context of ischemic eases has been discovered: clonal hematopoiesis (CH), stroke remains elusive. Applying bulk and single-cell defined by the acquisition of somatic mutations in hema- sequencing techniques to bio-banked blood samples topoietic stem cells, occurs in 20-30% of individuals from the Prospective Cohort with Incident Stroke Berlin > 60 years and is associated with a higher overall mor- (PROSCIS-B), I address the role of CH in patients suffering tality, an increased risk for cardiovascular events, and from ischemic stroke with respect to functional outcome a ten-fold risk for the development of hematologic malig- and risk for recurrent vascular events. A second focus nancies. Interestingly, a causal relation between CH and of the project is on CH in patients with non-hematologic the progression of coronary heart disease driven by an malignancies. By integrating sequencing data with clin- altered inflammatory function of mature mutated mono- ical data from a large phase III study of patients with cytes/macrophages has been described in preclinical metastasized colorectal cancer (FIRE-3), I aim to delineate models. These and other recent data pinpoint towards the implications of CH on treatment outcome and analyze pleiotropic effects of mutated clones in individuals with the clonal evolution of CH under the selective pressure CH, not only affecting self-renewal and differentiation of cytotoxic treatment. With the results I hope to con- but also inflammatory signaling of mature blood cells, tribute to a better understanding of this interesting new which become particularly pronounced in certain stress commonality between cardiovascular disease and scenarios such as cytotoxic chemotherapy, allogeneic cancer. stem cell transplantation and inflammation. The aim of this interdisciplinary project is to investigate the clinical implications of CH in different stress scenarios. Inflam- mation plays a crucial role in the pathogenesis of isch-
Mentors
Univ.-Prof. Dr. med. Lars Bullinger Prof. Dr. med. Frederik Damm Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Hematology, Department of Hematology, Oncology and Cancer Immunology Oncology and Cancer Immunology [email protected] [email protected] 18 Junior Clinician Scientists Junior Clinician Scientists 19
Dr. med. Aline Azabdaftari Dr. med. Francis Baumgartner
In Program From – to Fields of Research In Program From – to Fields of Research 01.2020–12.2021 › Paediatric gastroenterology 08.2020–07.2022 › ASXL1-mutated leukemias › Inflammatory bowel disease › IL6-STAT3 signalling in autoimmunity Contact Contact › Epithelial immunology › SUMOylation in Multiple Myeloma [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Pediatric Respiratory Department of Hematology, Medicine, Immunology and Critical Care Oncology and Cancer Immunology Medicine Director Director Univ.-Prof. Dr. med. Ulrich Keller Prof. Dr. med. Philip Bufler
Expression and Regulation of Interleukin-37 in Human Intestinal Forward Genetic Screen for Functional Characterization Epithelium During Health and Inflammatory Bowel Disease of ASXL1-Mutated Leukemias
The incidence of inflammatory bowel diseases (IBD) is lial function. The aim of this project is to understand the The epigenetic regulator Additional sex combs like 1 transposon mutagenesis screening is a powerful murine markedly rising in industrialized countries, with 25% of expression and regulation of IL-37 in the human intestinal (ASXL1) is one of the most frequently mutated genes in model system in which genome-wide in vivo screening patients being newly diagnosed in childhood and ado- epithelium. We investigate the expression of IL-37 and hematopoietic malignancies. ASXL1 mutations (ASXL1mut) for relevant genes in oncogenesis is feasible by random lescence. Alterations of the epithelial barrier appear to related genes using existing bulk transcriptomic datasets can be detected in up to 20% of patients* with acute activation and inactivation of all genes and regions. PB contribute towards generating a dysbalance of the intes- of children with newly diagnosed IBD and healthy con- myeloid leukemia (AML) and myelodysplastic syndromes transposons are short DNA elements that randomly inte- tinal immune response in genetically susceptible indi- trols (1). Using in vitro experiments, we explore the reg- (MDS) as well as other myeloid neoplasms and are prog- grate and de-integrate throughout the genome through viduals. Investigating the interplay of the intestinal ulation of IL-37 expression in the human intestinal epi- nostically unfavorable, especially in combination with PB transposase activity, resulting in a functionally rele- epithelial barrier and the gut immune system in health thelium. We therefor generate patient-derived intestinal known driver mutations such as DNMT3A, JAK2, TET2 and vant growth advantage in some cells via oncogene acti- and disease is crucial to understand the pathogenesis epithelial organoids as a model system (2). We then TP53. However, the exact mechanisms of ASXL1mut-me- vation or tumor suppressor inactivation. Integration sites of IBD and to improve future treatment strategies. The stimulate the intestinal organoids with different cyto- diated malignant transformation are poorly understood are then characterized at high resolution and classified epithelium is part of the intestinal immune system, pro- kines known to be involved in the pathogenesis of IBD and no targeted therapeutic strategy exists, thus there as statistically relevant affected common integration ducing antimicrobial peptides and interacting with (2) and investigate the time course of IL-37 mRNA expres- is great clinical need for improved molecular understand- sites. In this research project, a forward-genetics in vivo immune cells through the release of immunomodulatory sion (3). These experiments will contribute to our under- ing, establishment of predictive biomarkers, and devel- screen will identify genomic networks associated with cytokines. Interleukin-37 (IL-37) is an anti-inflammatory standing of the expression and regulation of IL-37 in the opment of targeted therapeutics. Large AML sequencing ASXL1mut, which will be further addressed experimentally member of the IL-1 cytokine family. It has been shown human intestinal epithelium. Functional studies are studies over the past decade have cataloged gene muta- in follow-up projects. The central research question is to protect mice from colitis and a homozygous mutation currently performed and will further help to unravel the tions and epigenetic alterations and identified numerous which genes in combination with ASXL1mut are drivers led to infantile onset IBD in a patient. The role of IL-37 role of IL-37 in the pathogenesis of IBD. prognostically relevant genes. However, identification of of leukemogenesis and how ASXL1mut contributes to leu- has mainly been investigated in the immune cell com- mutations causal for disease development and per- kemogenesis through epigenetic dysregulation. partment. However, our recent studies also showed IL-37 sistence and translation of these findings into clinical protein expression in the intestinal epithelium. We therapeutic strategies is currently very limited. Thus, only hypothesize that IL-37 contributes to the immune a few molecularly addressable mutations have been iden- homoeostasis of the gut and plays a crucial role as an tified so far, which is why the prognosis of AML patients anti-inflammatory cytokine regulating intestinal epithe- has hardly improved over the last decades. PiggyBac
Mentors Mentors
Dr. med. Stephan Henning Prof. Dr. Dr. med. Mathias Zilbauer Univ.-Prof. Dr. med. Philip Bufler Prof. Dr. med. Jan Krönke Univ.-Prof. Dr. med. Ulrich Keller Clinical Mentor Scientific Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Pediatric Respiratory Department of Pediatric Department of Pediatric Respiratory Department of Hematology, Department of Hematology, Medicine, Immunology and Critical Respiratory Medicine, Immunology Medicine, Immunology and Critical Oncology and Cancer Immunology Oncology and Cancer Immunology Care Medicine and Critical Care Medicine Care Medicine [email protected] [email protected] [email protected] [email protected] [email protected] 20 Junior Clinician Scientists Junior Clinician Scientists 21
Dr. med. Niklas Beyhoff Dr. med. Philip Bischoff
In Program From – to Fields of Research In Program From – to Fields of Research 08.2020–07.2022 › Cardiooncology 01.2020–12.2021 › Single-cell RNA sequencing › Cardiology › Colorectal cancer Contact Contact › Cancer › Tumor heterogeneity [email protected] [email protected] › Lipidomics › Tumor microenvironment Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Cardiology Institute of Pathology Director Director Univ.-Prof. Dr. med. Ulf Landmesser Univ.-Prof. Dr. med. David Horst
Lipidomics in Anthracycline-Induced Cardiotoxicity – The Impact of Transcriptional Heterogeneity for Tumor Biology, Identification of Novel Signaling Pathways and Drug Targets Prognosis and Therapy Response in Colorectal Cancer
Anthracyclines are highly potent cytostatic drugs that ocytes. Additionally, biophysical studies indicate that Colorectal cancer is the third most common cancer and ma-cell rich microenvironment, which may further con- are widely used for the treatment of solid tumors (e.g, anthracyclines can hamper cell function by forming com- the second most frequent cause of cancer-related death found precise molecular classification when tested in bulk breast cancer or gastric cancer) as well as various leu- plexes with lipids of the inner mitochondrial membrane. worldwide. While early-stage tumors may be cured by transcriptome assays. Recently developed single-cell RNA kemias and lymphomas. Unfortunately, anthracyclines Novel mass spectrometry-based methods allow system- surgical resection, patients with advanced disease benefit sequencing techniques are promising to overcome previ- are associated with severe cardiotoxic side effects result- atic investigations of the totality of lipids in cells or from systemic chemotherapy but eventually often suc- ous limitations and may allow a yet unprecedented depth ing in dose limitation and substantial long-term compli- organs (»lipidomics«), however, data on their application cumb to the disease. Besides tumor stage and histological in the molecular characterization of colorectal cancers. cations like the development of congestive heart failure. in the context of anthracycline-induced cardiotoxicity grade, individual molecular characteristics of colorectal Within the Junior Clinician Scientist Program, I aim to dis- Although there is good awareness of the potential car- is currently lacking. This project aims to characterize the cancer have been identified that indicate patient prognosis sect the relevance of distinct tumor cell subpopulations diotoxicity and current guidelines recommend dose lim- lipidome changes of cardiomyocytes in response to anth- and response to systemic treatments, thus enabling more in primary patient-derived colorectal cancers for tumor itation in order to prevent those, cardiac damage is racycline treatment. Based upon this, novel signaling personalized therapeutic strategies. However, current biology, classification and therapeutic targeting by apply- evident in more than 20% of patients in current clinical pathways, changes in cell metabolism, and (sub-)cellular molecular characteristics guiding clinical management ing single-cell transcriptomics. This approach will yield a practice. Despite excessive research activities during drug targets will be identified. Ultimately, potential drug completely neglect that colorectal cancers in addition to much more precise transcriptional profiling and informa- the last decades, the underlying mechanisms of anth- candidates will be tested in vitro regarding their ability their intertumoral heterogeneity also display high degrees tion on functional interdependence of colorectal cancer racycline-cardiotoxicity are incompletely understood, to prevent/treat anthracycline-induced cardiotoxicity. of intratumoral cellular heterogeneity. Tumor cell subsets cells, and may result in a predictive and prognostic tool and effective strategies for prevention or treatment are may respond differently to targeted therapies and mediate that considers all relevant tumor cell subpopulations. This currently lacking. There is evidence that anthracyclines endogenous therapy resistance. This indicates the need may eventually guide clinical decisions including choice lead to changes in cardiac lipid metabolism and that for more effective therapeutic strategies that target dis- and combination of therapeutic regimens for patients their cardiotoxicity is mediated by generation of reactive tinct tumor cell subsets at the same time. Furthermore, with colorectal cancer. oxygen species damaging lipid membranes in cardiomy- colorectal cancers harbor a complex immune- and stro-
Mentors Mentors
Univ.-Prof. Dr. med. Ulf Landmesser Univ.-Prof. Dr. med. Ulrich Kintscher Univ.-Prof. Dr. med. David Horst Prof. Dr. rer. nat. Nils Blüthgen Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Molecular Cancer Research Center Department of Cardiology Institute of Clinical Institute of Pathology (MKFZ) Pharmacology and Toxicology [email protected] [email protected] [email protected] [email protected] 22 Junior Clinician Scientists Junior Clinician Scientists 23
Dr. med. Elisabeth Blüthner Dr. med. Ana Luísa de Almeida Marcelino
In Program From – to Fields of Research In Program From – to Fields of Research 08.2020–07.2022 › Intestinal failure 08.2020–07.2022 › Cerebral palsy › Intestinal failure-associated › Functional connectivity Contact Contact liver disease (IFALD) › Deep brain stimulation [email protected] [email protected] › GLP-2 analogues Clinic › Amyloidosis Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Hepatology Department of Neurology and Gastroenterology and Experimental Neurology Director Director Univ.-Prof. Dr. med. Frank Tacke Univ.-Prof. Dr. med. Matthias Endres
Effect of Genetics, Trace Elements and Parenteral Nutrition Functional Networks of Dyskinetic Cerebral Palsy: on Intestinal Failure Associated Liver Disease. a Lesion-Based Study
Epidemiological data have shown that the incidence of effect of genetics, serum trace elements and parenteral Infantile cerebral palsy is a broad term for pre- or peri- patterns in dCP might facilitate patient and target selec- chronic intestinal failure (CIF) is rising and is expected nutrition. This study will attribute to a greater under- natally acquired, non-progressive, predominantly motor tion for neuromodulatory treatments such as DBS. In to further increase in the next decades most likely due standing of the pathogenesis of IFALD and may lead to disorders that can affect muscle tone, strength and/or this study, we hypothesise that different clinical move- to complications of more aggressive surgical approaches targeted interventions to prevent and treat the condition posture. The dyskinetic subtype represents 10-14% of all ment disorder patterns (e.g. predominant dystonia or and improved perioperative management. Parenteral (e.g. individual manganese supplements, non-invasive cases and is characterised by the presence of complex chorea) in dCP are related to lesions in specific nodes nutrition (PN) remains the mainstay of treatment for CIF liver assessment in clinical routine workup, development hyperkinetic movement disorders including dystonia and of larger functionally connected networks. To test this but might be associated with potentially life-threatening of an accurate predictive score for IFALD). choreoathetosis. Current treatment is solely symptom- hypothesis, 30 patients with dCP will undergo a thorough complications. Intestinal failure associated liver disease atic and largely unsatisfactory. Dyskinetic cerebral palsy clinical examination aimed at characterising the clinical (IFALD) is one of the leading long-term complications (dCP) is associated with lesions in the basal ganglia, movement disorder pattern. In a second step, cranial and causes of deaths in adult CIF patients receiving home thalamus and cerebellum. To what extent lesion charac- MRIs of included patients will be analysed and existing parenteral nutrition. Of note, the pathophysiologic mech- teristics such as specific location or functional connec- lesions delineated in order to investigate their associa- anisms of IFALD have not been discovered yet and seem tivity are associated with clinical movement disorder tion with the individual movement disorder. Lastly, per- to be of multifactorial genesis. However, promising patterns is still not clear. Deep brain stimulation (DBS) turbed functional networks underlying different move- non-invasive liver function tests and new experimental is an established treatment for Parkinson’s disease or ment disorder patterns in patients with dCP will be results propose a novel holistic approach to completely primary dystonia and is known to modulate abnormal identified using lesion network mapping. On the long- understand the aetiology and pathophysiology of IFALD. motor network activity. In contrast to primary dystonia, term, these findings could be used to explore targeted The aim of this study is a comprehensive analysis of the DBS of the globus pallidus internus for patients with dCP treatments for dCP, taking into account individual clinical pathogenesis of hepatic damage in intestinal failure has shown heterogeneous results. Understanding which phenotypes of this heterogeneous disease entity. patients receiving parenteral nutrition based on the functional networks underlie specific movement disorder
Mentors Mentors
Univ.-Prof. Dr. med. Frank Tacke Dr. med. Ulrich-Frank Pape Univ.-Prof. Dr. med. Matthias Endres Univ.-Prof. Dr. med. Andrea Kühn Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Hepatology Department of Hepatology and Department of Neurology Department of Neurology and Gastroenterology Gastroenterology and Experimental Neurology and Experimental Neurology [email protected] [email protected] [email protected] [email protected] 24 Junior Clinician Scientists Junior Clinician Scientists 25
Dr. med. Lucia Katharina Feldmann Dr. med. Vivien Leonie Friedrich
In Program From – to Fields of Research In Program From – to Fields of Research 01.2021–12.2022 › Parkinson's disease 01.2018–07.2022 › Brain Development › Deep Brain Stimulation › Oligodendroglia and Purkinje Cells Contact Contact › Neuromodulation › Hyperoxia [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology Department of Neonatology and Experimental Neurology Director Director Univ.-Prof. Dr. med. Christoph Bührer Univ.-Prof. Dr. med. Matthias Endres
Towards the Clinical Implementation of Adaptive Neurostimulation: Disturbed Interaction of Purkinje Cells and Oligodendroglia Evaluation of Chronic Electrophysiological Biomarkers in the Postnatal Cerebellum Caused by Oxygen
Deep brain stimulation (DBS) is an established, effective stable, chronic electrophysiological biomarker for long- Preterm birth is one of the major pediatric problems impaired neuronal and impaired oligodendroglial devel- therapy for movement disorders, improving motor symp- term application in everyday-life, reflecting motor per- worldwide. Although advances in medical care led to opment, which is also seen in preterm infants. The devel- toms and restoring a better quality of life. Moreover, the formance, affective symptoms and therapy effects. In increased survival, long-term neurodevelopmental dis- opment of oligodendroglia is highly dependent on inter- possibility to record electrophysiological activity in the the first study part, a cohort of chronically implanted ability remains an area of concern. The impact of preterm actions with neurons. Cerebellar development is regu- basal ganglia through the implanted DBS electrodes has PD patients (>3 months after DBS surgery) will participate birth on psychomotor and behavioral development is lated by the Purkinje cell neuron. We now aim to expanded the pathophysiological understanding of in a monopolar review with stepwise stimulation increase reflected in diverse neurological problems such as investigate in the impact of Purkinje cell injury on oli- movement disorders. Beta frequency band (13-35 Hz) and corresponding motor performance assessments, ON delayed neurobehavioral development, poor cognition godendroglial development. We intend to analyze A) the activity in the subthalamic nucleus (STN) is characteristic and OFF dopaminergic medication. This allows the eval- and academic performance. The risk of neurological influence of hyperoxia to the function and development for Parkinson’s disease (PD) and a potential biomarker, uation of therapy effects and symptom severity in rela- sequelae after preterm birth rises with prematurity of of Purkinje cells, B) the interaction of Purkinje cells and as activity levels correlate with symptom severity and tion to biomarker activity. In a second step, long-term the neonate. Recent studies of neonatal brain damage oligodendroglia after hyperoxia exposure and c) the are modulated through therapy. Adaptive DBS (aDBS) is characteristics of biomarker peak activity will be focus on the cerebellum. Brain expansion increases in influence of GABA/-antagonist as a major transmitter a concept aiming to provide stimulation titrated to the assessed for two weeks, in relation to factors such as the last trimester of pregnancy. The cerebellum reaches released by Purkinje cells on the development of oligo- real-time analysis of biomarker activity. To date, most motor activity, mood, therapy changes or circadian a growth rate that cannot be found in any other brain dendroglial precursor cells. aDBS studies have been limited to short-term experi- rhythms documented in patient diaries and clinical region. Human birth leads to increased oxygen tension mental, acute peri-operative settings, and little is known scores. Overall, the results of this study will provide a levels in the blood even without supplemental oxygen about the validity of beta-band activity as a chronic better understanding of chronic biomarker dynamics. As administration. The relative hyperoxia hits the immature biomarker. Using the novel Percept neurostimulator the Percept neurostimulator also has the potential of cerebellum of preterm infants in a phase of very dynamic (Medtronic, Minneapolis, USA), STN local field potential aDBS therapy, this study lays the foundation for the growth and cellular development indicating a high vul- recordings can now be streamed from chronically implementation of neurophysiological research in ther- nerability to external toxic stimuli. Our goal is to inves- implanted DBS electrodes, with the advantage of elec- apy optimization, towards the clinical application of tigate the impact of oxygen toxicity on neonatal brain trophysiological recordings over long time periods, in personalized adaptive neurostimulation. development in a hyperoxia rodent model. In our previ- freely moving patients, and without acute peri-operative ous studies, we could show short- and long-term injuries limitations. We hypothesize that beta band activity is a of the cerebellum caused by hyperoxia. We investigated
Mentors Mentors
Univ.-Prof. Dr. med. Matthias Endres Univ.-Prof. Dr. med. Andrea Kühn PD Dr. med. Thomas Schmitz Prof. Dr. med. Angela Kaindl Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology Department of Neurology Department of Neonatology Department of Pediatrics, and Experimental Neurology and Experimental Neurology Division of Neurology [email protected] [email protected] [email protected] [email protected] 26 Junior Clinician Scientists Junior Clinician Scientists 27
Dr. med. Teresa Gerhardt Dr. med. Carl Christoph Goetzke
In Program From – to Fields of Research In Program From – to Fields of Research 01.2020–12.2021 › Vascular immunology in acute coronary 09.2019–11.2021 › Autoinflammatory diseases syndromes caused by Plaque Erosion › Autoinflammation Contact Contact › Proteasome [email protected] [email protected] › Regulation of inflammation Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Cardiology Department of Pediatric Neurology Director Director Univ.-Prof. Dr. med. Ulf Landmesser Prof. Dr. med. Angela Kaindl
Characterization of the Function of T-Adaptive Immunity in Identification of Novel Genetic Mutations Involved in Different Pathophysiologies of Acute Coronary Syndrome Proteasome-Assosiated Autoinflammatory Syndrome
Rupture of atherosclerotic plaque is the most common characterization of local adaptive immune processes in Monogenic autoinflammatory diseases are characterized regulation of the ubiquitin-proteasome system, which cause of acute coronary syndrome (ACS with ruptured IFC- and RFC-ACS, using a novel combination of OCT imag- by an unprovoked overreaction of the immune system contributes to inflammation, and additional molecular fibrous cap, RFC-ACS). In about one third of ACS-events, ing, catheter-based sample acquisition, flow-cytometry, including many organs and are characterized by high mor- genetic insights into the regulation of the proteasome or however, the causative acute pathology is plaque erosion, multiparameter proteomics and CITE-Seqeuncing. bidity and mortality. An example of a very rare autoin- discovery of further proteasome system components, characterized by coronary thrombus formation at a culprit flammatory disease is CANDLE syndrome (»chronic atypical which can be used to develop further therapeutic options plaque with intact fibrous cap (IFC-ACS). The pathomech- neutrophilic dermatosis with lipodystrophy and elevated for PRAAS/CANDLE syndrome. anism of this important pathology is largely unknown. temperature«). This is a proteasome-associated autoin- Within the translational OPTICO-ACS study program, we flammatory syndrome (PRAAS) in which autoinflammation recently observed significant enrichment of cytotoxic- and is triggered by a malfunction in the ubiquitin-proteasome helper T-cells selectively at the culprit lesion site of IFC- system. The aim of my project is to study an index patient ACS, but phenotypical and functional details of the with a so far on a genetic level unexplained cause for his observed T-cell response remain unknown. In a delicate CANDLE syndrome as a basic model to identify further balance, the principal CD4+ T-helper (TH)-subsets (regu- components of the ubiquitin-proteasome system that latory T cells (Tregs, CD127lo,CD25+), TH1- (CXCR3+), TH2- contribute to autoinflammation. Mutations known so far (CCR4+CCR6-), TH17- (CCR4+CCR6+), TH9- (CCR4-CCR6+) and concern the proteasome-core complex or assembly pro- T follicular helper (TFH, CXCR5+) cells) mediate distinct teins. We hypothesize that mutations in other protea- pro-inflammatory, destabilizing (e.g. TH1, TH17) or anti-in- some-associated genes may also cause CANDLE syndrome. flammatory, protective (e.g. Treg, TH2) effects on coronary The aim is to further investigate the causes of CANDLE atherosclerosis. The aim of the current project is in depth syndrome. This is expected to yield new insights into the
Mentors Mentors
Univ.-Prof. Dr. med. Ulf Landmesser PD Dr. med. David Manuel Leistner Prof. Dr. rer. nat. Elke Krüger PD Dr. med. Tilmann Kallinich Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Institut für Medizinische Biochemie Charité – Universitätsmedizin Berlin Department of Cardiology Department of Cardiology and Molekularbiologie Department of Pediatric Respiratory Medicine, Immunology and Critical [email protected] [email protected] [email protected] Care Medicine [email protected] 28 Junior Clinician Scientists Junior Clinician Scientists 29
Dr. med. Julius Grunow Dr. med. Eva Käbisch
In Program From – to Fields of Research In Program From – to Fields of Research 11.2020–10.2022 › Intensive Care Unit acquired Weakness 01.2020–03.2022 › B cell receptor sequencing › Translational Research › B cell reconstitution Contact Contact › Muscle Homeostasis › Bone Marrow Niche [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Anesthesiology and Department of Hematology, Oncology Operative Intensive Care medicine and Cancer Immunology Director Director Univ.-Prof. Dr. med. Claudia Spies Univ.-Prof. Dr. med. Lars Bullinger
The Impact of Bioenergetic Failure on Muscular Function Characterization of the Human Bone Marrow Niche and Immune in Critically Ill Patients Reconstitution after Allogeneic Stem Cell Transplantation
Intensive Care Unit-acquired Weakness (ICUAW) is a clin- but also cannot be explained by muscle atrophy. These Despite the rapid advances in cancer therapies, alloge- alloHSCT via immunofluorescence confocal microscopy ical diagnosis defined by a reduction in maximal muscle findings led us to the conclusion that limited muscle neic hematopoietic stem cell transplantation (alloHSCT) as well as single-cell analyses. Our goal is to decipher strength, which cannot be explained by anything other endurance, dissociation of muscle mass and muscle still remains an integral part of curative therapeutic the therapy-induced alterations and reconstitution of than critical illness itself. It can be observed in the major- strength as well as variable contractile response to neu- strategies in the field of hematology. During alloHSCT the bone marrow niche with focus on the interaction of ity of critically ill patients and is further characterized romuscular electrical stimulation are most likely caused the recipient is conditioned with high-intensity chemo- immune and stroma cells. We will further implement flow by an early-onset, rapid muscle atrophy. Short-term as by a dysfunctional energy supply. Considering mitochon- therapy and/or irradiation in order to deplete residual cytometry analyses of B cell subpopulations in peripheral well as long-term mortality and morbidity are signifi- dria are the main energy provider for the human body tumor cells and to facilitate the rooting of donor’s hema- blood and B cell receptor sequencing at various time cantly increased in patients with ICUAW. In a previous and especially for muscle activity extending beyond short topoietic stem cells within the recipient’s bone marrow points before and after alloHSCT, in order to evaluate project, we discovered that preservation of muscle mass bursts of maximal strength, we hypothesized that niche. Recent studies were able to show that the interplay the B cell regeneration and BCR repertoire after trans- in critically ill patients is not able to counteract devel- impaired mitochondrial function – bioenergetic failure between non-hematopoietic bone marrow and hemato- plantation. Pairing these findings with information on opment of weakness and further does not improve recov- – could be the main culprit leading to the observed phe- poietic cells is essential for an efficient immune recon- clinical features, we hope to shed some light on the ery within one year after ICU discharge. We further notype. We therefore aim in a first step to do a thorough stitution after transplantation. Several factors such as pathomechanisms of bone marrow niche damage and noticed that, while muscle strength fully recovered after characterization of mitochondrial function, mitochon- the occurrence of bone marrow graft-versus-host disease hampered B cell reconstitution and to develop individual ICU discharge, muscle endurance remained impaired. drial biogenesis as well as related pathways and in a as well as irradiation have been identified to hamper the strategies for improving humoral immunity after alloge- During commencement of our trial we performed neu- second step correlate our molecular findings to the clin- process of immune and B cell reconstitution due to niche neic HSCT. romuscular electrical stimulation and noticed that ical, metabolic and electrophysiological data in order to damage, resulting in a higher risk for infections and patients contractile response was highly variable, identify key mechanisms as possible therapeutic thereby increased morbidity and mortality after alloHSCT. declined over time and dependent on the degree of ill- targets. We are underway to conduct a full characterization of ness. An observation that had been disregarded earlier the human bone marrow niche before, during and after
Mentors Mentors
Prof. Dr. med. Steffen Weber-Carstens Univ.-Prof. Dr. med. Jens Fielitz Univ.-Prof. Dr. med. Lars Bullinger Univ.-Prof. Dr. med. Il-Kang Na Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Experimental and Clinical Research Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Anesthesiology and Center (ECRC) Department of Hematology, Oncology Department of Hematology, Operative Intensive Care medicine and Cancer Immunology Oncology and Cancer Immunology [email protected] [email protected] [email protected] [email protected] 30 Junior Clinician Scientists Junior Clinician Scientists 31
Dr. med. Arne Kienzle Dr. med. Leif Torben Koschützke
In Program From – to Fields of Research In Program From – to Fields of Research 10.2020–09.2022 › Bone Metabolism 07.2019–10.2021 › Motor rehabilitation › Joint Infection › Stroke Contact Contact › Osteitis › Optogenetics [email protected] [email protected] › Arthroplasty › Deep Brain Stimulation Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Center for Musculoskeletal Surgery Department of Neurology and Experimental Neurology Director Univ.-Prof. Dr. med. Carsten Perka Director Univ.-Prof. Dr. med. Matthias Endres
Role of Osteitis and Osteomyelitis in Altered Bone Homeostasis Neural Mechanisms of Motor Recovery After Stroke in Patients with Periprosthetic Joint Infection
Despite increased use of antibiotics and improved asep- tially impact the regenerative function of osteoblasts Stroke is one of the most common diseases with acute the critical parts of the serotonergic system using those tic surgical techniques, periprosthetic joint infections and thus disturb the bone and bone marrow homeostasis, onset. It is considered to be among the leading causes of modulations and immunohistological analyses. These (PJI) still occur in 1-5% of primary total knee arthroplas- subsequently altering bone density and metabolism. Our disability worldwide, resulting mainly from remaining experiments have to be considered as groundwork in the ties. In PJI, microorganisms form a biofilm on the implant clinical observations suggest that these changes persist motor deficits. There are a lot of efforts to improve emer- understanding of underlying mechanisms of longterm making the infection highly resistant to antibiotic treat- despite guideline compliant anti-microbial and surgical gency care and early rehabilitation with notable improve- rehabilitation after stroke and can possibly contribute to ment. Once a biofilm forms on the implant, complete treatment. In this respect, affected patients could benefit ment in the therapies for stroke patients. However, little the refinement of rehabilitation paradigms. removal of the infected prosthesis and, in most cases, from treatments that restore bone homeostasis and is understood regarding the cellular mechanisms of motor in a second-stage surgery, reimplantation of a new pros- counteract osteitis and bone loss. Additionally, profiling recovery after stroke especially in patients who are thesis is necessary. After PJI-dependent revision surgery, patient’s systemic immune competence from peripheral severely disabled. Studies and previous experiments hint we found a drastically elevated risk for prosthesis failure: blood samples may help identify patients especially at at the neurotransmitter serotonin to play an important In this study, 22% of all patients suffered from long-term risk for impaired bone formation and thus consecutive role in the recovery of motor deficits. We hypothesize that complication aseptic loosening and 16% from recurrent prosthesis failure. an increase in serotonergic transmission in the surround- PJI; suggesting PJI significantly and lastingly alters the ings of the brain tissue affected by stroke (penumbra) bone metabolism. Our research focuses on understand- will improve the motor deficits. In our methodological ing the altered pathomechanisms involved in this pathol- approach we are using different state-of-the-art tech- ogy. We hypothesize that the increased risk for aseptic niques to examine and modulate the serotonergic system loosening after PJI is due to an inflammatory response in mice, e.g. with chemogenetic, optogenetic and electric in the bone and bone marrow, i.e. osteitis and osteomy- stimulations. Furthermore, we are expecting to show elitis. In PJI, adaptive immunological processes poten- improvement of motor recovery and be able to identify
Mentors Mentors
Univ.-Prof. Dr. med. Carsten Perka Univ.-Prof. Dr.-Ing. Georg Duda Univ.-Prof. Dr. med. Matthias Endres Univ.-Prof. Dr. med. Christoph Harms Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Center for Musculoskeletal Surgery Julius Wolff Institute for Department of Neurology Center for Stroke Research Berlin Biomechanics and Musculoskeletal and Experimental Neurology [email protected] Regeneration [email protected] [email protected] [email protected] 32 Junior Clinician Scientists Junior Clinician Scientists 33
Dr. med. Jana Krech Dr. med. Jakob Kreye
In Program From – to Fields of Research In Program From – to Fields of Research 01.2020–12.2021 › Translational Medicine 01.2021–12.2022 › Neuroscience › Pediatric Cardiology › Neuroimmunology Contact Contact › Inflammation › Humorla Immune Response [email protected] [email protected] › Autoimmunity Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Pediatric Cardiology Department of Pediatric Neurology and Congenital Heart Disease Director Director Prof. Dr. med. Angela Kaindl Univ.-Prof. Dr. med. Felix Berger
Cold Inducible RNA-Binding Protein (CIRBP) as a Diagnostic Evaluation of Humoral Cross-Reactivity to Viral Antigens Marker in Pediatric Cardiac Surgery and Central Nervous Autoantigens in Encephalitis
Both inflammatory reactions and capillary leak syndrome trations in peripheral blood after cardiac surgery in Encephalitis is a rare but serious disease with neuro- without clinical HSE, possibly hinting towards a molec- are frequent complications after open-heart surgeries children with congenital heart disease, the present pilot logical dysfunction in the context of inflammation of ular mimicry as a trigger of autoantibody production. in children with congenital heart disease. Capillary leak study is designed to evaluate CIRBP as a potential diag- the brain parenchyma, with a disease peak in infancy But also around a third of post-HSE patients also develop syndrome is primarily induced by endothelial dysfunction nostic marker in this cohort. Therefore, patients up to with 13.5 cases per 100,000. While the causal clarification auto-antibodies against other neuronal. In addition, AIEs and is characterized by intravasal volume- and protein the age of 18 years undergoing a corrective or palliative remains unclear in over 30% of the cases, two main have also been described in association with other viral depletion, as well as edema. Inflammatory reactions and cardiac surgery at our center will be recruited for the forms can be distinguished in the other cases. On the infections, which suggests general trigger factors. Fur- capillary leak syndrome crucially influence postoperative study. Blood samples will be collected directly before one hand, primarily infectious encephalitis occurs as a ther studies are therefore necessary to understand the morbidity as they are associated with a longer stay on and during the first 24 hours after operation at defined result of direct invasion of the central nervous system host and environmental factors that lead to the pro- the pediatric intensive care unit, prolonged mechanical time points. In addition to analyzing CIRBP, proinflam- (CNS) by a pathogen, usually neuroinvasive viruses, most duction of autoantibodies in patients after viral enceph- ventilation and higher demands for catecholamines and matory cytokines, and markers for endothelial dysfunc- commonly herpes simplex viruses. On the other hand, alitis.Using established methods in the recombinant sedative medication. To date, only a few risk factors have tion, serum samples will be incubated with human mono- auto-antibodies can cause so-called autoimmune generation and characterization of disease-specific been identified for the development of inflammatory cytes (THP-1) and endothelial cells (HUVECs) in the exper- encephalitis (AIE) as part of an aberrant immune reaction, antibodies from patients’ CSF or blood samples this reactions and capillary leak syndrome. However, we are imental part of the study to analyze induced mechanisms such as anti-NMDA receptor encephalitis. AIE is more project aims to expanded understanding of anti- still lacking suitable biomarkers, which can be used to on a cellular level. likely to be associated with viral infections, best shown body-mediated neurological and psychiatric diseases, detect and treat patients at risk early on. Cold inducible for AIE after herpes simplex encephalitis (HSE), which thereby specifically addressing the following questions:1. RNA-binding protein (CIRBP) belongs to the family of cold- typically occurs two months after viral infection in 27% Do defined pathogenic autoantibodies from AIE patients shock proteins and has been identified as a potent of Anti-NMDA receptor antibodies can be detected in (without a history of viral encephalitis) have cross-re- inflammatory mediator. So far, basic research and clinical about two thirds of these patients a phenomenon that activities against viral targets?2. Can monoclonal anti- studies indicate that CIRBP may be of both diagnostic has been shown in a similar manner after experimental viral antibodies be isolated from patients with viral and therapeutic use for inflammatory reactions. Further- HSV infections in a mouse model.However, the mecha- encephalitis or AIE after viral encephalitis? Are reactiv- more, experimental studies have shown that CIRBP is nisms underlying AIE after HSE have so far remained ities against central nervous autoantigens detectable involved in the pathogenesis of endothelial dysfunction. largely unclear. Increased titers of serum HSV antibodies for these antiviral antibodies or other antibodies from As there have been no studies analyzing CIRBP concen- were found in patients with NMDA receptor encephalitis the same patient sample?
Mentors Mentors
Univ.-Prof. Dr. med. Felix Berger Prof. Dr. med. Katharina Schmitt PD Dr. med. Ellen Knierim Univ.-Prof. Dr. med. Harald Prüß Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Pediatric Cardiology Department of Pediatric Cardiology Department of Pediatric Neurology Department of Neurology and Congenital Heart Disease and Congenital Heart Disease and Experimental Neurology [email protected] [email protected] [email protected] [email protected] 34 Junior Clinician Scientists Junior Clinician Scientists 35
Dr. med. Joseph Kuchling Dr. med. Anna Kufner, PhD
In Program From – to Fields of Research In Program From – to Fields of Research 03.2020–02.2022 › Neurology 01.2020–12.2022 › Ischemic stroke › Neuroimaging › Magnetic resonance imaging (MRI) Contact Contact › Neuroinflammation › Contrast-enhanced MRI [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology Department of Neurology and Experimental Neurology and Experimental Neurology Director Director Univ.-Prof. Dr. med. Matthias Endres Univ.-Prof. Dr. med. Matthias Endres
7 Tesla T2*-Weighted MRI Mapping in Multiple Sclerosis Training-Induced Changes in Vascular Morphology and Cerebral and Neuromyelitis Optica Spectrum Disorders Perfusion after Stroke – a Multiparametric MRI Study
Multiple sclerosis (MS) and neuromyelitis optica spec- MRI-based quantification of brain myelin content to Early rehabilitation is an essential part of the recom- opments in magnetic resonance imaging (MRI) suggest trum disorders (NMOSD) are both neuroinflammatory differentiate multiple sclerosis (MS) from neuromyelitis mended therapy following an acute cerebrovascular that selected sequences – such as vessel size imaging diseases with overlapping clinical and paraclinical pre- optica spectrum disorders (NMOSD) by assessing quan- event due to unequivocal evidence that regular physical (VSI) – now allow for an in vivo assessment of cerebral sentation. Despite the introduction of NMO-specific titative T2* parameters within inflammatory lesions and activity not only mitigates risk factors (i.e. hypertension, microvasculature in patients. With this novel imaging aquaporin-4-antibody (AQP4-ab) and quite recently in different brain regions apart from overt lesion sites. dyslipidemia) but also has a beneficial effect on func- technique in mind, an exploratory sub-study of the PHYS- myelin-oligodendrocyte-glycoprotein-antibody (MOG- In our clinical study, we investigate patients with MS tional recovery following stroke. However the underlying STROKE trial was designed called BAPTISe (Biomarkers ab) into neurological diagnostic workup, accurate dif- and antibody-associated NMOSD with regards to their mechanisms of physical activity leading to an improved and perfusion – training induced change after stroke), ferential diagnosis in patients with acute and relapsing clinical and 7 T T2* MRI mapping features to evaluate outcome are poorly understood. Pre-clinical studies from in which a subgroup of patients receive multiparametric CNS inflammation still remains difficult. As a conse- sensitivity and specificity of T2* mapping to distinguish our research group have demonstrated the beneficial contrast-enhanced MRI before and after intervention quence, the different disease entities are still frequently between MS and NMOSD. The ultimate goal is to not only effects of exercise on long-term stroke outcome in (aerobic fitness vs. relaxation). The aim of the current misdiagnosed and existing effective therapy is withheld visualize different myelin concentrations within brain rodents and have attributed the observed effect to train- project is to translate our own pre-clinical findings on from a considerable number of MS and NMOSD patients. tissue of different disease entities in vivo, but also to ing-induced angiogenesis. Physical activity not only led the effects of exercise on cerebral perfusion and angio- However, overt histopathological differences between improve current MR differential diagnostic criteria to to a histological increase in microvessel density but also genesis into clinical research with the use of multipara- MS, AQP4-NMOSD and MOG-NMOSD with particular allow for early and accurate differential diagnosis for led to visible changes in vessel morphology and ulti- metric, contrast-enhanced MRI. The aim of this project regards to myelin content within and outside of lesion patients with neuroinflammatory diseases in a clinical mately resulted in enhanced cerebral flood flow and is to assess whether VSI can reliably assess the cerebral formations have been previously described. The advent setting. better long-term functional recovery in rodents following microvasculature in-vivo in acute and sub-acute stroke of modern T2* MRI mapping techniques allows for MRI- minor ischemic stroke. In patients, the mechanisms patients. Furthermore, we aim to assess whether physical based quantification of myelin content within brain underlying the beneficial effects of exercise following training will result in changes in MRI-derived microvas- tissue in vivo. By use of 7 Tesla MRI at ultrahigh field stroke are far less explored. In 2013, our research group cular morphology and cerebral perfusion parameters strengths, we further augment image contrast and designed and initiated the PHYS-STROKE Trial (a Phase in stroke patients, corresponding to pre-clinical myelin quantification accuracy of T2* sequences com- III randomized controlled trial [RCT]) – which was the findings and whether these changes can predict stroke pared to conventional routine MRI at 3 Tesla. Therefore, first trial designed to assess the effect of physical activity outcome. we attempt to explore the potential of ultrahigh field on functional outcome following stroke. Recent devel-
Mentors Mentors
PD Dr. med. Klemens Ruprecht Univ.-Prof. Dr. med. Friedemann Univ.-Prof. Dr. med. Matthias Endres Prof. Dr. med. Jochen Fiebach Clinical Mentor Paul Clinical Mentor Scientific Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology NeuroCure Clinical Research Center Department of Neurology Department of Neurology and Experimental Neurology and Experimental Neurology and Experimental Neurology [email protected] [email protected] [email protected] [email protected] 36 Junior Clinician Scientists Junior Clinician Scientists 37
Dr. med. Michael Launspach Dr. med. Jochen Michely
In Program From – to Fields of Research In Program From – to Fields of Research 03.2020–02.2022 › Pediatric Oncology 08.2020–04.2023 › Computational Psychiatry › Regenerative Therapies › Cognitive Neuroscience Contact Contact › Gene Therapy › Psychopharmacology [email protected] [email protected] › Cell engeneering › Neuroimaging Clinic › CRISPR/Cas Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Pediatric Oncology Department of Psychiatry and and Hematology Neurosciences Director Director Univ.-Prof. Dr. med. Angelika Eggert Univ.-Prof. Dr. med. Dr. phil. Andreas Heinz
Neuroblastoma Tumor Microenvironment Alteration Through a Towards a Computational Account of Ketamine’s Gene Therapeutic Approach to Enhance Adoptive T Cell Therapy Antidepressant Effect
The gene therapeutic approach we are developing aims With an estimated 350 million people affected globally, in patients undergoing ketamine treatment. Over the to modify neuroblastoma cells by CRISPR/Cas9 technol- depression represents one of society’s most challenging course of the study, patients will be repeatedly tasked ogy to express transgenes that encode for a T cell-at- and costly health burdens. Traditional pharmacotherapy on a bespoke decision-making task that I have recently tracting chemokine: CXCL10. By doing so, we aim improve of depression increases brain levels of monoaminergic validated in a similar pharmacological study (Michely et CAR T cell infiltration and subsequently efficacy, even in neurotransmitters, such as serotonin. However, effects al., 2020, Nat Commun). This gamified computer task tumors with a T cell excluding signature. To achieve trans- of monoaminergic antidepressants are often modest, enables a precise assessment of how patients learn from, gene expression predominantly in cancer cells we will and benefits emerge slowly, over a time course of weeks. and emotionally respond to, rewarding experience. Addi- be using the sequence specificity of the CRISPR/Cas9 Recently, an NMDA receptor antagonist, ketamine, was tionally, I will use non-invasive, functional magnetic system. We thereby compare different genomic targets found to improve mood in severe, treatment-resistant resonance imaging (fMRI), allowing me to probe activation in terms of integration frequency, transgene expression depression. Unlike traditional therapy, ketamine acts of brain circuits involved in human reward processing. and tumor specificity. rapidly, producing antidepressant effects within hours Building on a computational psychiatry approach, I aim of application. Moreover, ketamine targets glutamate to decipher the cognitive mechanisms that give rise to neurotransmission, rather than impacting brain mono- ketamine’s antidepressant effect, and identify neuro- amine levels. Consequently, the serendipitous discovery computational markers for a clinical response to inter- of this novel, rapid-acting antidepressant is hailed as vention. Informed by a deeper understanding of the one of the most important advances of modern psychi- neurobiology of depression and its treatment, my goal atry. However, despite ketamine’s promising clinical is to improve tailoring of currently available, and devel- impact, the mechanisms through which it may work opment of novel antidepressant therapies in the future. remain elusive. To utilise the enormous therapeutic potential of ketamine, we require a better mechanistic, neuroscientifically grounded, understanding of its effect on brain function. In this project, I will use cognitive assessment, brain scanning and mathematical modelling,
Mentors Mentors
Univ.-Prof. Dr. med. Angelika Eggert PD Dr. med. Annette Künkele Dr. Ralf Kühn Prof. Dr. med. Stephan Köhler Univ.-Prof. Dr. med. Philipp Sterzer Clinical Mentor Scientific Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin MDC – Max Delbrück Center Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Pediatric Oncology Department of Pediatric Oncology for Molecular Medicine Berlin Department of Psychiatry and Department of Psychiatry and and Hematology and Hematology Neurosciences Neurosciences [email protected] [email protected] [email protected] [email protected] [email protected] 38 Junior Clinician Scientists Junior Clinician Scientists 39
Dr. med. Simon Moosburner Dr. med. Christopher Neumann, M. Chem.
In Program From – to Fields of Research In Program From – to Fields of Research 01.2021–12.2022 › Liver Transplantation 01.2021–12.2022 › Pancreatic cancer › Extended Criteria Donor Organs › Organoid cultures Contact Contact › Proteomics › Personalised therapies [email protected] [email protected] › Aging Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Surgery Department of Hematology, Oncology and Cancer Immunology Director Univ.-Prof. Dr. med. Johann Pratschke Director Prof. Dr. med. Sebastian Stintzing
Extracorporeal Evaluation of Liver Grafts from Older Donors Potential of Organoid Cultures to Predict the Therapeutic Response in Patients.
Liver transplantation is the treatment of choice for evaluation and characterization prior to transplantation, Pancreatic cancer is a highly malignant tumor with a of the primary and metastatic sides to various targeted patients with advanced liver cirrhosis, hepatocellular 3) optimized transplantation logistics, 4) potential for dismal prognosis. Non-specific symptoms, rapid progress, and well-known chemotherapies and to use proteomics carcinoma within Milan-criteria, and severe metabolic metabolic conditioning during perfusion. Ex vivo machine a high rate of metastasis and very little progress in treat- to classify subgroups and identify potential bio- or autoimmune hepatic disorders. However, the number perfusion therefore has the potential to increase the ment options result in a five-year survival rate of less markers of the tumor. By correlating the in-vitro data to of patients waiting for liver transplantation exceeds the pool of available organs for transplantation. Currently, than 10% with the only curative treatment to be the sur- the clinical response rate of these patients, the organoid number of available organs. Notably, in Germany, the around 15% of potential liver grafts are declined in Ger- gical resection of the tumor. Pancreatic cancer is expected model can be evaluated as to whether more personalised success of liver transplantation has been limited by a many due to donor age or morbidity. Indeed, this problem to be the second deadliest cancer by 2030. Once metas- therapeutic approaches can become future clinical dramatic decline in organ donation over the last decade. exists worldwide with similarly high decline rates in the tasised the treatment is purely palliative. Only very few practice. To alleviate the supply and demand imbalance, an United States with 13%. However, it still remains unclear chemotherapeutic regimes can be administered. None increasing proportion of grafts meeting so called why some organs from older age donors perform better of them taking into account the specific metastatic pat- extended donor criteria (i.e. high donor age or macrove- after transplantation than others. The aim of the project terns patients present. Previous results of the CONKO-01 sicular steatosis hepatis) are accepted for transplanta- EvALT (Extracorporeal Evaluation of Liver Grafts from and -05 study group, however, were able to show a sig- tion. These extended criteria donor organs are usually older Donors) is therefore to characterize older donor nificantly prolonged overall survival of isolated pulmo- discarded due to a higher susceptibility for ischemia organs during NEVLP using a previously developed small nary metastasis after initial surgical resection compared reperfusion injury (IRI), which associated with an animal model for NEVLP and possibly identifying thera- to isolated hepatic metastasis (30,4 vs. 18,1 months) increased rate of primary non-function and early allograft peutic targets for future graft optimization prior to representing a differential physiology of the tumor. Con- dysfunction. IRI is initiated during warm reperfusion of transplantation. sequently, possible subgroups of the metastatic stage livers in situ after static cold storage, which remains the might benefit from more personalised treatment options. current standard of care. A recent alternative to static By establishing and analysing patient derived organoid cold storage is normothermic ex vivo liver machine per- models not only from the primary tumor but also from fusion (NEVLP): livers are perfused with an oxygenated the different metastatic sides, the tumor physiology as medium to achieve an almost physiological milieu prior a whole can be understood more thoroughly. The aim of to transplantation. NEVLP enables 1) reduced IR, 2) organ this project is to expose patient derived tumor organoids
Mentors Mentors
Univ.-Prof. Dr. med. PD Dr. med. Nathanael Raschzok PD Dr. med. Uwe Pelzer Univ.-Prof. Dr. med. Ulrich Keilholz Igor Maximilian Sauer Scientific Mentor Clinical Mentor Scientific Mentor Clinical Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Surgery Medical Department Campus Charité Charité Comprehensive Cancer Center Department of Surgery Mitte, Division of Hematology and [email protected] [email protected] Oncology [email protected] [email protected] 40 Junior Clinician Scientists Junior Clinician Scientists 41
Dr. med. Julian Pohlan Dr. med. Rosa Rößling
In Program From – to Fields of Research In Program From – to Fields of Research 01.2021–12.2022 › Thermoablation 08.2020–06.2023 › Autoimmune encephalitis › CT-Thermography › Neuronal surface antibodies Contact Contact › Dual-energy computed tomography › CRISPR Cas technology [email protected] [email protected] › Sepsis Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Radiology Department of Neurology and Experimental Neurology Director Univ.-Prof. Dr. med. Bernd Hamm Director Univ.-Prof. Dr. med. Matthias Endres
CT-Thermography for Intraprocedural Ablation Zone Monitoring Identification of New Antibody Targets in Autoimmune Encephalitis
Using density data routinely acquired by computed Autoimmune encephalitis caused by antibodies targeting bacterial genome by inducing double strand-breaks and tomography but neglected so far, it is now possible to neuronal surface antigens is an only recently explored thus providing a vaccination against future viral invasion. provide an estimate on tissue temperature during ther- neurological disease that leads to psychiatric and mnes- In our project we use a mutated, catalytically inactive moablation for operator feedback. Previous experiments tic deficits as well as epileptic seizures and focal neu- (dead) nuclease dCas9 which is still able to bind DNA in ex vivo porcine liver tissue indicated that heat ablation rological signs. New disease-causing antibodies are with high precision. If the dCas9 is led to the promoter yields more accurate temperature estimates than cryoab- frequently being detected. Yet in clinical routine, we see region of its target gene by a so-called single guide RNA lation. Current challenges include the optimized coreg- many patients with unclear antibody findings, with the (sgRNA), it can act as a transcriptional regulator, amplify istration of images in order to reduce breathing artifacts pathogenicity being unknown. Precise description of the gene expression, and thereby promote expression of in the living animal. We are working on CT-Thermography antigen could not only work as proof of pathogenicity receptor subunits or whole receptors to the cell surface. to improve the quality of thermoablation especially in but also justify advanced immunotherapy in patients. It The use of a genome-wide library of guide RNAs, con- renal cell carcinoma and thereby fight local recurrence. thus represents an immediate medical need. Today taining all possible antibody targets, allows for inducing detection of an autoantibody using immunohistochem- the overproduction of each single antigen in the respec- ical methods is relatively easy and well established. The tive cells. If a patient-derived antibody now binds to one exact identification, however, of the antigen targeted by of these cells, we can stain this antibody-labelled cell, the antibody is still challenging. Even advanced methods sort it by flow cytometry, and select the positive cells. using mass spectrometry or phage display fail to identify Cells can then be analysed by next-generation sequenc- the complex membrane-expressed native receptor pro- ing. Identification of the antigens would allow to better teins. The proposed project therefore aims at identifying judge the autoimmune findings, guide therapeutic the surface receptors targeted by anti-neuronal auto- options, and facilitate development of target-selective antibodies by applying a new genome-wide screening immunotherapy in the future. method using the CRISPR/Cas9 activation technology. The CRISPR/Cas system is originally known from bacteria where exposition to viral DNA leads to integration in the
Mentors Mentors
PD Dr. med. Christian Althoff PD Dr. med. Torsten Diekhoff Univ.-Prof. Dr. med. Matthias Endres Univ.-Prof. Dr. med. Harald Prüß Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Radiology Department of Radiology Department of Neurology Department of Neurology and Experimental Neurology and Experimental Neurology [email protected] [email protected] [email protected] [email protected] 42 Junior Clinician Scientists Junior Clinician Scientists 43
Dr. med. Lynn Jeanette Savic Dr. med. Julia Scheiermann
In Program From – to Fields of Research In Program From – to Fields of Research 01.2020–12.2021 › Interventional Oncology 01.2021–12.2022 › Allogeneic Stem Cell Transplantation › Molecular MR Imaging › Intestinal Microbiome Contact Contact › Hepatocellular Carcinoma [email protected] [email protected] › Tumor Microenvironment Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Radiology Department of Pediatric Oncology and Hematology Director Univ.-Prof. Dr. med. Bernd Hamm Director Univ.-Prof. Dr. med. Angelika Eggert
Novel Molecular Imaging Biomarkers of Liver Tumor Adaptation Effect of Allogeneic Stem Cell Transplantation and to Hypoxia and Immune Evasion Cyclophosphamide (PTCy) on Intestinal Microbiome in Mice
Hepatocellular carcinoma (HCC) is the fourth most com- patients resulting in heterogenous susceptibility, which Allogeneic hematopoietic stem cell transplantation (HSCT) the microbiome changes occurring with the bone marrow mon cause of cancer-related deaths worldwide with the may cause a substantial barrier to clinical efficacy of is a curative treatment for many hematological, malignant transplantation and post-transplant treatment with PTCy. majority of cases being diagnosed at intermediate or TACE applied alone or with immunotherapies. Thus, an diseases and as well as for primary immune deficiencies. We specifically study the effects of letal radiation, fol- advanced stages. In these patients, transarterial chemo- unmet clinical need exists for novel methodologies to The major causes of mortality after HSCT are relapse, graft- lowed by bone marrow cell transplantation, and later PTCy embolization (TACE) is a guideline-approved therapy non-invasively characterize the hypoxic and immune versus-host disease (GVHD), and infections. Research has and antibiotic treatment. After collection of serial fecal based on the synergistic effects of chemotherapy and phenotype of the tumor and monitor TACE-triggered recently highlighted the importance of the composition samples, DNA is extracted from the stool samples, ischemia-induced cell death. However, efficacy of TACE alterations in order to ultimately design strategies to of the gut bacteria (intestinal microbiome) for the out- sequenced for the genomic 16S V1-V9 regions and then remains limited by high rates of local tumor recurrence. mitigate its immuno-inhibitory effects. Therefore, the comes of patients after HSCT as well as in development analyzed. The primary objective of this murine study is Postulated underlying factors are associated with tumor goal of our translational research project is to develop of graft-versus-host disease (GVHD). There are limited to evaluate the dynamic changes of the microbial com- hypoxia. Inter alia, it promotes the upregulation of var- and establish novel MR-based molecular imaging probes data available on how the conditioning regimens change position of murine fecal samples taken at different time ious growth factors, which propagate the expression of for the quantitative monitoring of tumor adaptation to the intestinal microbiome and how intestinal microbiome points before and after HSCT in order to determine the immune-checkpoints and promote regulatory T-cell acti- TACE-induced hypoxia and interactions with the local itself can influence the long term outcome in patients effects of the individual treatment steps, which are widely vation, both of which contribute to immune evasion and immune response in liver cancer. To ensure clinical trans- after HSCT. Moreover, post-transplant cyclophosphamide used in human conditioning regimens. Specifically we seek dismal prognosis.Along with tissue destruction and a latability of the newly developed imaging techniques, (PTCy) treatment is widely used and has been proven to to determine how lethal radiation trauma, PTCy and anti- possibly favorable exposure of tumor-associated anti- we will use a stepwise experimental design including 3D be highly effective at preventing severe acute and chronic biotic treatments modulate the microbial community and gens to the immune system, TACE-induced ischemia is organotypic cell cultures and an orthotopic rabbit tumor GVHD after hematopoietic cell transplantation by inducing how the start of immunological reconstitution of graft known to exacerbate tumor hypoxia and thus affect the model for TACE in liver cancer. Such imaging techniques allo-reactive T-cell dysfunction and promoting preferen- transplantation influences the bacterial composition of local immune response. Therefore, exposure to sublethal will help exploit TACE as a conditioning tool for the tumor tial regulatory T-cell reconstitution. However, effector the intestinal microbiome. ischemia is hypothesized to promote tumoral adaptation microenvironment and develop targeted approaches to T-cell function may be influenced by the gut microbiota, mechanisms that facilitate the creation of an immu- disrupt resistance mechanisms. This is envisioned to which recently has been demonstrated to be associated no-compromised, pro-tumorigenic niche, where cancer transform TACE into a personalized and systematic »one- with the severity of GVHD and overall survival after HSCT. cells can survive and regrow. However, TACE-induced stop-shop« treatment that ultimately improves the clin- In this project we use an MHC-haploidentical mouse model tumor adaptation mechanisms are highly variable among ical outcome in liver cancer patients. of allogeneic bone marrow transplantation to investigate
Mentors Mentors
Prof. Dr. med. Bernhard Gebauer Prof. Dr. med. Rolf Günther PD Dr. med. Annette Künkele Dr. med. Lena Oevermann Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Radiology Department of Radiology Department of Pediatric Oncology Department of Pediatric Oncology and Hematology and Hematology [email protected] [email protected] [email protected] [email protected] 44 Junior Clinician Scientists Junior Clinician Scientists 45
Dr. med. Christian Schinke Dr. Leon Amadeus Steiner, MD/PhD
In Program From – to Fields of Research In Program From – to Fields of Research 01.2020–12.2021 › Neurology 01.2021–04.2023 › Deep Brain Stimulation › Stem cell technologies › Synaptic Mechanisms Contact Contact › Disease modeling › Human Single Cell Research [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology Department of Neurology and Experimental Neurology and Experimental Neurology Director Director Univ.-Prof. Dr. med. Matthias Endres Univ.-Prof. Dr. med. Matthias Endres
Induced Pluripotent Stem Cell Derived Sensory Neurons as a Synaptic Mechanisms to Retune Inhibitory Control of the Patient-Specific Model of Chemotherapy-Induced Neuropathy Subthalamic Nucleus in Patients with Parkinson’s Disease
Chemotherapy-induced neuropathy (CIN) is a frequent, Deep brain stimulation (DBS) of the Subthalamic Nucleus the unique opportunities of intraoperative microelec- potentially irreversible adverse effect of cytotoxic che- (STN) is an effective treatment for Parkinson’s Disease trode and human single-neuron recordings, this study motherapy often leading to treatment reduction or dis- symptoms. However, DBS only provides transient relief aims to elucidate effects of the activation of inhibitory continuation which directly affects patients' prognosis. of symptoms, which rapidly return when stimulation is projections to STN by DBS in humans. Understanding the There is significant heterogeneity between patients discontinued. To advance DBS therapy, a more thorough underlying physiological mechanisms of this aspect of regarding development and severity of CIN and suscep- understanding of fundamental mechanisms is needed. DBS may be critical in optimizing DBS stimulation tibility to different neurotoxic compounds. While the Evidence from rodent studies has shown the potential paradigms. majority of patients develops CIN to variable extent, of microcircuit interventions to induce long-lasting some patients are spared from these neurotoxic side recovery of movement. Specifically, selective stimulation effects. To date, however, neither predictive biomarkers of inhibitory projections to the STN have been implicated nor preventive treatments for CIN are available, which in these effects. In humans, there is exciting new evi- is partially due to a lack of suitable experimental models. dence that deep brain stimulation may serve to retune We therefore aim to evaluate whether sensory neurons inhibitory synaptic control of basal ganglia structures. derived from induced pluripotent stem cells (iPSC-DSN) At present, however, inhibitory synaptic plasticity in of genetically distinct donors can serve as human disease basal ganglia structures has exclusively been studied in model system for CIN. This could open new avenues for STN output structures in humans. In the rat, we have personalized medicine with individual risk prediction, previously shown that the input of inhibitory projections choice of chemotherapeutic compounds and preventive is sustained at high stimulation frequencies in contrast treatments. to rapidly depressed excitatory input. Capitalizing on
Mentors Mentors
PD Dr. med. Wolfgang Böhmerle Univ.-Prof. Dr. med. Matthias Endres Univ.-Prof. Dr. med. Matthias Endres Univ.-Prof. Dr. med. Andrea Kühn Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology Department of Neurology Department of Neurology Department of Neurology and Experimental Neurology and Experimental Neurology and Experimental Neurology and Experimental Neurology [email protected] [email protected] [email protected] [email protected] 46 Junior Clinician Scientists Junior Clinician Scientists 47
Dr. med. Helena Stengl Dr. med. Rahel Maria Strobel
In Program From – to Fields of Research In Program From – to Fields of Research 08.2020–07.2022 › Neurology 08.2020–07.2022 › Visceral surgery › Stroke › Oncology Contact Contact › Patient-reported quality of life [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology Department of General, and Experimental Neurology Visceral and Vascular Surgery Director Director Univ.-Prof. Dr. med. Matthias Endres Univ.-Prof. Dr. med. Martin Kreis
Brain Morphometry and Resting State Functional Connectivity NOTE – Necessity of Protective Ileostomy in Rectal Resection? to Study Heart and Brain Interaction
Severe cardiac complications occur in 15-20% of patients acute myocardial injury (individual vulnerability). By Low anterior rectal resection for rectal cancer goes along patients without protective ileostomy have a better qual- during the first few days after acute ischemic stroke. using different morphometric and functional MR-imaging with the creation of a protective ileostomy in most of ity of life one year after rectal resection than patients Myocardial injury (i.e. elevated cardiac troponin levels) analyses, we aim to identify MR-biomarkers associated the cases. A protective ileostomy can cause an immense with protective ileostomy measured by the mean score is one of the most common and relevant post-stroke with myocardial injury after stroke. In a prospective deterioration of the patients‘ quality of life. Furthermore, of the category »physical function« of European Organ- cardiac complications. Patients with myocardial injury observational cohort of stroke patients (BeLOVE), we will postoperative complications such as excoration of the isation for Research and Treatment of Cancer Quality of during the first days after an ischemic stroke are at conduct an analysis of structural imaging data (sur- peristomal skin, peristomal abscesses, prolapse of the Life Questionnaire Core 30 (EORTC QLQ-C30). There will increased risk of unfavorable outcomes. Until now, the face-based morphometry (SBM) and voxel-based mor- ileostomy or renal failure because of high fluid losses be 224 patients overall, 112 each group, when a dropout underlying mechanisms are not well understood. There phometry (VBM)) as well as a functional-connectivity occur in nearly 15%. Ileostomy reversal requires surgery rate of 10% is assumed. After randomisation of 25 is evidence that stroke-induced functional and structural analysis in resting state fMRI to compare anatomical once again with inherent hospital stay, healthcare costs patients in each group a safety analysis regarding oper- interference in the central autonomic network may con- differences and connectivity pattern of regions within and possible complications. But the patient’s safety in ative revision because of insufficiency of rectal anasto- tribute to the occurrence of myocardial injury after stroke. the CAN between stroke patients with and without acute rectal resection must be mentioned as well. There are mosis will be conducted. All, inclusion criteria, surgical In a previous voxel-based lesion-symptom mapping myocardial injury. This project represents a new approach data that a protective ileostomy can lower septic com- technique and perioperative management will be stan- (cerebral MRI), it has been shown that stroke lesions in in investigating the role of the autonomic nervous system plications caused by insufficiency of the rectal anasto- dardized. Three year follow-up of the patients includes the right anterior insular cortex are associated with the in stroke-associated myocardial injury and would be an mosis. To further evaluate the necessity of protective both clinical examination and questionnaires as well as extent of acute myocardial injury. The right insular cortex important step towards a better understanding of the ileostomy in low anterior rectal resection we conduct oncological outcome. is an important region of the central autonomic network mechanisms of cardiac complications after stroke. the NOTE trial which is a multicentric, prospective, ran- (CAN) and involved in the autonomic cardiac control. In domised-controlled trial comparing patients with and this project, we hypothesize that structural or functional without protective ileostomy undergoing rectal resection alterations within the CAN promote the occurrence of because of rectal cancer. Primary hypothesis says that
Mentors Mentors
Univ.-Prof. Dr. med. Matthias Endres PD Dr. med. Jan Friedrich Scheitz PD Dr. med. Johannes Lauscher PD Dr. med. Johannes Lauscher Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology Department of Neurology Department of General, Visceral and Department of General, Visceral and Experimental Neurology and Experimental Neurology Vascular Surgery and Vascular Surgery [email protected] [email protected] [email protected] [email protected] 48 Junior Clinician Scientists Junior Clinician Scientists 49
Dr. med. Jonas Wizenty Dr. med. Marco Zierhut
In Program From – to Fields of Research In Program From – to Fields of Research 10.2020–09.2022 › Gastrointestinal Barrier, 01.2020–03.2022 › Schizophrenia Regeneration and Carcinogenesis › Negative symptoms Contact Contact › Tissue Microbiology › Empathy [email protected] [email protected] › Stem Cell Biology › Electroconvulsive therapy Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Hepatology and Department of Psychiatry and Gastroenterology Neurosciences Director Director Univ.-Prof. Dr. med. Frank Tacke Univ.-Prof. Dr. med. Dipl.-Psych. Isabella Heuser-Collier
Inflammatory Mechanisms of Gastric Stem Cells Upon Infection The Contextual Influence of the Oxytocin System on Empathy in Patients with Schizophrenia.
Mechanisms by which mucosal surfaces discriminate as important sensors and effectors of bacterial infec- In previous studies the neuropeptide oxytocin has been to play an important mediating role here. Another study between harmless bacteria and pathogens are not well tions and establish a novel link between stem cell sig- in particular associated with social enhancing and anx- demonstrated a significantly lower expression of empa- understood. Helicobacter pylori colonizes the stomach naling and mucosal immunity. Mechanistically, the inter- iety relieving effects. The purpose of this study is to thy as well as significantly lower oxytocin levels in of about 50% of the world´s population and is the main play between R-spondin and NF-κB signaling and their investigate the effect of oxytocin on empathy in patients patients with schizophrenia compared to healthy sub- risk factor for gastric cancer. A subpopulation of gland-as- impact on epithelial homeostasis, inflammation and with schizophrenia. On a neurobiological level, social jects. According to the theory of social salience, which sociated bacteria, in contrast to bacteria found on the infection will be explored. effects mediated by oxytocin are based on oxytocin`s describes an increased importance of certain social surface, induces an inflammatory response, which leads influence on the complexly regulated mesocorticolimbic stimuli, the effect of oxytocin varies depending on spe- to chronic gastritis as well as gland hyperplasia and dopamine system. Preliminary studies have already cific contexts and individual variables of the perceiving metaplasia, which are precursor lesions for gastric cancer. shown that oxytocin increases neuronal connections person. One of the individual variables is the degree of To maintain gland homeostasis, a close interplay between between social reward expectancy networks and net- negative symptoms in schizophrenic patients. Therefore, epithelial and stromal cells builds a molecular signaling works for socioemotional processes in the brain. On a based on such preliminary findings, the research project network that controls epithelial turnover and differen- behavioral level this leads to increased social activation, will explore an effect of oxytocin, given by nasal spray, tiation. The gastric gland base contains gastric stem motivation, and also improved social perception.Fur- on empathy within a positively experienced and con- cells that are characterized by high Wnt signaling and thermore, an increase in empathy modulated by the trolled context, especially in patients with schizophrenia expression of stem cell markers such as Axin2 and Lgr5. amygdala has been shown in healthy individuals follow- regarding their negative symptoms. This cell population relies on stromal-derived R-spondin. ing oxytocin administration. In particular, primary psy- Using in vivo mouse models, in which the stem cell com- chotic disorders, such as schizophrenia, are associated partment can be altered, and the organoid culture system, with deficits in the domain of social cognition, including we will demonstrate that gland base stem cells function empathy. The degree of negative symptoms is expected
Mentors Mentors
Univ.-Prof. Dr. med. Frank Tacke PD Dr. med. Michael Sigal Univ.-Prof. Dr. med. Malek Bajbouj Dr. med. Eric Hahn Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Hepatology and Department of Hepatology and Department of Psychiatry and Department of Psychiatry and Gastroenterology Gastroenterology Psychotherapy Psychotherapy [email protected] [email protected] [email protected] [email protected] Junior Clinician Scientist Alumni 51
Dr. med. Judith Altmann
In Program From – to Fields of Research 07.2019–06.2021 › Preeclampsia › Oocyte-donation pregnancies Contact › Perinatal Medicine [email protected] › Obstetrics Clinic Charité – Universitätsmedizin Berlin Department of Hematology, Oncology and Cancer Immunology Junior Junior Director Clinician Clinician Univ.-Prof. Dr. med. Friedemann Paul Scientist Scientists Immunological and Cardiovascular Inbalance in Alumni Alumni Oocyte-Donation Pregnancies
Our main research area is preeclampsia (PE), the sudden placentation owing to an immunological response of the onset of hypertension (blood pressure > 140/90 mmHg) mother to the fetus appears to be the cause of the high after the 20th week of pregnancy accompanied by pro- rate of PE in OD pregnancies. To investigate the pathway teinuria of >0,3g in 24 hours. Severe PE causes intrauter- leading to preeclampsia we currently enroll pregnant ine growth restriction (IUGR) of the fetus, preterm deliv- women in prospective clinical trials, the »Berlin Bran- ery or even stillbirth. If PE is not detected and treated denburg Pregnancy Cohort« and the »oocyte-donation at an early stage, it leads to eclampsia, a tonic-clonic pregnancy cohort« due to the high risk of preeclampsia seizure, and a hypertensive crisis. During the seizure, the in oocyte-donation pregnancies. During the visits, preg- fetus might die within the uterus and the mother might nant women are assessed using detailed cardiovascular suffer permanent cerebral damage if emergency Cae- and immunological phenotyping at three time points sarean section is not performed immediately. Thus, PE during the pregnancy, at delivery and 2-5 years after is the leading cause of maternal and fetal morbidity and pregnancy (to further reveal the cardiovascular long term mortality, causing 20-25% of overall perinatal mortality consequence of PE). The aim of this study is to develop and 16% of overall maternal mortality. The underlying a profound understanding of the immune cells playing pathomechanism of PE and the reliable prediction of the a pivotal role at the fetal-maternal interface and their onset of the disorder are still unknown. However, it is role in the development of preeclampsia in oocyte-do- evident that the placenta plays a major role in the devel- nation pregnancies via single-nucleus RNA sequencing opment of this disease. In our clinical experience in one (sNuc-Seq) using samples from healthy controls and of the largest obstetric care units in Berlin (Charité), the preeclamptic pregnancies resulting from Berlin and Oslo number of pregnancies resulting from oocyte donation cohorts. Furthermore, we plan to process a subset of (OD) - performed abroad due to legal restrictions in Ger- samples for spatial transcriptomics. many - rise continuously. Several studies conducted in OD pregnancies support the hypothesis that abnormal
Mentors
Univ.-Prof. Dr. med. Wolfgang Henrich PD Dr. med. Ralf Dechend Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Experimental and Clinical Research Department of Obstetrics Center (ECRC) [email protected] [email protected] 52 Junior Clinician Scientists Alumni 53
Dr. med. Viktor Arnhold Dr. med. Aitomi Bittner
In Program From – to Fields of Research In Program From – to Fields of Research 03.2015–03.2017 › Neuroblastoma 04.2015–03.2017 › Patient-Derived Xenografts › Signal transduction pathways › Lymphomagenesis Contact Contact › Personalized Medicine [email protected] [email protected] › Diffuse Large B-Cell Lymphoma Clinic Clinic › Personalized Medicine Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Pediatrics, Department of Hematology, Division of Oncology and Hematology Oncology and Cancer Immunology Director Director Univ.-Prof. Dr. med. Angelika Eggert Univ.-Prof. Dr. med. Lars Bullinger
Pharmacological Reactivation of the P53 Pathway Establishment of Diffuse Large B-Cell Lymphoma PDX-Models for by DS3032b in Neuroblastoma Functional Lymphoma Pathogenesis and Personalized Medicine
Neuroblastoma is the most common extracranial child- ising therapeutic options. A prerequisite to clinical test- Experimental studies in animal models, particularly in tor (BCR)/NF-B axis, at both proximal (BTK) and distal (IB hood tumor. Despite aggressive multimodal therapy, ing of DS3032b in patients with neuroblastoma is the transgenic mice models, led to a fundamental under- [an endogenous NF-B inhibitor]-degrading proteasome) survival of patients with high-risk neuroblastoma, which comprehensive preclinical evaluation of the antitumor standing of the functional role of activated oncogenes ends. Comparable patients, but not fitting the »Imbru- represent the majority of neuroblastoma patients, is effect of this compound against neuroblastoma cells in and inactivated tumor suppressor genes as well as of VeRCHOP« trial criteria are recruited into our local Charité <40% and the outcome of patients with relapsed neuro- vitro and in vivo. As a basis for clinical testing of DS3032b stress-response-programs as apoptosis or cellular ›Match point‹ clinical registry as control cohort receiving blastoma is almost always fatal. In addition, side effects in neuroblastoma patients, we will analyze the effect of senescence in human diffuse large B-cell lymphoma standard therapy. To test whether our PDX-DLBCL models of current multimodal therapeutic regimens for the treat- these compounds on cell lines in vitro and in subcuta- (DLBCL). However, due to species differences, these mod- recapitulate treatment response and long-term outcome ment of neuroblastoma are high, often resulting in life- neous xenograft models in vivo. In a first step, we plan els can only recapitulate parts of the temporospatial of individual DLBCL cases observed in the clinic, the same long sequelae in survivors. Therefore, the development to analyze the antitumor activity of DS3032b using cell genetic complexity of human lymphoma pathogenesis. chemotherapy received by the patient is administered of targeted approaches with fewer adverse effects is of growth, proliferation, senescence and apoptosis assays, In order to recapitulate human biological systems more to the corresponding PDX model. Individual components major importance for patients with primary high risk or flow cytometer, Western blotting and reverse transcrip- closely, sophisticated small-animal models are acutely of the »ImbruVeRCHOP« protocol are applied as a sin- relapsed neuroblastoma, who are in urgent need of addi- tion-quantitative PCR (RT-qPCR) analysis of p53 target required. Systemic-orthotope propagation of primary gle-agent or multi-drug-combined therapies to unveil tional effective therapies. The tumor suppressor gene genes. The specificity of the effect of DS3032b treatment patient-derived tumor-material in immunodeficient mice the unique dynamic and outcome attributed to each drug. TP53 is involved in the formation of different malignan- should be detected by »rescue« experiments. In addition, (so-called »Patient-derived Xenografts [PDX]«) is one Tumor materials have been collected as tumor chunk cies. Inactivating mutations in the TP53 gene are rare in we want to examine the activity of DS3032b in a subcu- solution. These DLBCL cases comprise our in-house before treatment, as intra-vital punch biopsies 24 hours neuroblastoma, but overexpression of MDM2 resulting taneous xenograft mouse model. patients who received standard therapy (R CHO[E]P) as after treatment exposure to assess acute drug responses, in functional p53 inactivation is commonly detected. well as patients enrolled in our active recruiting inves- and at relapse. The samples will then be subjected to Specific antitumor activity of compounds targeting the tigator-initiated trial »ImbruVeRCHOP« (PI/LKP: Clemens targeted re-sequencing to investigate therapy-driven p53-MDM2 axis has been demonstrated. Treatment with A. Schmitt). In this multi-center first-line trial, high-risk clonal evolution and development of resistance. A long- MDM2 inhibitors reduced cell viability in vitro and in vivo elderly DLBCL patients receive two additional small com- term aim of this clinical-translational project is to use by re-activating p53 function. On the basis of the existing pounds (the BTK inhibitor Ibrutinib and the proteasome this PDX-DLBCL-models for prediction of individual ther- data, functional reactivation of p53 and/or inhibition of blocker Bortezomib) as an extension to the R-CHOP back- apy response to one or a combination of new target- the p53/MDM2 axis in neuroblastoma are therefore prom- bone, intended to double-target the pivotal B-cell recep- ed-therapies, biologicals and antibodies.
Mentors Mentors
Univ.-Prof. Dr. med. Angelika Eggert PD Dr. med. Patrick Hundsdörfer Univ.-Prof. Dr. med. Lars Bullinger Univ.-Prof. Dr. med. Clemens Schmitt Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Pediatrics, Division of Department of Pediatrics, Division of Medical Department, Division of Medical Department, Division of Oncology and Hematology Oncology and Hematology Hematology, Oncology and Tumor Hematology, Oncology and Tumor Immunology Immunology [email protected] [email protected] [email protected] [email protected] 54 Junior Clinician Scientists Alumni 55
Dr. med. Friederike Borngräber PD Dr. med. Catharina Busch
In Program From – to Fields of Research In Program From – to Fields of Research 08.2018–07.2020 › Musician’s Dystonia 07.2015–05.2017 › Complement system › Electrical Cerebellar Stimulation › Age-related macular degeneration Contact Contact › Retinal pigment epithelium [email protected] [email protected]leipzig.de Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology Department of Ophthalmology and Experimental Neurology Director Director Univ.-Prof. Dr. med. Antonia Joussen, FEBO Univ.-Prof. Dr. med. Matthias Endres
Characterization of Cerebellar Function in Musician’s Dystonia Influence of AMD Patients’ Sera on ARPE-19 Cells Patients and its Electrical Modulation Capability
Musician’s dystonia (MD) is a task-specific form of focal pianists to take in to account sensorimotor adaptation Being responsible for more than 40 % of all cases, age-re- insights into the involvement of the complement system dystonia that manifests itself as a loss of voluntary motor due to prior musical training. Electroencephalographical lated macular degeneration is the leading cause for in the cellular pathophysiological processes of the RPE control when playing an instrument. Up to 1-2% of pro- measurements before and after the intervention will blindness in industrial countries. AMD is a neurodegen- in the context of AMD using Ca2+ imaging and gene fessional musicians are affected, and in many cases, the help to explore the stimulations’ effect on different fre- erative disease, caused by environmental factors, such expression analysis. As a source for active complement disorder terminates the professional career. The under- quency bands of the cortex. Clinical outcome will be as age, smoking or obesity as well as individual genetic components sera of AMD patients with known genotype lying pathophysiology is not fully understood. However, measured via MIDI recordings of the piano playing, scor- risk factors. A strong association was found for poly- of CFH and ARMS-2 are used. recent findings suggest a cerebellar contribution to the ing parameters like the variability of inter-onset intervals, morphism on the complement factor H (CFH)- gene and disease. For instance, cerebellar activity is reduced in velocity and error rate. The findings of this study may age- related maculopathy susceptibility 2 (ARMS2)- gene. other forms of isolated dystonia like cervical dystonia have considerable consequences for the therapeutic Several studies already revealed the involvement of the leading to an abnormal excitability of the cortex. There- treatment of MD patients. complement system in the local AMD pathogenesis and fore, the study aims at investigating the cerebellar influ- progression, mainly regarding the retinal pigment epi- ence to the pathomechanism of MD. We hypothesize that thelium (RPE). It is already known that AMD patients’ sera reinforcement of the cerebellar output will lead to a are characterized by an altered serum complement level. clinical improvement of symptoms. In order to modulate However, it is still unknown how far this elevated levels the cerebellar activity, we will apply oscillating transcra- of serum complement and increased activity of the alter- nial direct current (o-tDCS), alternating current (tACS) native complement pathway influence the RPE. Genewsky and placebo stimulation to the cerebellum on three dif- et al. revealed that active complement components don’t ferent days. A cohort of 15 pianists with focal hand dys- induce a direct cell lysis in the RPE but a deficient reg- tonia will be compared to a control group of 15 healthy ulation of cell functions. This study aims to gain new
Mentors Mentors
Prof. Dr. med. Christoph Ploner Univ.-Prof. Dr. med. Andrea Kühn Prof. Dr. med. Alexander Schmidt Univ.-Prof. Dr. med. PD Dr. med. Ralf Dechend Clinical Mentor Scientific Mentor Scientific Mentor Antonia Joussen, FEBO Scientific Mentor Clinical Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Experimental and Clinical Research Department of Neurology and Department of Neurology and Berlin Center of Musicians Medicine Charité – Universitätsmedizin Berlin Center (ECRC) Experimental Neurology Experimental Neurology Department of Ophthalmology [email protected] [email protected] [email protected] [email protected] [email protected] 56 Junior Clinician Scientists Alumni 57
Dr. med. An Bin Cho Dr. med. Anja-Maria Davids, PhD
In Program From – to Fields of Research In Program From – to Fields of Research 07.2019–09.2021 › Borderline Personality Disorder February, 2015 › Retinal Degeneration › Posttraumatic stress disorder › Neuroinflammation Contact Contact › Social cognition › Radiation Retinopathy [email protected] [email protected] › Oxytocin Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Psychiatry and Department of Ophthalmology Neurosciences Director Director Univ.-Prof. Dr. Antonia Joussen, FEBO Univ.-Prof. Dr. med. Dipl.-Psych. Isabella Heuser-Collier
Impact of the Oxytocin System on Intrusive Symptoms after The Fractalkine Receptor CX3CR1 and its Role in the Pathogenesis of Analog Trauma: A Model to Study Posttraumatic Stress Disorder Choroidal Neovascularizations and Radiation-Induced Retinopathy
Intrusive symptoms, i.e. aversive, unwanted memories receive 24 I.U. intranasal oxytocin or placebo right after Vascular disorders of the retina with choroidal neovas- of trauma, are core symptoms of post-traumatic stress watching a film sequence showing physical and sexual cularisations are one of the most common causes of disorder (PTSD). Yet, little is known about biological fac- violence, which has been frequently used as a trauma blindness. The aim of this project is to investigate the tors leading to the formation of these intrusive symptoms. film paradigm in previous studies. Primary outcome is role of inflammation in the pathogenesis of CNV and to Oxytocin seems to play a key role in the onset of PTSD. hereby the number of intrusive symptoms in the following identify a link between vascular proliferation and neu- Previous studies point to anxiolytic effects of oxytocin, 4 days. roretinal degeneration, which allows a treatment opti- e.g. via the hypothalamus-pituitary-adrenal axis. Recent mization of vascular diseases of the retina. Our hypoth- studies postulate a social salience hypothesis, which esis is that a local or systemic cellular immune response states that the oxytocin effect is dependent on context precedes the development of a CNV. To test this hypoth- and person variables. In our previous study, the admin- esis we examine the Migration of Leukocytes and devel- istration of intranasal oxytocin imminently before an opment of a CNV in the fractalkine receptor (CX3CR1) analogue trauma lead to an increase in intrusive symp- mouse as the receptor is involved in the migration of toms in healthy women. This raises the question how immune cells. oxytocin may influence intrusive symptoms in a non-neg- ative context, and whether the timing (acquisition vs. consolidation of a memory) of oxytocin administration influences its effect on intrusive symptoms. In this exper- imental, randomized, double-blind, placebo-controlled trial, 220 healthy women aged 18-45 years will either
Mentors Mentors
Univ.-Prof. Dr. med. Christian Otte Prof. Dr. med. Stefan Röpke Univ.-Prof. Dr. Antonia Joussen, FEBO Univ.-Prof. Dr. rer. nat. Olaf Strauß Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Psychiatry and Department of Psychiatry and Department of Ophthalmology Department of Ophthalmology Neurosciences Neurosciences [email protected] [email protected] [email protected] [email protected] 58 Junior Clinician Scientists Alumni 59
Dr. med. Uta Margareta Demel Dr. med. Fabian Dirks
In Program From – to Fields of Research In Program From – to Fields of Research 10.2019–09.2021 › Hematology/Oncology 01.2016–12.2017 › Acute coronary syndrome › Tumor Immunology › Atherosclerosis Contact Contact › Translational Medicine › Immunology [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Hematology, Oncology Department of Cardiology and Cancer Immunology Director Director Univ.-Prof. Dr. med. Ulf Landmesser Univ.-Prof. Dr. med. Ulrich Keller
Targeting the SUMO Pathway as a Novel Tumor Therapy – The Role of Neutrophil Granulocytes and Neutrophil Effects on Hematopoiesis and the Immune System Extracellular Traps in Distinct Pathophysiological Mechanisms of Acute Coronary Syndrome
Covalent ligation of the small ubiquitin-like modifier tumor killing efficacy of SUMOi we want to focus on asso- One of the most important acute manifestations of Car- novel pathways and mechanisms in the ischemic dam- (SUMO1, SUMO2 or SUMO3) moiety to target proteins ciated mechanisms how hyperSUMOylation leads to a diovascular Disease (CVD) is acute coronary syndrome aged heart remain to be discovered. Interestingly, neu- (SUMOylation) belongs to the group of post-translational survival advantage in tumor cells. RNA expression pro- (ACS). Recent studies brought about the understanding trophil granulocytes seem to play a key role in the inflam- protein modifications that control the localization, sta- filing linked the hyper-SUMOylated state to a downreg- of plaque rupture (PR) and plaque erosion (PE) as two matory component of plaque formation and acute com- bility and activity of target proteins. Importantly, various ulation of the antigen presenting machinery in B cell distinct pathophysiological processes triggering throm- plications of atherosclerosis. In recent past a distinct components of the SUMO core machinery are upregulated lymphoma. In this project we aim at deepening the botic vascular occlusion. It was demonstrated that in ability of neutrophil granulocytes was discovered: by in cancer. Augmented SUMOylation is associated with understanding about the role of SUMOylation in the cases of PR a preexisting thin-capped fibroatheroma formation of neutrophil extracellular traps (NETs) these overexpression of the onocogene MYC and both hyper- tumor’s immune evasion strategy to depict SUMO inhi- (TCFA) ruptures, exposing an underlying necrotic core cells release a variety of intracellular components includ- SUMOylation and MYC expression are linked to aggressive bition as a potential therapeutic option to overcome the and lipid-rich, thrombogenic material to the blood ing proteins from azurophilic granules and chromatin, cancer phenotypes and thus to poor prognosis. Address- immune escape phenomenon in lymphomas. stream, thus leading way to thrombus formation and thereby forming extracellular matrices that not only ing possibilities of taking advantage of MYC-induced arterial occlusion. On the other hand, PE is categorized serve as physical barriers, entrapping pathogens, but cancer cell vulnerabilities like SUMOylation could be as endothelial deterioration leading to thrombus forma- also have antimicrobial properties. Our study will define exploited for future clinical use. We here report that tion, but with a thick fibrous cap, reinforced with smooth for the first time the role of neutrophil granulocytes and pharmacological SUMO inhibition leads to a complete muscle cells underneath. Indeed, investigators now sup- neutrophil extracellular traps (NETs) for different patho- eradication of the tumor cell population in a MYC-induced port the idea that these two processes might have dif- physiological mechanisms in acute coronary syndrome. lymphoma model in vivo, concluding that hyperSUMOy- ferent underlying mechanisms. Numerous studies Hence, we will provide deeper mechanistic insight into lation is crucial for proliferation of MYC-induced lym- demonstrated that inflammation plays an important role inflammatory processes triggering acute myocardial phoma and therefore presents a therapeutic vulnerability in CVD with promotion and resolution of innate and adap- infarction and determine the relevance of NET formation in B cell lymphoma treatment. Surprised by the massive tive immune responses in a delicate balance. However, as a potential therapeutic target for human ACS patients.
Mentors Mentors
PD Dr. med. Jan Eucker Univ.-Prof. Dr. med. Ulrich Keller Univ.-Prof. Dr. med. Ulf Landmesser Dr. rer. nat. Nicolle Kränkel Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Hematology, Oncology Department of Hematology, Oncology Department of Cardiology Department of Cardiology and Cancer Immunology and Cancer Immunology [email protected] [email protected] [email protected] [email protected] 60 Junior Clinician Scientists Alumni 61
Dr. med. Matthaeus Felsenstein Dr. med. Florian Nima Fleckenstein
In Program From – to Fields of Research In Program From – to Fields of Research 07.2019–06.2021 › Pancreas adenocarcinoma (PDAC) 08.2018–03.2021 › Interventional Oncology › Genomics › Quantitative MR Imaging Contact Contact › Gene editing (CRISPR/Cas9) › Machine Learning [email protected] [email protected] › Carcinogenesis Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Surgery Department of Radiology Director Director Univ.-Prof. Dr. med. Johann Pratschke Univ.-Prof. Dr. med. Bernd Hamm Univ.-Prof. Dr. med. Marcus Bahra
Derivation of Normal Pancreatic Duct Cells from Human Development of Multipurpose Polymer-Microspheres Primary Tissue and Their Genetic Modification in Vitro for the Use of Catheter-Based Embolization
Pancreatic adenocarcinoma (PDAC) is an aggressive dis- stand when and how dysplastic cells manifest traits of »… the vascular catheter can be more than a tool for oping multi-purpose microspheres that (i) can be used ease with overall poor survival rates. PDAC growth and uncontrolled proliferation, invasion, metastasis and passive means for diagnostic observations: used with for intra-arterial embolization, (ii) can be loaded with dissemination is preceded by specific driver gene alter- other hallmark functions, to define biologically relevant imagination, it can become an important surgical instru- chemotherapeutics and (iii) are degradable, hence offer- ations present already in pancreatic precursor lesions. targets. Suitable human in vitro models together with ment.« Dr. Charles T. Dotter Catheter-based emboliza- ing the option of temporary embolization, we aim to Current view suggests, that early oncogenic activation modern genome engineering techniques may generate tions form a key treatment pillar in the field of interven- solve this problem. In extensive in-vitro tests, we believe of KRAS is followed by inactivation of tumor suppressors new strategies for targeted therapies. tional radiology. The broad range of clinical indications to have identified two materials deriving from gelatine (CDKN2A, TP53, SMAD4) in higher grade lesions. The cen- reaches from active arterial bleedings to state-of-the-art and PMMA, that meet the above-mentioned requirements tral aim of this study is to model carcinogenesis in vitro tumor therapies. Generally, an embolic agent is admin- for an ideal embolization material. Within the next two and derive novel immortalized pancreatic duct cell lines istered into the target vessel via a previously placed years we will in-vivo test both newly developed embo- with well-defined genetic alterations. This should improve catheter, hence occluding the vessel. In this context, the lization materials in several embolization- and future experimental investigation of pancreatic precursor treatment of primary and metastatic liver tumors take tumor-models and hope to add to the development of lesions in vitro and will guide us to better understand a special role. Transarterial Chemoembolization (TACE) new and advanced clinical treatment options. the specific roles of pancreatic driver genes. Curative is a minimally invasive procedure performed to restrict treatment options for pancreatic adenocarcinoma rely a tumor’s blood supply while simultaneously locally on the combination of surgery and (neo-)adjuvant chemo- treating the tumor with high doses of chemotherapeutic radiation. Relatively low efficiency of chemotherapeutics drugs. To date, the targeted tumor-feeding arteries are warrants efforts to find molecular targets in terms of embolized permanently making it impossible to use for precision medicine. To date, all main driver genes have re-interventions, while also triggering tumor-neoangio- not been shown druggable. As such, we need to under- genesis. This leads to a therapeutic dilemma. By devel-
Mentors Mentors
Univ.-Prof. Dr. med. Bernd Hamm Univ.-Prof. Dr. Helmut Kettenmann Univ.-Prof. Dr. med. Bernd Hamm Prof. Dr. Rolf W. Günther PD Dr. med. Federico Collettini Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Max Delbrück Center for Molecular Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Radiology Medicine Berlin Department of Radiology Department of Radiology Department of Radiology Cellular Neurosciences [email protected] [email protected] [email protected] [email protected] [email protected] 62 Junior Clinician Scientists Alumni 63
Dr. med. Lea Gerischer Dr. med. Georg Girke
In Program From – to Fields of Research In Program From – to Fields of Research 01.2016–12.2017 › Dementia due to Alzheimers Disease 01.2016–12.2017 › Complement activation › Mild Cognitive Impairment › Acute coronary syndrome Contact Contact › MRI-Imaging [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology Department of Cardiology and Experimental Neurology Director Director Univ.-Prof. Dr. med. Ulf Landmesser Univ.-Prof. Dr. med. Matthias Endres
High Resolution MR-Elastography of the Hippocampus Complement Activation in Acute Coronary Syndrome in Patients with Alzheimer’s Disease
Alzheimer’s disease (AD), the most common cause of elasticity of the hippocampus between patients with In this project, mechanisms and effects of activated be performed again. However, a C1 esterase inhibitor will dementia, is marked by progressive neurodegenerative clinical diagnosis of the AD and healthy controls. This is complement system in acute coronary syndrome (ACS) be applied and mutually compared. Finally, this study changes of brain tissue. One of the regions to be affected a pilot study including patients with clinical diagnosis will be investigated. It is assumed that intracoronary will investigate which anaphylatoxins accumulate due early in the course of the disease is the hippocampus. of AD and age- and sex-matched healthy controls. To complement activation is partly responsible for post-isch- to ACS and which complement inhibiting properties can Current diagnostic methods (structural MRI, PET-imaging, quantify memory performance, all study participants emic damage of endothelium and myocardium in ACS. In be acquired by coronary endothelial cells. Effects of and analysis of cerebrospinal fluid) are either invasive undergo standardized neuropsychological test batteries the first phase of this project intracoronary blood from pharmacological complement inhibition on endothelial or detect changes only late in the course of the disease. (MMSE and CERAD). Further, all study participants ACS patients will be obtained and compared to healthy cells in ACS will be determined. The search for non-invasive methods for early diagnosis undergo a structural MRI-Scan (including T1-, T2- and control groups in terms of included complement proteins, of the AD is ongoing. MR elastography is a non-invasive DTI-sequence) and the MMRE (single-shot EPI-based MRE analphylatoxins as well as further proinflammatory cyto- technique that measures the elasticity of brain tissue. sequence). The elasticity parameters of the Hippocampus kines. Thus, an encompassed knowledge about relevant It has been hypothesized that tissue elasticity is a sur- region and a reference region are extracted from the key proteins of intracoronary complement activation will rogate parameter for microstructural architecture and images and compared between the two groups. We be achieved. In the second phase cell culture conditions therefore an interesting parameter to investigate struc- hypothesize that patients with AD have lower elasticity will provide endothelial cell responses under hypoxia tural changes of brain tissue in the course of neurode- measures in the hippocampal region compared to healthy after ACS patient plasma stimulation. Cell vitality, generative diseases such as the AD. Whole brain MR controls. If these hypotheses can be confirmed, the changes in expression of cell adhesion proteins and elastography has been demonstrated to detect decreased detection of decreased hippocampal stiffness may membrane associated complement regulators will be overall brain stiffness in AD compared to healthy controls. become a biomarker for early diagnosis and progression explored. The third phase will determine the effects of In this project, we investigate whether multifrequency monitoring in the AD. pharmacological complement inhibition by use of cell MR elastography (MMRE) can detect differences in the cultures. In line with the second phase, experiments will
Mentors Mentors
Univ.-Prof. Dr. med. Matthias Endres Univ.-Prof. Dr. med. Agnes Flöel PD Dr. med. David Manuel Leistner Dr. rer. nat. Nicolle Kränkel Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin University Medicine Greifswald Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology Department of Neurology Department of Cardiology Department of Cardiology and Experimental Neurology [email protected] [email protected] [email protected] [email protected] 64 Junior Clinician Scientists Alumni 65
Dr. med. Frank Graef Dr. rer. nat. Rene Hägerling
In Program From – to Fields of Research In Program From – to Fields of Research 01.2018–12.2019 › Fracture Healing and Traumatic 07.2019–06.2021 › Lymphovascular Medicine Brain Injury › Genetics Contact Contact › Polytrauma › Imaging [email protected] [email protected] › Histopathology Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Center for Musculoskeletal Surgery Department of Cardiology Director Director Univ.-Prof. Dr. med. Dr. h.c. Univ.-Prof. Dr. med. Ulf Landmesser Michael Schütz
Clinical Study on the Phenomenon of Improved Fracture Lightsheet Microscopy-Based 3D-Histology Healing After Traumatic Brain Injury of Human Tissue Samples
Although the development of modern osteosynthesis duce this phenomenon. Furthermore, we could demon- Over the last years, there was a lot of progress in iden- allows the visualization of the entire vascular network. techniques within the last 20 years has vastly improved strate that the osteoinductive effect after TBI is depen- tifying genes, which cause primary lymphedema in Using automated data extraction and analysis algorithms, the operative outcome after fracture treatment, we can dent on intact leptin signaling. On the basis of the results humans, but how genetic abnormalities cause lymph- the underlying histology is described and quantified in still observe fracture non-unions in up to 10%. Non- from our screening studies on mice we hypothesize that edema at the cellular level is still unknown. This lack of 3-dimensional space. This knowledge on the underlying unions have a tremendously negative effect on the qual- changes in energy homeostasis and immunological cel- mechanistic insight is associated with the absence of pathology and alterations associated with the disease ity of life of patients and generate exuberant health-eco- lular (CD4/CD8) and humoral (IL-1, IL-6, TNF α) responses suitable microscopic imaging techniques for the visual- is a prerequisite for future pharmacological interventions nomic costs. Previous approaches aimed at improving after TBI are responsible for the improved fracture heal- ization of the vasculature as classical 2-dimensional as it supports clinicians’ decision-making by improved bone healing biologically were only of mediocre success. ing. In our clinical study, we include patients who are histology is not sufficient to understand the complex patient stratification. In summary, this approach for This is surprising because bone is one of only two organs admitted to the emergency room of our trauma depart- lymphatic vessel architecture. This has been one of the 3D-histology allows 3-dimensional visualization of the in humans that can regenerate itself without scar-tissue ment and demonstrate with an isolated long-bone shaft major contributing factors to the lack of detailed knowl- entire blood and lymphatic vasculature in lymphedema formation. Patients with long-bone fractures can demon- fracture, an isolated TBI or the combination of both edge of the pathogenesis of lymphedema. To understand patients and therefore facilitate a deep-phenotyping of strate with improved fracture healing and significantly injuries. Blood samples and X-rays are taken from the the underlying vascular alteration causing lymphedema patients’ tissue, which is not possible by using classical increased callus formation if they suffer from an addi- patients in a specific timely manner in order to confirm in more detail and to overcome the limitations of clas- methods, e.g. 2D-histology. By using state-of-the-art tional traumatic brain injury (TBI). This is remarkable the results from our studies on mice. sical histology, we have developed innovative and opti- imaging techniques, this study will expand our current because increasing degrees of trauma severity can neg- mized immunofluorescence staining protocols for entire knowledge on primary lymphedema significantly and will atively influence bone regeneration. Although the phe- tissue biopsies from patients suffering from lymphedema. set the basis for new treatment regimens. nomenon of increased callus formation after TBI has Following immunofluorescence staining, we apply VIPAR long been known to the clinician since the 19th century, (volume information-based histopathological analysis the pathological pathways which are triggered after trau- by 3D-reconstruction and data extraction), a novel diag- matic damage to the brain and accelerate bone healing nostic tool for vascular diseases, on tissue biopsies from could not be identified yet. Our research group could lymphedema patients. ViPAR, a lightsheet microsco- already establish a highly standardized and reproducible py-based approach for optical of entire tissue biopsies, combined trauma model for mice in which we could repro- is based on digital 3-dimensional reconstruction and
Mentors Mentors
Univ.-Prof. Dr. med. Dr. h.c. Univ.-Prof. Dr.-Ing. Georg Duda Univ.-Prof. Dr. med. Stefan Mundlos Prof. Dr. med. Malte Spielmann Michael Schütz Scientific Mentor Clinical Mentor Scientific Mentor Clinical Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin University Clinic Schleswig-Holstein Charité – Universitätsmedizin Berlin Julius Wolff Institute for Institute of Medical and Human in Lübeck and Kiel Center for Musculoskeletal Surgery Biomechanics Genetics Institut of Human Genetics and Musculoskeletal Regeneration [email protected] [email protected] [email protected] [email protected] 66 Junior Clinician Scientists Alumni 67
Dr. med. Adriane Halik Dr. med. Lisa Hartmann
In Program From – to Fields of Research In Program From – to Fields of Research 08.2018–10.2020 › Leukemogenesis 01.2016–12.2017 › Postoperative Ileus › Acute Myeloid Leukemia › Small Bowel Obstruction Contact Contact › Single-Cell Analysis [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Medical Department, Division of Hematology, Department of General, Oncology and Tumor Immunology Visceral and Vascular Surgery Director Director Univ.-Prof. Dr. med. Lars Bullinger Univ.-Prof. Dr. med. Martin Kreis
From Clonal Hematopoiesis to Relapsing Leukemia: Effect of Preoperative Selective Decontamination of the Tracing the Roots of AML on Single Cell Level Digestive Tract (SDD) and Mechanical Bowel Preparation (MBP) on Postoperative Ileus in Mice
Acute Myeloid Leukemia (AML) – the most common type display only an average molecular image of a diverse The phenomenon of postoperative ileus (POI) frequently came to a renaissance. In 2015 a large retrospective study of acute leukemia in adults – remains a demanding chal- cell population. In contrast, single-cell DNA genotyping occurs after abdominal surgical interventions. Conse- showed that the combination of MBP with SDD reduces lenge for researchers and physicians all over the world now allows for the revelation of the clonal evolution of quences of POI are delayed ingestion, prolonged enteral POI in patients. Up to this point, there is a lack of exper- with a 5-year survival rate of less than 30%. It originates the tumor genome and a more precise detection of inter- nutrition, pain and sustained hospitalization. In single imental data concerning this matter, especially regarding from early pre-leukemic hematopoietic stem cells which cellular variety. Using a combination of whole-exome cases, POI-associated vomiting, followed by aspiration POI. We induce postoperative ileus in mice after lapa- gain additional leukemia-defining mutations over time. sequencing (WES) and single-cell DNA genotyping, I aim can lead to life-threatening situations. Consequently, rotomy and systemic manipulation of the intestine. After- In some patients, these pre-leukemic lesions persist in to unravel the phylogeny of AML and trace the clonal the incidence of POI is highly expensive, due to prolonged ward, the intestinal barrier dysfunction is being tested remission after intensive chemotherapy. Recent studies evolution from diagnosis to relapse. Therefore, I will treatment and patient’s inability to work. Although sev- in Ussing-chambers and by immunohistochemistry. have shown that the persistence of pre-leukemic lesions analyze bone marrow and peripheral blood samples from eral aspects of POI pathophysiology are described, inter- Therefore the aim of our work is to determine whether in these patients associates with a higher risk of disease a target cohort of 30 AML patients. WES will be applied vention procedures or therapies are not effective enough intestinal permeability and leukocyte infiltration of the relapse. Managing disease recurrence embodies a major to identify tumor-specific genetic target alterations. For to prevent or inhibit POI completely, so far. Especially, intestinal wall decrease during SDD and/or MBP in POI therapeutic challenge as relapsed AML is accompanied Fluidigm-based targeted single-cell genotyping defined in case of an advanced state, therapeutically intervention in mice. by the high prevalence of therapy resistance. From a flow-sorted stem cell fractions will be used. By means is difficult. Therefore, an early intervention during the molecular point of view, this can be explained by a sig- of bioinformatic and statistical analysis, an individual initial phase seems more promising. In the 1970´s the nificant genetic evolution of the tumor genome. In the phylogenetic tree will be created for each patient. Hereby, combination of mechanical bowel preparation (MBP) and past few years, multiple next-generation sequencing I aim to identify novel therapeutic targets and thus selective decontamination of the digestive tract (SDD) (NGS) studies have already paved the way for the reve- improve the therapeutic management of AML. has been routine practice in colorectal surgery. After lation of the genetic heterogeneity of AML. However, by research indicating that MBP may be harmful, it has been using bulk DNA, the obtained findings by NGS methods completely abandoned. Since this decade the discussion
Mentors Mentors
Univ.-Prof. Dr. med. Lars Bullinger Prof. Dr. med. Frederik Damm PD Dr. med. Mario Müller Univ.-Prof. Dr. med. Martin Kreis Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Medical Department, Division of Medical Department, Division of Department of General, Visceral and Department of General, Visceral and Hematology, Oncology and Tumor Hematology, Oncology and Tumor Vascular Surgery Vascular Surgery Immunology Immunology [email protected] [email protected] [email protected] [email protected] 68 Junior Clinician Scientists Alumni 69
Dr. med. Karl Hillebrandt Dr. med. Judith Holstein
In Program From – to Fields of Research In Program From – to Fields of Research 07.2019–06.2021 › Regenerative Medicine/Oncology 02.2015–01.2017 › GPCR biology › Intracellular signaling Contact Contact › Glomerular disease of the kidney [email protected] [email protected] Clinic Clinic Department of Surgery Charité – Universitätsmedizin Berlin Department of Nephrology and Director Internal Intensive Care Medicine Univ.-Prof. Dr. med. Johann Pratschke Univ.-Prof. Dr. med. Marcus Bahra Director PD Dr. med. Andreas Kahl
Decellularized Human Liver Slices as a Three-Dimensional Platform Involvement of Functional Antibodies Targeting GPCRs in to Generate In Vitro Intrahepatic Cholangiocarcinoma Glomerular Disease of Native and Transplant Kidneys
Intrahepatic cholangiocarcinoma (iCCA) is the second tumor cells and tumor-organoids still showed differences Our group has pioneered the concept that functional severe pathologies of transplant and native kidneys. This most common tumor entity of the liver. The only curative in mutations-patterns in comparison to native tumor antibodies targeting G-protein coupled receptors (GPCRs) combined epidemiologic and experimental approach treatment options for patients suffering from an iCCA is tissue. In a recently published study, the value of decel- including the angiotensin type 1 receptor (AT1R) and should help to provide the template for future analysis surgical resection. iCCA show a high rate of intrahepatic lularized rat lung and liver tissue on the in vitro formation endothelin type A receptor (ETAR) induce severe pathol- of novel antibody candidates. Moreover, a yeast model, recurrence, which was found to be up to 60 %. For patients of colorectal metastasis has been described. We hypoth- ogies in autoimmune disease and organ transplants modified to express human AT1- or ETA-receptors, where with recurrence, primary metastatic cancer, lymph node esize that decellularized human liver tissue will promote independent of HLA recognition mechanisms (Dragun D growth is linked to receptor activation, may well serve metastasis or R1 resection, chemotherapy or local abla- the in vitro tumor formation of iCCA tumors with a better et al., N Engl J Med. 2005). My project focuses on trans- for screening of mimotopes aiming to attenuate antibody tive therapies are the remaining treatment options. preservation of tumor microenvironment, genetic muta- plant glomerulopathy as a leading chronic lesion in kid- mediated actions. Aim is to finalize screening of inde- Unfortunately, these therapeutic concepts have poor tion pattern and therefore will reflect a better clinical ney transplants responsible for chronic dysfunction and pendent cohorts with glomerular disease of native kid- response rates. Considering this there is the need to correlation for adjuvant treatments in comparison to 2D late graft loss. The mechanisms involved in development neys and transplants with our assays detecting antibod- explore new therapeutic options: In vitro models are primary culture and tumor organoids. of transplant glomerulopathy remain largely unknown. ies targeting AT1- and ETA-receptors. Functionality of essential tools to investigate tumor biology and the Significant phenotypic overlap in pathohistological antibody binding will be studied in the yeast model using effect of certain pharmaceuticals. Despite iCCA cell lines description with native kidney disease entities such as native or mutated receptors. Differences and similarities and 2D primary cell cultures gave insights into the biology membranoproliferative glomerulonephritis, thrombotic of antibody-receptor interaction should help to identify of these tumors, they have some important drawbacks microangiopathy, focal segmental glomerulosclerosis, various conformational epitopes and help explain dis- like the poor translational value due to the artificial cul- and lupus nephritis make the diagnosis difficult, yet may ease heterogeneity. ture conditions. New approaches for in vitro studies are suggest common pathophysiologic mechanisms. We the formation of 3D spheroids and organoids. Neverthe- expect to link epitope recognition with signaling and less, these approaches have also shown a selection of effector functions of two important GPCRs mediating
Mentors Mentors
Univ.-Prof. Dr. med. Marcus Bahra Univ.-Prof. Dr. med. Igor Maximilian PD Dr. med. Andreas Kahl Univ.-Prof. Dr. med. Duška Dragun † Clinical Mentor Sauer Clinical Mentor Scientific Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Surgery Charité – Universitätsmedizin Berlin Department of Nephrology and Department of Nephrology and Department of Surgery Internal Intensive Care Medicine Internal Intensive Care Medicine [email protected] [email protected] [email protected] 70 Junior Clinician Scientists Alumni J unior Clinician Scientists Alumni 71
PD Dr. med. Johannes Kahn Dr. med. Ahmed Abdelrahim Khalil
In Program From – to Fields of Research In Program From – to Fields of Research 07.2015–09.2017 › Computed Tomography 07.2019–06.2021 › Neurology › Magnetic Resonance Imaging › Radiology Contact Contact › Cerebrovascular disease [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Radiology Department of Neurology and Experimental Neurology Director Univ.-Prof. Dr. med. Bernd Hamm Director Univ.-Prof. Dr. med. Matthias Endres
Iterative Reconstruction – Dose and Quality Optimized Validation of a Non-Invasive, Automated Perfusion Computed Tomography MRI Method in Stroke Patients
Various novel technical solutions are subsumed under Cerebrovascular diseases and stroke are some of the the term of iterative reconstruction (IR). Its goal is the leading causes of morbidity and mortality worldwide. efficient reduction of image noise and radiation dose in Understanding which pathophysiological mechanisms computed tomography (CT). The objective of this project are responsible for perpetuating tissue damage in indi- is to investigate whether iterative reconstruction allows vidual patients can help clinicians make better decisions for an effective reduction of dose without having to about how to treat these patients. Much of this infor- accept a significant loss of image quality. The use of mation is, however, unavailable to clinicians in routine first-generation iterative image reconstruction tech- practice because the methods used to assess these niques (ASIR) allows for a dose reduction of about one pathophysiological phenomena are inconvenient, unre- third compared to conventional filtered back projection liable, or inaccessible. As a result, more than two-thirds (FBP) image reconstruction while maintaining image qual- of stroke patients are not eligible for crucial treatments ity. Particularly young patients who often receive mul- in the very early stages of the disease, where the benefit tiple follow-up CT exams may benefit from this reduction. of these treatments is highest. My research focuses on To define more individualized and dose optimized CT developing and validating neuroimaging techniques that examination protocols, additional patient populations are easier for clinicians to access, use, and interpret. The need to be studied. In a next step, the previous research aim is to use these techniques to provide clinicians with on radiation dose reduction and image optimization is individualized and readily interpretable information on to be continued and expanded in studies at the institute’s stroke pathophysiology using efficient and convenient own research CT. It would be a milestone in CT diagnostic methods, which could potentially improve how, and how imaging if the expected dose values in the sub-mil- many, strokes are treated. lisievert range together with a corresponding good image quality turn out to be realistic.
Mentors Mentors
Prof. Dr. med. Florian Streitparth Univ.-Prof. Dr. med. Bernd Hamm Prof. Dr. med. Jochen Fiebach Univ.-Prof. Dr. med. Andreas Meisel Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Radiology Department of Radiology Department of Neurology Department of Neurology and Experimental Neurology and Experimental Neurology [email protected] [email protected] [email protected] [email protected] 72 Junior Clinician Scientists Alumni 73
Dr. med. Roxanne Lofredi Dr. med. Agata Mossakowski
In Program From – to Fields of Research In Program From – to Fields of Research 07.2018–06.2020 › Parkinson’s Disease 07.2016–06.2018 › Intravital Microscopy and Fluorescence › Deep Brain Stimulation Lifetime Microscopy Contact Contact › Motor Control › Neuromuscular Diseases [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology Department of Neurology and Experimental Neurology and Experimental Neurology Director Director Univ.-Prof. Dr. med. Matthias Endres Univ.-Prof. Dr. med. Matthias Endres
Network Modulation of Motor Inhibition in Parkinson’s Disease Oxidative Stress in Muscle Diseases
Subthalamic deep brain stimulation (DBS) is a well-es- of PD patients with subthalamic DBS will perform ON Oxidative stress is a major factor in the progression of diagnose oxidative shifts in muscle tissue even before tablished and effective treatment option for patients and OFF stimulation, the differential effect of DBS on muscle diseases, proving to affect cellular signaling the appearance of histopathological changes. The with Parkinson’s disease (PD) leading to better motor movement termination will be quantified across patients. pathways, enzyme expression, membrane stability and method can potentially be used to monitor disease-mod- performance and quality of life. A common side effect In a second step, the patient-specific connectivity profile cellular regeneration. Conclusions about the origin of ifying therapies by directly detecting the dynamics and of dopaminergic medication consists in involuntary of DBS-electrode localization will be reconstructed and oxidative stress are currently drawn indirectly on the impact of antioxidants on the ROS production in muscle movements, so-called dyskinesia. Dyskinesia can also related to the DBS-related effect on movement termi- presence of free radicals, their oxidation products and tissue. The aim of this work is thus to establish NAD(P) be evoked by high stimulation intensities and lesioning nation. The results of this study can be integrated in a expression subunits of the enzymes involved. With the H-fluorescence lifetime microscopy, previously used in of the subthalamic nucleus (STN). Taken together, these broader goal of developing a personalized DBS with establishment of NAD(P)H-fluorescence lifetime micros- other tissues and cell types, in muscle tissue and to observations suggest a major role of the STN in motor optimal efficacy / side effects profile. With a similar copy in chronic neuroinflammation we were able to for ensure a valid transfer between intravital and ex vivo inhibition, with special emphasis on control of involun- approach, a previous study of our group was able to the first time monitor the genesis of oxidative stress measurements. We use a custom-built multiphoton laser tary movements. In this study, we will investigate the predict a »sweet spot« for DBS with best clinical outcome. intravitally, in real time and without influencing the sys- microscope with a time-correlated single photon counter neuronal network of motor inhibition in PD patients and The localization of an important motor side effect of DBS tem through staining or fixation by measuring the activity as part of the intravital microscopy network JIMI (German its modulation by subthalamic DBS. We hypothesize that would further refine this optimal stimulation spot. Given of NADPH-oxidase, the main source of reactive oxygen Rheumatism Research Center, Max Delbrück Center and subthalamic DBS facilitates the initiation of voluntary that new types of DBS electrodes allow a precise and species (Mossakowski et al, Acta Neuropathologica 2015). Hans Knoell Institute) and cooperate with Dr. rer. nat. movements while impeding their termination. This may directional current steering, this may lead to a direct Instituting NAD(P)H-fluorescence lifetime microscopy in Raluca Niesner, group leader of Biophysical Analytics at rely on the modulation of an inhibitory network between clinical benefit for patients with subthalamic DBS. muscle tissue will complement the hitherto existing the German Rheumatism Research Center. the STN and other brain regions that depends on the means of diagnostics and pathophysiological research exact connectivity profile at the DBS-electrode position. in neuromuscular disease, adding a new metabolic mon- With the help of a behavioural paradigm that a cohort itoring system that, in the long run, might be used to
Mentors Mentors
Univ.-Prof. Dr. med. Matthias Endres Univ.-Prof. Dr. med. Andrea Kühn PD Dr. med. Katrin Hahn Dr. rer. nat. Raluca Niesner Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin German Rheumatism Research Department of Neurology Department of Neurology Department of Neurology Center Berlin and Experimental Neurology and Experimental Neurology and Experimental Neurology Biophysical Analytics [email protected] [email protected] [email protected] [email protected] 74 Junior Clinician Scientists Alumni 75
Dr. med. Thilo Müller Dr. med. Yannick Palmowski
In Program From – to Fields of Research In Program From – to Fields of Research 07.2017–06.2019 › Stem Cell Transplantation 10.2019–09.2021 › Spinal surgery › Graft-Versus-Host Disease › Osteology Contact Contact › Extracellular Vesicles [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Pediatrics, Division Center for Musculoskeletal Surgery of Oncology and Hematology Director Director Univ.-Prof. Dr. med. Carsten Perka Univ.-Prof. Dr. med. Angelika Eggert
Preclinical Evaluation of Mesenchymal Stromal Cell-Derived Evaluation of the Validity of New Methods for the Assessment Exosomes for GvHD-Therapy of Bone Quality Using Vertebral Biopsies
Hematopoietic stem cell transplantation (HSCT) is cur- supernatant. Exosomes are 70-140 nm microvesicles In osteroporosis, changes in bone composition and struc- mined on the basis of vertebral body biopsies and rently the only therapeutic option for a number of malig- secreted by cells that contain a variety of biomolecules, ture result in reduced bone stability. In orthopedic sur- whether they are suitable for assessing the risk of mate- nant and nonmalignant diseases. Graft-versus-host and are thought to function as intercellular messengers. gery, such a »weak« bony bearing represents a significant rial loosening after spinal surgery. disease (GvHD) is the most common complication, mainly This project will establish a patient-derived exosome challenge intraoperatively and can have serious conse- mediated by donor T lymphocytes attacking host cells characterization pipeline that assesses biomolecular quences for affected patients due to resulting implant and causing multiorgan damage especially affecting the content via RNA sequencing (RNA-Seq) and allows func- failure. To avoid such complications, preoperative diag- skin, liver and intestines. A severe GvHD is associated tional in vitro testing via T-cell proliferation assays to nostics are necessary to allow the timely initiation of with 90% patient mortality. Steroids are the standard qualitatively and quantitatively explore the immune- adequate therapeutic measures (e.g., cement augmen- first-line therapy. Cell-based second-line therapy with modulatory potential. Furthermore, exosomes from dif- tation). However, reliable methods that allow preoper- MSCs is standard treatment for steroid-refractory GvHD ferent donors will be compared, and exosomes from ative prediction of intraoperative findings are still lacking. cases since ten years, and administering MSCs stimulates patients will be associated with their clinical course in The current clinical standard for the assessment of bone a response and improves 2-year survival in ~50% of these terms of GvHD occurrence to predict associations with quality is Dual Energy X-ray Absorptiometry (DXA), which patients. In the last years it was demonstrated that MSCs specific exosome contents. measures the mineralization density of bone using 2D do not engraft in the patients, what lead tot he specu- X-ray projections. In a previous study, we demonstrated lation that soluble factors secreted by the administered that DXA is unsuitable for assessing bone quality at the MSCs may be driving patient response. This was sup- lumbar spine. In this research project, we therefore want ported by a recent case report of one patient with ste- to examine whether the alternative methods Trabecular roid-refractory GvHD that showed substantial improve- Bone Score (TBS) or Bone Material Strength index (BMSi) ment after administration of exosome-enriched MSC reflect the actual bone quality at the lumbar spine deter-
Mentors Mentors
Univ.-Prof. Dr. med. Angelika Eggert Dr. med. Lena Oevermann Univ.-Prof. Dr. med. Carsten Perka Univ.-Prof. Dr. -ing. Georg Duda Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Julius Wolff Institute of Biomechanics Department of Pediatrics, Department of Pediatrics, Center for Musculoskeletal Surgery and Musculoskeletal Regeneration Division of Oncology and Hematology Division of Oncology and [email protected] Hematology [email protected] [email protected] 76 Junior Clinician Scientists Alumni 77
Dr. med. Livius Penter Dr. med. Lennart Pfannkuch
In Program From – to Fields of Research In Program From – to Fields of Research 07.2016–06.2018 › Hematologic malignancies, tumor 01.2018–12.2019 › Innate Immunity immunology, single cell sequencing, › Helicobacter Pylori Contact Contact clonal evolution › Signal Transduction [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Hematology, Medical Department, Division of Oncology and Cancer Immunology Infectiology and Pneumonology Director Director Univ.-Prof. Dr. med. Lars Bullinger Univ.-Prof. Dr. med. Norbert Suttorp
Immunologic Biomarkers and Therapeutic Targets Characterization of a Pro-Inflammatory Pathway in Rectal Cancer Triggered by Bacterial Sugar Molecule
Early disease and relapse detection are critical for col- will result in a phenotypic, functional, and molecular Activation of the transcription factor NF-κB is a linchpin a row of infections with gramnegative bacteria making orectal cancer prognosis. However, the reliable identi- immunology approach to the human immune system in in the initiation of an inflammatory process in cells of this a likely candidate for induction of a pro-inflammatory fication of relapse can be challenging, especially if the rectal cancer. Emerging technologies including cytometry the adaptive and innate immune response. Chronic or response in a multitude of infectious settings. Yet the suspected tumorous lesions are small in size and/or not by time-of-flight (CyTOF) and single cell next-generation inadequate activation can lead to deleterious outcomes exact function of the ALPK1 in the activation of this path- easily accessible, underlining the need for highly specific sequencing (NGS) will help to detect cancer-associated like the development of cancer. In 2015, a bacterial sugar, way is not yet understood. Aim of this project is to get and sensitive biomarkers. Most of the established tumor immune responses as a highly specific and sensitive D-glycero-beta-D-manno-heptose 1,7-bisphosphate a deeper insight in this novel-signaling axis, understand- markers are not cancer-specific and show poor sensitivity immune-biomarker. We hypothesize that unique rectal (HBP), an intermediate metabolite of LPS synthesis, was ing the way of induction and the regulatory mechanisms for relapse detection varying between 15 and 70%. There cancer-associated, clonally related T lymphocytes are identified as novel Pathogen Associated Molecular Pat- it induces and additionally deciphering how HBP is is increasing evidence that tumor-infiltrating (immune) detectable in the tumor tissue and peripheral blood of tern (PAMP) inducing NF-κB activation in epithelial cells. sensed in infected cells. Finally, with this project we want cells are critical for disease development, spreading, and patients and that their frequencies correlate with disease In a Helicobacter pylori (H. pylori) infection model we to understand the impact of ALPK1 on the outcome of patient survival and frequencies of tumor-infiltrating burden which makes them useful as immune biomarkers have recently identified a HBP triggered NF-κb activating an infection in vivo. lymphocytes (TILs) correlate with the clinical outcome for early relapse detection. Selectively expanded T cell signaling axis. We demonstrated that HBP is delivered regardless of the tumor stage. Our group could show clones and phenotypes can be quantified and possibly via H. pylori’s Type 4 Secretion System to the host cell. that colorectal cancer is infiltrated with T lymphocytes used as highly sensitive and specific cancer-associated Here ALPK1 and TIFA act as indispensable host cell factors of a highly specialized T cell receptor (TCR) repertoire markers for therapy monitoring and early relapse for the early activation of NF-κB. This renders ALPK1 a and distinct functions suggesting a tumor-driven T cell detection. central infection specific actor in activating a pro-in- reaction. Therefore, technologies for cancer (-relapse) flammatory signaling pathway. The general importance detection could significantly benefit from the inclusion of this pathway is underlined by the fact that HBP has of disease-associated immune measurements. This study already been identified as a pro-inflammatory factor in
Mentors Mentors
Prof. Dr. med. Jörg Westermann PD Dr. med. Leo Hansmann Univ.-Prof. Dr. med. Norbert Suttorp Clinical Mentor Scientific Mentor Clinical Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Hematology, Oncology Department of Hematology, Department of Infectious Diseases and Cancer Immunology Oncology and Cancer Immunology and Respiratory Medicine [email protected] [email protected] [email protected] 78 Junior Clinician Scientists Alumni 79
Dr. med. Bianca Raffaelli PD Dr. med. Bernhard Ralla
In Program From – to Fields of Research In Program From – to Fields of Research 01.2019–12.2020 › Migraine 07.2015–08.2017 › Renal Cell Carcinoma › Sex hormones Contact Contact [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology Department of Urology and Experimental Neurology Director Director Univ.-Prof. Dr. Thorsten Schlomm Univ.-Prof. Dr. med. Matthias Endres
Plasma CGRP Levels in Patients with Migraine Prediction of Primary Resistance to First-Line Treatment with and Endometriosis the Tyrosine Kinase Inhibitor Sunitinib in Renal Cell Carcinoma Specimens by MiRNA Profiles
Migraine and endometriosis are two of the most preva- neurons during attacks, the evidence for a role of CGRP The introduction of targeted therapy agents has signifi- study were (a) to identify typical microRNA profiles in lent disorders in women with a significant burden of in endometriosis pain is limited. The release of CGRP cantly improved the overall survival (OS) of patients with nephrectomy specimens from the two groups of mRCC disease, high socioeconomic costs, and a relevant impair- seems to have an impact on the neurogenic inflammatory metastatic renal cell carcinoma (mRCC). The VEGF-inhib- patients under sunitinib treatment, (b) to explore under ment of quality of life. Epidemiological studies report a reaction in this endometriosis tissue and might be also itor sunitinib (sun) is considered the standard of care high statistical power the most discriminative microRNAs solid comorbidity between migraine and endometriosis. involved in proliferation and growth of endometriotic for the first-line treatment of these patients, however, between the two patient groups as predictive biomarkers From adolescence onwards, women with endometriosis cells. Despite these findings, CGRP and CGRP-related the tumor response to this drug at first evaluation is of primary resistance and (c) to validate the data quan- have a two- to threefold higher risk of suffering from mechanisms have not been studied to date in vivo in crucial. Patients with a primary resistance inherit a poor tified by reverse transcription quantitative polymerase migraine compared to the general female population, women with endometriosis.In the current project, we overall survival. A reliable prediction of the primary chain reaction (RT-qPCR) additionally through sophisti- and vice versa, patients with migraine have a twice higher aim to analyze CGRP plasma concentrations in patients resistance to sun therapy could be helpful to avoid use- cated digital PCR technique and decision curve analysis probability to develop endometriosis. Fluctuations in with migraine and endometriosis, compared to patients less treatment trials of patients with extremely expen- in comparison to conventional clinicopathological ovarian sex hormones modulate the course of both dis- with migraine only, endometriosis only, and healthy con- sive drugs and to save time to select other therapeutic variables. eases and severe pain attacks occur often during the trols. For each group, we will compare CGRP concentra- options. So far, there has been no approved biomarker perimenstrual period. Previous research pointed to a tions during menstruation and in the intermenstrual in form of a companion diagnostic test to correctly pre- possible common etiological background for migraine period. It is our hypothesis that CGRP levels increase dict the response to targeted therapy in these patients. and endometriosis. Shared pathophysiological mecha- during menstruation with most pronounced changes In this regard, microRNAs (miRNAs, miRs) as small, nisms include impaired regulation of inflammatory sig- in women with the comorbidity of migraine and non-protein coding transcripts could be considered as naling pathways and neurotransmitters such as Calci- endometriosis. suitable biomarkers because of their important role as tonin Gene-Related Peptide (CGRP). While acute migraine posttranscriptional regu‑lators in all network processes is clearly linked to CGRP release from trigeminal afferent of carcinogenesis and metastasis. So, the aims of this
Mentors Mentors
Prof. Dr. med. Uwe Reuter, MBA PD Dr. med. Jonas Busch Prof. Dr. med. Klaus Jung Univ.-Prof. Dr. med. Kurt Miller Clinical Mentor Clinical Mentor Scientific Mentor Clinical Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology Department of Urology Department of Urology Department of Urology and Experimental Neurology [email protected] [email protected] [email protected] [email protected] 80 Junior Clinician Scientists Alumni 81
Dr. med. Lisa-Maria Rosenthal Dr. med. Maren Schmiester
In Program From – to Fields of Research In Program From – to Fields of Research 07.2017–06.2019 › Hypoplastic Left Heart Syndrome 01.2019–03.2021 › Lymphoma › Genetics of Congenital Heart Disease › Host‑Microbiota Interactions Contact Contact › Flow Cytometry [email protected] [email protected] Clinic Clinic German Heart Center Berlin Charité – Universitätsmedizin Berlin Department of Congenital Heart Disease Department of Hematology, Pediatric Cardiology Oncology and Cancer Immunology Director Director Univ.-Prof. Dr. med. Felix Berger Univ.-Prof. Dr. med. Lars Bullinger
Genetic Analysis and Risk for Cardiac Malformations in Families Analysis of the Interdependence Between the Intestinal Microbiota, with Hypoplastic Left Heart Syndrome Lymphoma Disease and Therapeutic Immunochemotherapy
The Hypoplastic Left Heart Syndrome (HLHS) is a rarecon- children with HLHS and their relatives are phenotypically Constant crosstalk between immune cells and the intes- dependence. We plan to address the possible link genital heart defect, where the structures of the left and genetically characterized, we hope to identify new tinal microbiota at the level of the gut allows for a sym- between lymphoma disease and the intestinal microbiota heart and the aortic arch are severely hypoplastic. With- genetic variants and recapitulate cardiac maldevelop- biotic tolerance, modulates local immunity and impacts by analysing the microbial composition of healthy sub- out surgical treatment, term infants die within the first ment of HLHS. We expect that the identification of genetic innate and adaptive immune response. While the immune jects and lymphoma patients at the point of diagnosis days of life. With a three-stage palliative surgical pro- underpinnings will result in better understanding of HLHS system has long been recognized as a major factor in and longitudinally during immunochemotherapy. To do cedure creating a circulatory system with a single ven- and lead to new approaches in the care of HLHS patients cancer control, there is recent mounting evidence sup- so, we will establish a flow cytometric-based approach tricle, newborns with HLHS can survive today. Neverthe- and their families. porting the influence of the microbiota on both carcino- for human samples, perform segregated analyses of cell less, long-term prognosis for patients with HLHS is dis- genesis and on the response to immunochemotherapy abundances in microbial subcommunities and examine appointing, only 50%-70% of newborns surive to age 5 across various forms of malignant disease. Vice versa, their dynamic changes. To validate our findings, we will years and survival is associated with significant long- immunochemotherapy is known to disrupt microbial also employ the gold standard for microbiota profiling, term morbidity. Several observations support a genetic homeostasis and thereby contribute to therapy-related 16s ribosomal DNA sequencing. The analyses are embed- cause for HLHS, as it occurs in children with chromosomal complications such as bloodstream infections. Malignant ded in a comprehensive immune monitoring algorithm, abnormalitis and syndromal diseases and seems to have lymphoma is innately linked to the immune system: it allowing us to integrate various patient and tumor param- a strong familiar clustering with an increased prevalence arises from lymphoid cells and its progression is char- eters. Correlations with clinical and laboratory param- of CHD in families with HLHS. The identification of specific acterized by numerous mechanisms of immune escape. eters (e.g. incidence, duration and type of infections, genetic variants has been difficult because of the com- The close physical contact of circulating lymphoid cells treatment response, blood counts) will be performed to plex inheritance and the low prevalence of HLHS. With and the microbiota within the intestinal immune system determine the impact of the microbiota on the clinical new technological and analytical approaches and the and their bidirectional relationship is highly suggestive outcome of lymphoma patients. establishment of a Family-Screening Programm, where of a complex and thus far insufficiently examined inter-
Mentors Mentors
Prof. Dr. med. Katharina Schmitt Univ.-Prof. Dr. med. Silke Rickert-Sperling Univ.-Prof. Dr. med. Il-Kang Na Univ.-Prof. Dr. med. Il-Kang Na Clinical Mentor Scientific Mentor Clinical Mentor Clinical Mentor German Heart Center Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin, Department of Congenital Heart and Max Delbrück Center Department of Hematology, Oncology Department of Hematology, Oncology Disease for Molecular Medicine Berlin and Cancer Immunology and Cancer Immunology Pediatric Cardiology Experimental and Clinical Research Center [email protected] [email protected] [email protected] [email protected] 82 Junior Clinician Scientists Alumni 83
Dr. med. Jens Schrezenmeier Dr. med. Stefanie Schulte
In Program From – to Fields of Research In Program From – to Fields of Research 07.2019–06.2021 › Long-read sequencing 09.2018–11.2020 › Neuroblastoma › Genomics › MicroRNAs in Tumor Biology Contact Contact › Hematologic Malignancies › Targeted Cancer Therapy/Survivin [email protected] [email protected] › Molecular Diagnostics Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Hematology, Department of Pediatrics, Oncology and Cancer Immunology Division of Oncology and Hematology Director Director Univ.-Prof. Dr. med. Lars Bullinger Univ.-Prof. Dr. med. Angelika Eggert
Improved Molecular AML Diagnostics-Prerequisite Targeting Survivin in Neuroblastoma for Individualized Patient Management
Genetics and cytogenetics play a pivotal role in diagnosis Neuroblastoma is the most common extracranial solid grafts with the Survivin inhibitor YM-155 resulted in cell and treatment of acute myeloid leukemia (AML) but also tumor of childhood, accounting for approximately 20% death and tumor regression. However, more recent stud- other malignancies such as Lung Cancer and Multiple of all childhood cancer deaths. The relapse rate of high- ies revealed YM-155 treatment to result in unspecific DNA Myeloma. Improvements in AML genetic diagnostics are risk neuroblastoma exceeds >50% despite most intensive damage and other unspecific effects rather than specific a prerequisite for individualized patient management. multimodal treatment, and relapsed neuroblastoma is inhibition of Survivin. In the current project we (a) analyze Yet, current second generation sequencing methods are almost always fatal. Therefore, new treatment strategies the contribution of Survivin to neuroblastoma patho- hard to implement into daily clinical routine with regard for high-risk neuroblastoma are an urgent, but still unmet genesis and metastasis, (b) assess the specific functions to the application of rapid cytogenetics and methylation medical need. The most common genomic alterations in of Survivin in neuroblastoma, and (c) model specific profiling. To address these clinical needs in AML and high-risk neuroblastoma comprise amplification of the strategies to inhibit Survivin. other malignancies we will use third generation long-read MYCN oncogene (in approx. 40% of all cases) and gain (Nanopore) sequencing that allows to directly read infor- of chromosome 17q (in >60% of all cases). The oncogene mation from the nucleic acid strand enabling rapid BIRC5 (encoding the protein Survivin) is located on chro- high-resolution karyotyping and access to DNA and RNA mosome 17q, upregulated by MYCN, and was found to be modification information that was out-of-reach in molec- strongly overexpressed in high-risk neuroblastoma. Sur- ular diagnostics. Access to this new dimension of molec- vivin is involved in suppression of apoptosis, mitosis, ular information will lead to a better understanding of cell cycle, metabolism, invasion and several other key disease biology and improve treatment approaches. cellular functions. Knock-down of Survivin in neuroblas- toma cell lines resulted in cell death. Treatment of neu- roblastoma cell lines or mice with neuroblastoma xeno-
Mentors Mentors
Prof. Dr. med. Jörg Westermann Univ.-Prof. Dr. med. Lars Bullinger Univ.-Prof. Dr. med. Angelika Eggert PD Dr. med. Patrick Hundsdörfer Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Hematology, Oncology Department of Hematology, Oncology and Department of Pediatrics, Department of Pediatrics, and Cancer Immunology Cancer Immunology Division of Oncology and Hematology Division of Oncology and Hematology [email protected] [email protected] [email protected] [email protected] 84 Junior Clinician Scientists Alumni 85
Dr. med. Emanuel Schulz Dr. med. Vera Seidel
In Program From – to Fields of Research In Program From – to Fields of Research 07.2016–06.2018 › Gastrointestinal inflammation 07.2016–06.2018 › Maternity care for migrant women in › Epithelial barrier Berlin – perceptions of health care Contact Contact › Intestinal pathogens professionals and patients [email protected] [email protected] › Public health Clinic Clinic › Migrant care Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin › Infectious diseases Medical Department, Department of Obstetrics › Violence against staff Division of Gastroenterology, Director Infectiology and Rheumatology Univ.-Prof. Dr. med. Wolfgang Henrich Director Univ.-Prof. Dr. med. Britta Siegmund
Epithelial Polarity and Intestinal Inflammation Maternity Care for Migrant Women in Berlin – Perceptions of Health Care Professionals and Patients
Phosphatidylinositol phopsphates (PtdInsP) sum up for scope. Using life cell imaging technique, changes in Berlin is a multicultural city and recently migration num- and experiences of medical personnel and migrant just a small percentage of the lipids in the plasma mem- PtdIns(4,5)P2-distribution could be observed in the bers are further increasing. Studies in Berlin have shown women especially in the context of limited German-pro- brane in epithelial cells. Yet, as a source important sec- course of cell infection with bacterial pathogens. In a that communication problems are the principal source ficiency during labor to inform policy and clinical practice. ond messengers they are key substrates in multiple screening with various intestinal pathogens we identified of doctor’s dissatisfaction in doctor-patient encounters A quantitative survey and a qualitative design using membrane functions, e.g. endocytosis, exocytosis, an Escherichia coli exotoxin that induces a delocalization in emergency departments (Babitsch et al. 2008). Low grounded theory methodology are currently in progress. enzyme activation and actin skeleton organization, to of the PtdIns(4,5)P2-signal from the plasma membrane. German-proficiency correlates with less frequent use of In a second step, an intervention study is planned to name but a few. Their asymmetric distribution on the Barrier analyses on confluent polarized PLC-delta-PH- antenatal care (Brenne et al. 2015) and dissatisfaction improve the obstetric care for migrant women with the inner leaflet of the plasma membrane is crucial for cell GFP-transfected Caco2-monolayers revealed simultane- with inpatient hospital care on the side of migrant women targeted use of modern communication technology. homeostasis and differentiation. An essential enzyme ously occurring barrier defects of the epithelium. Our (Borde et al. 2002). Migrant women have higher rates of in the PtdInsP metabolism is Phosphatase and Tensin goal is to gain further insight into the underlying mech- overweight (Reiss et al. 2015) and anemia, less frequently homolog (PTEN). It dephosphorylates PtdIns(3,4,5)P3, anisms and depict the cellular structures which are receive peridural anesthesia during birth (David et al. thereby suppressing Akt/PKB activation. PTEN localizes involved in the toxin-induced perturbation of the epi- 2006) and their crash cesarean section rates are higher in the apical membrane during epithelial morphogenesis thelial barrier. (David et al. 2015). Migrant women in Australia have a and polarization and leads to apical enrichment of less satisfying birth experience (Small et al. 2002). PtdIns(4,5)P2. In our study we developed a transfection Migrant women from third world countries in Sweden model of intestinal Caco2 cells with a GFP-linked have higher levels of stress in the first year after birth PtdIns(4,5)P2-binding domain (PLC-delta-PH-GFP). (Fabian et al. 2008). Causative factors for these disparities Thereby we are able display the PtdIns(4,5)P2- distribu- need to be identified in order to design targeted inter- tion among the cells with a focal laser scanning micro- ventions. This study aims at exploring the perceptions
Mentors Mentors
Dr. med. Michael Schumann PD Dr. rer. nat. Roland Bücker Univ.-Prof. Dr. med. Wolfgang Henrich Prof. Dr. Matthias David Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Medical Department, Department of Clinical Physiology, Department of Obstetrics Department of Gynecology Division of Gastroenterology, Division of Gastroenterology, [email protected] [email protected] Infectiology and Rheumatology Infectiology and Rheumatology [email protected] [email protected] 86 Junior Clinician Scientists Alumni 87
Dr. med. Jonas J. Staudacher Dr. med. Heiner Stuke
In Program From – to Fields of Research In Program From – to Fields of Research 07.2017–07.2019 › TGF-Beta Superfamily Signaling 01.2019–12.2020 › Schizophrenia › Pancreatitis › Dopamine Contact Contact › Gastrointestinal Cancer › Functional MRI [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Medical Department, Department of Psychiatry and Division of Gastroenterology, Neurosciences Infectiology and Rheumatology Director Director Univ.-Prof. Dr. med. Dr. phil. Andreas Heinz Univ.-Prof. Dr. med. Britta Siegmund
Activin as Novel Risk Stratifying Marker in Acute Pancreatitis The Role of Dopamine in Psychosis-Related Perceptual Aberrations
Acute pancreatitis, the sterile inflammation of the pan- reduced mortality significantly (Staudacher et al. Scien- Paranoid schizophrenia is a serious mental illness with sensory noise. Hence, a reduced ability to differentiate creas, is one of the most common gastroenterological tific Reports 2017). We are now investigating activin in a poorly understood etiology. Although acoustic halluci- between signal and noise and an increased tendency to causes for hospitalization today. Currently clinical man- prospective clinical cohort of acute pancreatitis and nations are the classic leading symptom of schizophrenia, interpret noise as a meaningful signal can result in a agement is restricted to pain medication, intravenous evaluating its potential as a clinical marker. Additionally, changes in visual perception are also typically found, tendency to hallucinations. A number of empirical studies rehydration and initial bowel rest. In about 15 percent to delineate activin’s mechanism of action in acute pan- the potential of which as a diagnostic marker could be confirm, especially in the domain of acoustic perception, of cases, severe acute pancreatitis with persistent organ creatitis, we are examining its function on immune cells, underestimated. It is believed that these symptoms are an increased perception of signal in noise in people with failure develops, which is accompanied with considerable namely neutrophils and macrophages, the dominant associated (among other things) with excessive dopa- psychosis, psychosis proneness or isolated hallucinosis. morbidity and mortality. To date, no treatment besides inflammatory cells in acute pancreatitis. minergic neurotransmission. A cognitive mechanism that The neurophysiological aberrations leading to such an aggressive early hydration therapy has been shown to has been related to the development of hallucinations increased perception of meaning in noise are largely reduce pancreatitis-induced mortality, and clinical mark- is an increased willingness to perceive significant struc- unexplained. This concerns both the aspect of the ers to stratify patients for their risk of developing severe tures in noisy sensory signals. The background to this involved neurotransmitter systems as well as the func- acute pancreatitis are missing. We are investigating novel consideration is the knowledge of perception research tionally affected brain areas. The present study aims to biomarkers and therapeutic possibilities for this clinical that the subjectively experienced clear perception is the contribute to closing this gap by firstly examining the challenge. Previously, we were investigating the role of result of a calculation process that uses probabilities, specific effect of a dopamine-enhancing drug modulation activin, a central immune modulatory cytokine and TGF- context information and signals from other sensory compared with placebo in healthy volunteers and sec- beta superfamily member. We were able to demonstrate modalities in order to generate reliable statements about ondly the involvement of specific brain areas through that in vivo, activin serum levels are specifically elevated the environment from an extremely noisy sensory signal. functional MRI during an face detection task. in acute severe pancreatitis but not mild acute pancre- A constant challenge in this calculation process is the atitis, and furthermore that the inhibition of activin distinction between really significant signals and pure
Mentors Mentors
Univ.-Prof. Dr. med. Britta Siegmund Dr. rer. nat. Rainer Glauben Prof. Dr. med. Felix Bermpohl Univ.-Prof. Dr. med. Philipp Sterzer Clinical Mentor Scientific Mentor Clinical Mentor Clinical Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Medical Department, Medical Department, Department of Psychiatry and Department of Psychiatry and Division of Gastroenterology, Division of Gastroenterology, Neurosciences Neurosciences Infectiology and Rheumatology Infectiology and Rheumatology [email protected] [email protected] [email protected] [email protected] 88 Junior Clinician Scientists Alumni 89
Dr. med. Dorothea Theilig Dr. med. Hannah Woopen, MSc
In Program From – to Fields of Research In Program From – to Fields of Research 01.2016–12.2017 › Chronic Obstructive Pulmonary 07.2015–05.2018 › Longterm Survival with Ovarian Cancer Disease › Polypharmacy in Ovarian Cancer Contact Contact › Endoscopic Lung Volume Reduction › Supportive Care in Ovarian Cancer [email protected] [email protected] › Quantitative CT Scan Analysis Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Radiology Department of Gynecology Director Director Univ.-Prof. Dr. med. Bernd Hamm Univ.-Prof. Dr. med. Jalid Sehouli
Evaluation and Optimisation of Endoscopic Lung Volume Caroline Meets HANNA – Holistic Analysis of Longterm- Reduction Therapy in Patients with Pulmonary Emphysema Survivors with Ovarian Cancer by Means of Quantitative Lung Parenchyma Analysis
Chronic obstructive pulmonary disease (COPD), which is Factors that influence the outcome of ELVR are sought Ovarian cancer is the leading cause of mortality of all of this study: Mrs. Caroline Masur, who was diagnosed often accompanied by emphysema in its final stages, is after as well as selection criteria for the targeted lobe. gynecological cancers. Despite radical surgery followed with ovarian carcinoma more than ten years ago and still one of the leading causes of death worldwide. Air trap- Already established factors that have an impact on the by adjuvant platinum-based chemotherapy 75-80% of experienced no relapse. As well as on Hanna, a Catholic ping in the alveoli causes permanent enlargement of the outcome of ELVR are emphysema heterogeneity and col- patients relapse within the first years after chemotherapy nun, who survived the disease despite a relapse for more airspaces distal to the terminal bronchioles thereby lateral ventilation of the targeted lobe. How to determine and die from the disease. However, there is a rare patient than eight years. More information can be found at: www. decreasing the surface area for gas exchange. Overall these factors in the best possible way in clinical routine group who survives longer than eight years after initial carolinmeetshanna.com increased lung volume, in turn, leads to impaired breath- will also be part of this research project. diagnosis, sometimes even despite several recurrences ing mechanics furthering the problem. A more recent of the disease. Typical prognostic factors such as age, therapeutic approach to severe COPD with emphysema FIGO stage, and tumor residuals after cytoreductive sur- is endoscopic lung volume reduction (ELVR) therapy. ELVR gery cannot completely explain this phenomenon. The works by inducing atelectasis in one lobe thereby allow- aim of this study is to identify factors that are unique in ing the rest of the lung to expand and breathing mechan- longterm-survivors regarding tumor biology, immuno- ics to be somewhat restored. The aim of this project is logical features, resilience and clinical factors such as to improve the understanding of pulmonary emphysema comedication, polypharmacy, and comorbidities. Fur- and to evaluate and optimize ELVR therapy. To this end, thermore, we are investigating lifestyle factors such as we will make use of the software MeVisPULMO 3D (Fraun- nutrition, physical activity, and sleep quality. Our results hofer MEVIS, Bremen, Germany), which allows quantifi- shall have an impact on survival of our ovarian cancer cation of emphysematous lung parenchyma and semi-au- patients – also by factors that patients can modify by tomatic lung lobe segmentation of CT scans of the lung. themselves. The project name is based on the patrons
Mentors Mentors
Univ.-Prof. Dr. med. Bernd Hamm PD Dr. med. Ralf-Harto Hübner Univ.-Prof. Dr. med. Jalid Sehouli Univ.-Prof. Dr. med. Elena Braicu, MSc Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Radiology Medical Department, Department of Gynecology Department of Gynecology Division of Infectiology and [email protected] [email protected] [email protected] Pneumonology [email protected] 90 Junior Clinician Scientists Alumni Clinician Scientists
Dr. med. Felix Zirngibl
In Program From – to Fields of Research 07.2017–06.2019 › Neuroblastoma › Immunooncology Contact › Bispecific Trifunctional Antibodies [email protected] Clinic Charité – Universitätsmedizin Berlin Department of Pediatrics, Division of Oncology and Hematology Director Clinician Univ.-Prof. Dr. med. Angelika Eggert Scientists
Functional and Therapeutic Evaluation of a Trifunctional Bispecific Antibody Against Neuroblastoma
Neuroblastoma is the most common solid tumor of child- nant melanoma. Tumor cells can circumvent the host hood. Approximately 50% of all children initially present immune system by expressing surface proteins that with a high-risk disease, for which therapeutic options interact with T cells, which immune checkpoint inhibitors are extremely aggressive and have limited cure rates. Of block, to avert this escape mechanism. Through combin- the high-risk patients treated in Germany between 1990 ing trifunctional bispecific antibodies with checkpoint and 2007, 56% relapsed. Only very limited therapeutic inhibitors, we aim to both enhance the direct cytotoxic options exist for relapsed neuroblastoma, and 5-year effect and achieve tumor vaccination. The proposed survival is < 10% in patients. New therapeutic options project will preclinically evaluate (i) the efficacy of tri- are needed to improve cure rates for patients with refrac- functional bispecific antibodies directed against the tory or relapsed neuroblastoma. Immunotherapies with neuroblastoma-specific marker, GD2, in vitro and in vivo monoclonal antibodies are gaining more importance for and (ii) the effectiveness of combining this type of immu- oncology. Treatment with the ch14.18 antibody was notherapy with checkpoint inhibitors. These necessary recently reported to improve 2-year survival in patients preclinical data will help develop a trial protocol for with high-risk neuroblastoma by 20%. Trifunctional patients with refractory or relapsed neuroblastoma. Our bispecific antibodies destroy tumor cells and prevent long-term aim is to improve survival of children diag- relapse by combining direct tumor lysis via simultaneous nosed with high-risk neuroblastoma. tumor and effector cell binding with a long-term vacci- nation. A trifunctional bispecific antibody has shown promising preclinical results in mouse models for malig-
Mentors
Univ.-Prof. Dr. med. Angelika Eggert PD Dr. med. Annette Künkele Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Pediatrics, Department of Pediatrics, Division of Oncology and Hematology Division of Oncology and Hematology [email protected] [email protected] 92 Clinician Scientists 93
PD Dr. med. Lisa Christine Adams Dr. med. Alessio Alogna, PhD
In Program From – to Fields of Research In Program From – to Fields of Research 07.2017–06.2022 › Experimental research 08.2019-07.2022 › Heart Failure › Molecular imaging › Hemodynamics Contact Contact › Quantitative MR imaging › Nanotechnologies [email protected] [email protected] › Deep learning with focus on radiology Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Radiology Department of Cardiology Director Director Univ.-Prof. Dr. med. Bernd Hamm Univ. Prof. Dr. med. Burkert Pieske
MR-Based Assessment of Aortic Aneurysms with Molecular Probes Inhalable Nanoparticle Formulations Targeting the Heart Targeted at the Extracellular Matrix
Rupture of an abdominal aortic aneurysm (AAA) is one oxide particles to assess rupture risk in a longitudinal Heart failure is defined as the inability of the left ventricle vide a preclinical proof-of-concept for a non-invasive of the most common causes of sudden death and is asso- setup in a murine model of AAA. Here, we found that to meet body’s demand at physiological filling pressures. (via inhalation) nanoparticle-based delivery of thera- ciated with a high mortality. Currently, there are only combining the information from collagen-related ECM Approximately 15 million Europeans and 6 million Amer- peutic biomolecules to the diseased heart. invasive treatment options with substantial peri-proce- remodeling and inflammatory activity was the most accu- icans suffer from HF, with annual direct and indirect costs dural risks. It is therefore desirable to reduce the number rate predictor for AAA rupture (sensitivity 80%, specificity in the billions. The prevalence of HF is about 1-2% in the of unnecessary procedures, but to date there are no 100%, area under the curve 0.85), being superior to infor- adult population in western countries, and, given the established biomarkers available, which would allow for mation from the individual probes alone. Based on a aging of the population, epidemiologists already in the a differentiation between rupture-prone and stable AAA. fully synthetic method, we are currently designing a new early 90s predicted an exponential increase of HF inci- As an AAA results from a weakness of the aortic wall, novel small-molecular-weight peptide targeted against dence and prevalence in the upcoming decades. However, investigating the extracellular matrix as the major struc- the metalloprotease ADAMTS-4, which was found to be in spite of all medical efforts, the 5-year mortality of tural component of the aortic wall is a promising approach strongly upregulated in unstable AAA. Consequently, our heart failure was decreased significantly less than that to identify early biomarkers of rupture-prone AAA. There novel ADAMTS-4-specific probe might enable a non-in- of malignant diseases. In fact, the day-to- day manage- are two main causes for weakness of the aortic wall: vasive differentiation between rupture-prone and stable ment of individual end-stage patients is still challenging First, the degradation of extracellular matrix proteins, AAA. The future goal for clinical implementation is that with only short-term benefits, and heart transplantation such as elastin or collagen, which provide tensile strength clinicians will be able to monitor individual AAA devel- is available only to a minority of patients. Altogether, to the wall, enabling it to resist intraluminal hemody- opment with targeted molecular probes to reliably assess this situation highlights the urgent need to overcome namic forces. And second, proinflammatory cells (e.g. rupture risk and provide personalized treatment. the difficulties associated with the use of conventional macrophages), which play an important role in the ini- pharmacological therapies (i.e. drug instability, ham- tiation of AAA and the degradation of extracellular matrix pered efficacy and collateral side effects due to unspecific proteins. Since these molecular changes can be visualized tissue targeting, invasive drug administration in end- by in vivo magnetic resonance imaging, we investigated stage disease) by developing novel groundbreaking ther- several multi-target approaches, including a combination apeutic strategies that go far beyond any current con- of collagen type I-specific probes with very small iron ventional medical approach. Aim of this study is to pro-
Mentors Mentors
Univ.-Prof. Dr. med. Bernd Hamm Univ.-Prof. Dr. med. Marcus Makowski Univ.-Prof. Dr. med. Burkert Pieske PD Dr. med. Heiner Post Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Radiology Department of Radiology Department of Cardiology Department of Cardiology [email protected] [email protected] [email protected] [email protected] 94 Clinician Scientists 95
Dr. med. Timo Alexander Auer Dr. med. Magdalena Balcerek
In Program From – to Fields of Research In Program From – to Fields of Research 01.2021–12.2023 › Multimodal liver imaging 03.2018–04.2023 › Paediatric Oncology and Haematology › Interventional therapy of liver tumors › Fertility Impairment Contact Contact › MR imaging of glioma › Quality of Life [email protected] [email protected] › Risk factors Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Anesthesiology Department of Pediatrics, and Operative Intensive Care Medicine Division of Oncology and Hematology Director Director Univ.-Prof. Dr. med. Bernd Hamm Univ.-Prof. Dr. med. Angelika Eggert Univ.-Prof. Dr. med. Ulrich Bick
MRI Morphologic Noninvasive Subclassification of FeCt Hematology, Fertility in Patients with Hematologic Diseases Hepatocellular Carcinomas – The »HepCasT«-Study
Hepatocellular carcinomas (HCCs) are a heterogeneous ing with the new HCC-subtypes, helping to classify them Diseases causing chronic anaemia require constant mon- of diagnosis) and data on pubertal development, preg- group of tumor subtypes with a different response behav- noninvasively. As a next step with the help of our col- itoring and treatment to avoid potentially life-threaten- nancies and births as well as clinical and laboratory find- ior and prognosis. As a reaction, the World Health Orga- laborators we will facilitate a radiological-pathological ing complications. Improvements in medical treatment ings, results of fertility testing and therapy data will be nization (WHO) in its 5th version (updated in 2019) clas- reference database. In a third step and with the help of in recent years has notably raised patient prognosis. collected from patient files/ data bases for data analyses. sifies no more two but eight subtypes, each with a dif- the data we curated we will try to identify morphologic Therefore, long-term consequences of the underlying Findings will be distributed to the disease- and treat- ferent tumor biology and outcome. The new classification imaging characteristics by the use of AI-based post-pro- disease and/or the necessary treatments as well as qual- ment-specific registries and working groups. Project may serve as a key factor optimizing a more personalized cessing algorithms to classify the subtypes noninvasively ity of life of those affected are of increasing relevance. output will help to (1) improve therapeutic strategies to therapeutic approach and therefore, especially diagnos- and to predict / estimate patients individual therapy A key aspect of high quality of life is successful family reduce adverse late effects, (2) assist therapists and tic disciplines have to implement these new subtypes response and prognosis. The last challenge will be to planning. However, patients with different anaemia may patients in optimizing family planning and (3) determine as soon as possible into their daily clinical routine algo- implement these algorithms into daily clinical routine, suffer from fertility impairment. FeCt-HAEMATOLOGY timing and choice of fertility-preserving measures and/ rithms. Imaging does play a key role in this situation. we therefore have to identify interface dilemmas and aims to identify prevalences, disease and therapy-related or reproductive therapies. Newer and advanced MRI techniques allow a precise present smart solutions to solve them. We are convinced risk factors and dynamics of fertility impairment in ado- tissue characterization. Furthermore, with the help of that by implementing the updated WHO-criteria into lescents and adults with different anaemia as well as latest generation hepatobiliary contrast agents it is pos- clinical workflows current believes and guidelines in the the psycho-social relevance of successful family planning sible to quantify and measure the organ function and diagnosis and therapy of HCC will change. The results of for those affected. The study will be conducted as a specific uptake behavior of focal liver lesions. Another our project may provide the knowledge to represent as multicentre retro- and prospective study in cooperation approach that hold promise for advancing the charac- a cornerstone in imaging and therapy assessment of HCC with disease-specific registries and working groups in terization of HCCs heterogeneity is the use and devel- to improve a personalized therapy approach. centres for paediatric and internal medicine in Germany, opment of artificial intelligence (AI)-based image post- Austria and Switzerland. The psycho-social relevance of processing algorithms including radiomics analysis. To successful family planning, patient education and utili- date there aren’t any established imaging features cor- zation of fertility preservation will be assessed with the relating with any of the new WHO HCC-subtypes. The goal help of a patient questionnaire. Medical data, such as of our project is to identify imaging biomarkers correlat- patient core data (sex, date of birth, diagnosis and date
Mentors Mentors
Prof. Dr. med. Wenzel Schöning PD Dr. med. Dominik Geisel Univ.-Prof. Dr. med. Angelika Eggert Prof. Dr. med. Anja Borgmann-Staudt Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Surgery Department of Radiology (including Department of Pediatrics, Department of Pediatrics, Pediatric Radiology) Division of Oncology and Hematology Division of Oncology and Hematology [email protected] [email protected] [email protected] [email protected] 96 Clinician Scientists 97
Dr. med. Frederik Bartels Dr. med. Sabine Bélard, PhD, DTM&H
In Program From – to Fields of Research In Program From – to Fields of Research 01.2021–12.2023 › Autoimmune Encephalitis 01.2015–11.2021 › Tuberculosis › Neuroimmunology › Infectious Diseases Contact Contact › Neuroimaging › Tropical Medicine [email protected] [email protected] › Point-of-care Ultrasound Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology Department of Pediatric Respiratory Medicine, and Experimental Neurology Immunology and Critical Care Medicine Director Director Univ.-Prof. Dr. med. Matthias Endres Univ.-Prof. Dr. med. Marcus A Mall
Longitudinal Structural Brain MRI Analysis and Cognitive Sonographic Point-of-Care Diagnostics for Tuberculosis Outcome in Anti-NMDA-Receptor Encephalitis
Anti-NMDA receptor encephalitis (NMDARE) is the most classification of these MRI changes and in particular their Tuberculosis, declared a global public health emergency attractive for children in low-resource settings where common form of autoimmune encephalitis, a group of clinical relevance remains unclear. The aim of this project by the World Health Organization in 1993, remains a major other imaging is limited but can also contribute to a recently identified autoantibody-associated inflamma- is, therefore, to systematically investigate i) the longi- global health concern despite worldwide efforts to timely diagnosis and a better delineation of TB disease tory brain disorders. It mainly affects young women and tudinal structural brain damage using advanced quan- increase tuberculosis control and reduce morbidity and in affluent settings. The aim of this work is to better children but can occur at any age. The clinical course is titative MRI techniques and ii) assess its role as a possible mortality. Children are particularly vulnerable to develop define and refine the diagnostic value of TB-focused usually monophasic with severe neurological and neu- correlate and predictor for persistent clinical and cog- tuberculosis disease and are at higher risk of severe and point-of-care ultrasound protocols and develop diag- ropsychiatric symptoms. Most patients have a good out- nitive long-term deficits in NMDARE patients. The detailed disseminated manifestations of tuberculosis. Tubercu- nostic algorithms for integration of TB-focused point- come based on physical disability after 24 months. How- MRI analyzes combined with specific assessments of losis is difficult to diagnose because clinical presentation of-care ultrasound in routine care in settings with dif- ever, recent studies and observations from clinical prac- neuropsychological and clinical outcome will help to is nonspecific, and microbiologic confirmation is only ferent TB endemicity. tice show considerable cognitive deficits after the acute better understand the disease mechanisms and long- achieved in a minority of children. Imaging therefore phase. The long-term outcome and course of these term effects of this autoimmune brain disease. Overall, plays an important diagnostic role. However, current cognitive deficits as well as the underlying mechanisms the project will thus contribute to increase diagnostic imaging tools are limited by sensitivity and specificity, are still unknown and have not been systematically inves- accuracy and identify more personalized therapeutic and in resource-constrained settings access to basic tigated. Interestingly, structural brain damage visualized strategies in order to improve long-term outcome and imaging is low. Pilot work from TB endemic settings on routine cerebral magnetic resonance imaging (MRI) help regain full cognitive performance and quality of life showed a promising role of standardized ultrasound has only been identified in around 50% of patients, in these mostly young patients. examinations within the diagnostic TB work-up and also despite a severe clinical course in most cases. Previous for monitoring treatment response. Point-of-care ultra- studies indicate that the presence of MRI changes cor- sound protocols focusing on the detection of pulmonary, relates with a worse outcome. However, a systematic extra-pulmonary, and mediastinal TB are particularly
Mentors Mentors
Prof. Dr. med. Christoph Ploner Prof. Dr. med. Carsten Finke Prof. Dr. med. Horst von Bernuth Prof. Dr. Dr. h.c. Stefan H.E. Kaufmann Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Max Planck Institute for Infection Department of Neurology Department of Neurology Department of Pediatric Respiratory Biology and Experimental Neurology and Experimental Neurology Medicine, Immunology and Critical [email protected] Care Medicine [email protected] [email protected] [email protected] 98 Clinician Scientists 99
Dr. med. Tim Bastian Brämswig Dr. med. Leon Alexander Danyel
In Program From – to Fields of Research In Program From – to Fields of Research 01.2021–02.2023 › Stroke 01.2021–12.2023 › Neurovascular disorders › Cerebral Small Vessel Disease › Diffusion-weighted imaging Contact Contact › Cerebral Imaging › Ocular vascular occlusive disorders [email protected] [email protected] › Central retinal artery occlusion Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology Department of Neurology and Experimental Neurology and Experimental Neurology Director Director Univ.-Prof. Dr. med. Matthias Endres Univ.-Prof. Dr. med. Matthias Endres
Sonolysis in Prevention of Silent Brain Infarction During Retinal Diffusion-Weighted Imaging in Central Transcatheter Mitral Valve Repair with The MitraClip-System Retinal Artery Occlusion
Silent cerebrovascular disease is the most commonly Clip-System. Cerebral microbleeds (CMB) are a common Central retinal artery occlusion (CRAO) constitutes a detected incidental finding on brain imaging. Although incidental finding when using blood-sensitive MRI, par- medical emergency as it leads to persistent and debili- called silent, these brain lesions are associated with ticularly in patients with cerebrovascular diseases. tating visual impairment of the affected eye. As the subtle deficits (e.g. cognitive and motor deficits, gait (Braemswig et al., 2019) Here, we examine the occurrence chance for visual recovery decreases with the duration impairment, impairments in activities of living). Further- of new CMBs in specific patient cohorts and their impact of retinal ischemia, therapeutics to achieve retinal reper- more, risk of future overt strokes and dementia is on subsequent cerebrovascular events. fusion have to be administered as early as possible. We increased in patients with silent cerebrovascular disease. recently identified retinal diffusion restrictions (RDR) as (Smith et al., 2017)This project focuses on two cardinal a frequent finding in CRAO patients on standard brain manifestations of silent cerebrovascular disease: Covert diffusion-weighted magnetic resonance imaging (DWI brain infarction and cerebral microbleeds.Ischemic brain MRI). Our research aims to further investigate RDR and lesions without a matching clinical syndrome are their utility for early diagnosis in CRAO with a series of described as covert brain infarction. Covert brain infarc- retrospective and prospective clinical trials. Our main tion occurs frequently after an overt stroke (Braemswig focus lies on the application of novel DWI sequence tech- et al., 2013, 2017 & 2018) and during surgery / transcath- niques, such as readout-segmented DWI and small field- eter cardiovascular interventions. In cooperation with of-view DWI to improve the detection of diffusion restric- the Department of Cardiology, we examine whether intra- tions in retinal ischemia. Finally, we hope to further operative sonolysis (continuous transcranial Doppler expand the application of retinal diffusion-weighted monitoring) reduces the risk of covert brain infarction imaging as a diagnostic modality to other ocular vascular during transcatheter mitral valve repair with the Mitra- occlusive diseases.
Mentors Mentors
Univ.-Prof. Dr. med. Matthias Endres Prof. Dr. med. Christian Nolte Prof. Dr. med. Christoph Ploner PD Dr. med. Eberhard Siebert Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology Department of Neurology Department of Neurology Institute of Neuroradiology and Experimental Neurology and Experimental Neurology and Experimental Neurology [email protected] [email protected] [email protected] [email protected] 100 Clinician Scientists 101
Dr. rer. nat. Jan Rafael Dörr Dr. med. Tomasz Dziodzio
In Program From – to Fields of Research In Program From – to Fields of Research 03.2020–08.2023 › Cancer 01.2021–12.2023 › Obesity › Senescence › Kidney transplantation Contact Contact › Cancer Immunotherapy [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Pediatric Oncology Department of Surgery and Hematology Director Director Univ.-Prof. Dr. med. Johann Pratschke Univ.-Prof. Dr. med. Angelika Eggert
Development of Minimal Invasive Diagnostic Tools Pathomechanisms of Obesity in the Field and Targeted Therapies for Tumor Cell Senescence of Kidney Transplantation
Despite our rapidly expanding knowledge of cancer Moreover, the targeted elimination of senescent tumor Morbid obesity is a globally increasing disease and to investigate the impact of obesity and weight loss genomes and their mutational landscapes, the functional cells presents a weakly explored therapeutic opportunity. affects 23% of the population in Germany. It is associated therapies for patients before and after kidney transplan- understanding of cellular failsafe programs, which pro- In the Clinician Scientist Program I therefore aim to elu- with numerous co-morbidities and a high mortality. tation. We plan to investigate the pathomechanisms of hibit cancer development and which underly cancer cidate senescence-induced modifications of the tumor Obese kidney transplant recipients show higher rates of obesity on graft function and the immunological response treatment principles, remains incomplete. Alongside stroma and the immune system predominantly in mouse delayed organ function and rejections. Therefore, obese in a rat model with obese Zucker Diabetic Fatty rats. In apoptosis premature senescence represents a major lymphoma as well as neuroblastoma models with the kidney transplant candidates are often denied access to addition, a clinical program for obese kidney transplant cellular failsafe mechanism in both mice and men, since goal to develop minimal invasive senescence screens organ transplantation. In Germany 50% of transplanta- candidates will be initiated to determine the metabolic it induces a terminal proliferation arrest of viable tumor and to explore novel senescence treatment strategies. tion centers use body mass index-linked thresholds as and immunological effects of conservative versus sur- cells. In this way senescence controls tumor growth as a selection criterion to grant access to the transplant gical weight reduction programs in these patients. part of cytotoxic therapies. Although therapy-induced waitlist. Bariatric surgeries are discussed as a solution senescence (TIS) can prolong tumor-free survival and to this ethical dilemma. Their safety and effectiveness improve treatment outcome, senescent tumor cells also have been confirmed in case studies and retrospective acquire harmful characteristics: They display an increased analyses, but positive effects on organ and patient sur- stemness potential and persistently remodel their tissue vival have not been proven prospectively. Furthermore, environment predominantly through their enhanced it has been shown that the expression of inflammatory secretory activity. In this way senescence contributes to markers, such as IL-6 and TNF-α, as well as CD4+ and treatment resistence. However, diagnostic tools, which CD8+ T lymphocytes can be affected by bariatric surger- faithfully detect TIS in the clinic and which could subse- ies. However, it is still unclear what additional value this quently guide treatment decisions, are largely missing. represents for transplant candidates. This project aims
Mentors Mentors
Univ.-Prof. Dr. med. Univ.-Prof. Dr. med. Univ.-Prof. Dr. med. Dr. rer. nat. Univ.-Prof. Dr. med. Jens Neudecker Prof. Dr. med. Robert Öllinger Angelika Eggert Clemens Schmitt Il-Kang Na Maja Milanovic Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Scientific Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Charité – Charité – Charité – Department of Surgery Department of Surgery Universitätsmedizin Berlin Universitätsmedizin Berlin Universitätsmedizin Berlin Universitätsmedizin Berlin [email protected] [email protected] Department of Pediatric Medical Department, Division Medical Department, Division Molecular Cancer Research Oncology and Hematology of Hematology, Oncology and of Hematology, Oncology Center (MKFZ) Tumor Immunology and Tumor Immunology [email protected] [email protected] [email protected] 102 Clinician Scientists 103
Dr. med. Cornelius Engelmann PD Dr. med. Philipp Euskirchen
In Program From – to Fields of Research In Program From – to Fields of Research 08.2020–07.2023 › Acute-on-chronic liver failure 01.2018 – 06.2021 › Neuro-Oncology › Regeneration › Third-generation sequencing Contact Contact › Senescence [email protected] [email protected] › Cell-Cell interactions mediating organ Clinic injury Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Hepatology and Department of Neurology Gastroenterology and Experimental Neurology Director Director Univ.-Prof. Dr. med. Frank Tacke Univ.-Prof. Dr. med. Matthias Endres
Exploring the Impact of Hepatocyte Senescence on Tissue Injury Molecular Mechanisms of Tumor-Immune and Regeneration in Acute-on-Chronic Liver Failure Cell Interaction in Glioblastoma
The acute-on-chronic liver failure (ACLF) is a complex ative and senescent pathways. Focus will be on the It has long been recognized that tumor-associated disease with devastating prognosis which develops on Mdm2-p53 pathway, which is the best-described senes- microglia and macrophages (TAMs) can account for 30% the basis of an acute decompensated liver cirrhosis in cence pathway. TLR4 signalling may triggers senescence or more of tumor cells in glioblastoma (GBM), the most combination with extrahepatic organ failures. Sudden and we hypothesis that this is mediated by TGF-β1 which frequent primary brain tumor in adults with a dismal disease worsening is frequently triggered by bacterial trans-activates the p53 pathway independent of DNA prognosis of about 15 months overall survival. Impor- infections or other precipitating events which are known damage or other forms of cellular injury. For both objec- tantly, we have recently shown that the amount of non-tu- to be more harmful when liver cirrhosis is present but tives the effect of targeted molecule silencing in vitro mor cells in GBM is a negative predictor of survival (Heul- easy to handle in patients without liver disease. This (e.g. siRNA) and in vivo (e.g. conditional knockout mice) ing et al., 2017). On the molecular level, a solid body of observation suggests an organ sensitisation of the liver allows to delineate the relevance of senescence pathways experimental evidence on the functional and molecular being the initiating mechanism for ACLF. In addition, a in ACLF. Furthermore we are planning to develop a liver interactions between glioma and local innate immune general lack of tissue regeneration was also linked to ACLF organoid model to mimic part of the complexity of cells convergently shows that microglia and macrophages patients’ persistent organ dysfunction and poor prog- ACLF in vitro. It will allow to pre-test multiple therapeutic support tumor growth in GBM. However, clinical trials of nosis. Upon injury hepatocytes may develop a cell cycle compounds to select those with high likelihood for in CSF1R inhibition to selectively deplete TAMs in GBM have arrest, so called cellular senescence, which has the vivo efficacy. The last objective will be to test pre-se- failed. In addition, the high interindividual variability of potential to explain both observations. Cellular senes- lected senolytic therapies in different ACLF mouse mod- immune infiltration across GBM remains largely unex- cence alters the phenotype and receptor expression of els and to select the most effective agent for translation plored. We have found strong associations between hepatocytes and the ability to proliferate and to replace into humans. Therefore, this project will combine basic mutually exclusive key driver mutations and the amount injured tissue. The main aim of that project will be to with translational science to understand the mechanism of immune infiltration, which might explain the failure explore the mechanistic role of hepatocellular senes- of regenerative response in ACLF, to develop new of clinical trials. The overall aim of this project is there- cence in modulating the course of ACFL and severity. As experimental techniques and also to pave the way for fore to identify patients that will benefit from targeted a first step human liver tissue from patients with different a novel treatment for a disease with still devastating therapy, gain mechanistic insights to establish causality severity grades of end-stage liver disease will be char- prognosis. and provide the diagnostic tools for patient-tailored acterised for the expression and activation of regener- precision oncology.
Mentors Mentors
Univ.-Prof. Dr. med. Johann Pratschke Univ.-Prof. Dr. med. Johann Pratschke Univ.-Prof. Dr. med. Matthias Endres Univ.-Prof. Dr. med. Christoph Harms Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Surgery Department of Surgery Department of Neurology Center for Stroke Research Berlin and Experimental Neurology [email protected] [email protected] [email protected] [email protected] 104 Clinician Scientists 105
Dr. med. Mathilde Feist Dr. med. Julian Friebel
In Program From – to Fields of Research In Program From – to Fields of Research 01.2019–09.2022 › Cancer Immunology 01.2020–12.2022 › Protease-activated receptors › Atherosclerosis Contact Contact › Heart failure [email protected] [email protected] › Atrial fibrillation Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Surgery Department of Cardiology Director Director Univ.-Prof. Dr. med. Johann Pratschke Univ.-Prof. Dr. med. Ulf Landmesser
Cytokine-Armed Onkolytic Vaccinia Virus Protease-Activated Receptors in Cardiovascular for Pancreatic Cancer Therapy Thromboinflammation
Immunotherapy is rapidly evolving and fighting cancer point blockade oncolytic virotherapy elicits systemic Protease-activated receptors (PARs) regulate platelet, PARs are important regulators of adverse extracellular by re-activating the patient’s immune system presents and potent anti-tumor immunity. The project aims to endothelial, and immune cells as well as fibroblast and matrix remodelling. Activation of PAR1 and PAR2 is asso- a promising therapeutic strategy in addition to standard explore the therapeutic potential of cytokine-armed cardiomyocyte function. PARs are a family of G-pro- ciated with cardiac fibrosis. PAR1 is the most abundant treatment options as surgery, chemotherapy, and radio- oncolytic vaccinia virus for pancreatic cancer in a pre- tein-coupled receptors (PAR1–PAR4) with a unique acti- G-protein–coupled receptor in cardiac fibroblasts. We therapy. In contrast to advances in other solid malig- clinical model reflecting human disease. The combination vation mechanism via cleavage by the serine proteases have shown that PAR2 is an important regulator of pro- nancies, the clinical success of checkpoint inhibitors to of oncolytic virotherapy with a specific stroma effect as of the coagulation cascade, like FXa and FIIa, immune fibrotic PAR1 signaling and TGF-β-receptor signaling. unlock T-cell immunity has failed in patients with Ductal well as checkpoint blockade to provide long-term anti-tu- cell-released proteases, and proteases from pathogens. Targeting the pleiotropic effects of the FXa/FIIa-PAR-axis, Pancreatic Adenocarcinoma (PDAC). PDAC is characterized mor memory may translate into clinical trials in human Our group has shown that the tissue factor (TF)/FXa/ which go beyond the anticoagulatory effects of FXa inhib- by an extensive fibroinflammatory stroma interfering patients in the near future. thrombin/PARs pathway plays a central role for the innate itors, reduced markers of cardiac fibrosis, and diastolic with an efficient anti-tumor immune response. Lacking immune response in the heart during myocarditis. PARs dysfunction in patients with heart failure with preserved effector T cell infiltration; CD4+ regulatory T cells, regulate immune response not only by sensing pathogens ejection fraction (HFpEF). Therefore, intervening in the myeloid-derived suppressor cells, macrophages and but also by direct activation of platelets and immune FXa/FIIa-PAR1/PAR2/TGF-β-axis might be a promising mast cells present the majority of the infiltrating immune cells, thereby mediating proinflammatory cytokine secre- synergistic approach in a selected cohort of patients cells. Based on the results I obtained during my time as tion and chemokine expression. Furthermore, endothelial with HFpEF to reduce cardiac fibrosis and inflammation. a postdoctoral fellow at Prof. David Bartlett´s laboratory, PARs activation, stimulates leukocyte adhesion, rolling, Next, we will study the role of PARs during the patho- Department of Surgery, University Pittsburgh Medical and migration. This cascade is initiated by TF. We have genesis of atherosclerosis and atrial fibrillation. Center (UPMC), we hypothesize a favorable strategy to recently demonstrated that the treatment with the PAR1 overcome immune evasion in pancreatic cancer might antagonist, vorapaxar, reduced inflammation in a met- be presented by oncolytic virotherapy. Our preliminary abolic disease model. Furthermore, we have shown that data indicate that application of oncolytic vaccinia viruses offers an effective strategy to induce an efficient anti-tumor T cell response independent of baseline T cell infiltration. Furthermore, in combination with check-
Mentors Mentors
Univ.-Prof. Dr. med. Marcus Bahra Univ.-Prof. Dr. med. Prof. Dr. med. Antje Beling Univ.-Prof. Dr. med. Ulf Landmesser Prof. Dr. med. Ursula Rauch-Kröhnert Univ.-Prof. Dr. med. Britta Siegmund Clinical Mentor Igor Maximilian Sauer Scientific Mentor Clinical Mentor Scientific Mentor Scientific Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Surgery Charité – Universitätsmedizin Berlin Institute for Biochemistry and Department of Cardiology Department of Cardiology Department of Gastroenterology, Department of Surgery Molecular Biology Infectious Diseases and [email protected] [email protected] [email protected] Rheumatology [email protected] [email protected] [email protected] 106 Clinician Scientists 107
Dr. med. Dr. phil. Dipl.-Psych. Eva Friedel Dr. med. Steffen Fuchs, MSc
In Program From – to Fields of Research In Program From – to Fields of Research 07.2016–12.2020 › Learning 07.2019–06.2024 › Neuroblastoma › (Epi)genetics › Pediatric Oncology Contact Contact › Alcohol Use Disorder › Gene expression regulation [email protected] [email protected] › Imaging › Circular RNA Clinic Clinic › Non-coding RNA Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Psychiatry Department of Pediatric Oncology and Psychotherapy and Hematology Director Director Univ.-Prof. Dr. med. Dr. phil. Andreas Heinz Univ.-Prof. Dr. med. Angelika Eggert
Imaging (Epi)Genetics in Alcohol Use Disorder Evaluating Circular RNAs in Neuroblastoma as Potential Therapeutic Targets
Alcohol dependence and harmful use are partially her- aims of the project are: To (i) perform chip-based genome Neuroblastoma, an embryonal tumor arising from periph- tified a subgroup of neuroblastoma-specific circRNAs. itable with an estimated contribution of genetics to wide genetic analyses of all samples and longitudinal eral sympathetic neuron precursor cells, is the most Selected circRNAs showed oncogenic properties in neu- phenotypic variance of between 40-60%. Recent large epigenetic analyses of selected candidate genes in common extracranial solid tumor of childhood. Approx- roblastoma cells. In this subsequent Clinician Scientist genome wide association studies (GWAS) have identified patient samples; (ii) to identify and replicate intermedi- imately half of all children diagnosed with neuroblastoma project we will evaluate the therapeutic potential of specific genetic variants, however such association stud- ate brain phenotypes of dysfunctional learning based present with high-risk disease, for which therapeutic circRNAs in neuroblastoma. For this purpose, we will ies require extremely large sample sizes. The combination on known risk variants (including polygenetic risk scores options are aggressive and have limited cure rates of at establish a knockdown screen to identify circRNAs affect- of genetics and imaging data (referred to as imaging and epigenetic information as well as neuroplastic bio- most 40%. No curative therapeutic options currently ing the phenotype of the cancer cells. Moreover, we will genetics) facilitates the identification of genetic risk markers such as BDNF) using the standard (voxel based) exist for relapsed neuroblastoma, emphasizing the create a pipeline by Oxford Nanopore to sequence the variants in considerably smaller sample sizes. The first and a »connectomics« (network based) approach to urgent need for the development of new strategies. Cir- full-length of circRNAs. This information will help us to goal of this project therefore is to identify intermediate imaging data; (iii) to use the identified intermediate brain cular RNAs (circRNA) arise by a form of alternative splic- thoroughly characterize the mechanism of action of can- phenotypes at the brain level using imaging genetics phenotypes and epigenetic information for classification ing, termed backsplicing, and have recently emerged as didate circRNAs and finally test their therapeutic poten- that can, in a subsequent step, be used for classification and prediction purposes. a new class of non-coding RNAs important for regulating tial in cell line and xenograft models. In this way, we or clinical prediction purposes allowing the consideration gene expression. They bind miRNAs or RNA binding pro- hope to not only add to the current understanding of of genetic as well as epigenetic information. To facilitate teins via specific sequences to inhibit their function and neuroblastoma pathogenesis, but also define new drug- this goal, we have collected blood and fMRI data from directly influence transcription. Circular RNAs were gable targets for high-risk disease. 150 patients with Alcohol Use Disorder and 200 Healthy recently shown to be highly abundant in neural tissues, Controls and will continue to collect 130 patients with especially during development. During my Junior Clinician Alcohol Use Disorder for replication. All patients per- Scientist fellowship we could detect for the first time formed basic learning paradigms during fMRI. The specific circRNAs in neuroblastoma by RNA sequencing. We iden-
Mentors Mentors
Univ.-Prof. Dr. med. Dr. phil. Prof. Dr. med. Dr. phil. Henrik Walter Univ.-Prof. Dr. med. Angelika Eggert Univ.-Prof. Dr. med. Johannes Schulte Andreas Heinz Scientific Mentor Clinical Mentor Scientific Mentor Clinical Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Psychiatry and Department of Pediatric Oncology Department of Pediatric Oncology Department of Psychiatry and Psychotherapy and Hematology and Hematology Psychotherapy [email protected] [email protected] [email protected] [email protected] 108 Clinician Scientists 109
Dr. med. Simon Gräber Dr. med. Lea-Maxie Haag
In Program From – to Fields of Research In Program From – to Fields of Research 09.2018–04.2022 › Cystic Fibrosis 09.2018–08.2023 › Immunometabolism in Inflammatory › CFTR Biomarker Bowel Diseases Contact Contact › CFTR Modulators › Cancer Immunology [email protected] [email protected] › Airway Hydration Therapies › Mucosal Immunology Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Pediatric Respiratory Medicine, Department of Gastroenterology, Infectious Immunology and Critical Care Medicine Diseases and Rheumatology Director Director Univ.-Prof. Dr. med. Marcus Mall Univ.-Prof. Dr. med. Britta Siegmund
Functional Characterization, Pharmacological Modulation Metabolic Profiling of the Monocyte-Macrophage and Genotype-Phenotype Correlation of Rare CFTR Mutations Compartment in Crohn’s Disease in Human Airway and Intestinal Epithelia
Cystic fibrosis (CF) is the most frequent lethal hereditary the correlation between the CF genotype and CFTR func- Intestinal macrophages (MΦ) have pivotal roles in main- these cells. Alterations in the metabolic signature of MΦ disease in Caucasians and is caused by mutations in the tion in the airway and intestinal epithelia and will help taining intestinal homeostasis, but are also implicated are present in different human diseases. For example, cystic fibrosis transmembrane conductance regulator to establish mutation-specific therapy for patients with in chronic pathologies of the gastrointestinal tract, such an atypical pro-inflammatory polarization has been dis- (CFTR) gene, which results in defective ion transport in rare CFTR mutations. as inflammatory bowel disease (IBD). These opposing cussed in metabolic diseases. The importance of MΦ epithelial organs. Meanwhile, more than 2000 mutations properties can be attributed to the enormous plasticity metabolism is furthermore underlined by the study of have been identified in the CFTR gene. Despite the fast of these cells, reflected by different polarization states. tumour-associated MΦ, that impact the metabolic profile development of modulators for common mutations, func- Large advances in our understanding of the role of MΦ of the tumour microenvironment and have a major influ- tional consequences of many rare CF-causing mutations in inflammatory conditions is based on murine studies. ence on disease progression and resistance to therapy. remain unknown. Further, large clinical trials with CFTR In the murine tissue, resident MΦ are constantly replen- For inflammatory conditions, enforcing a pro-resolving modulators in patients with rare CFTR mutations are ished from blood monocytes that acquire an anergic MΦ phenotype could be a potential therapeutic approach. often impossible. The aims of the project are therefore phenotype under steady state conditions. However, when Changes in both monocyte and MΦ population have been to first characterize the function of different classes of recruited to inflamed tissue, they become effector mono- reported in CD patients. However, it is unknown how rare CFTR mutations in human native respiratory and cytes that actively drive inflammation and give rise to these cells contribute to disease pathogenesis and pro- intestinal epithelia, by using sweat test, intestinal current pro-inflammatory MΦ. Data on MΦ biology and function gression. Moreover, it is not understood, if monocytes measurement (ICM) and nasal potential difference (NPD), in inflammation of the human gut is sparse. It has been have a dual capacity to give rise to pro- or anti-inflam- and further correlate the genotype and CFTR function suggested, that an altered monocyte to MΦ differenti- matory MΦ, e.g. depending on the microenvironment with the clinical phenotype assessed by lung function ation is involved in the development and perpetuation that they enter. Strikingly, the metabolic signature of measurements, anthropometry and lung imaging with IBD. However, many aspects of human intestinal MΦ both monocytes and MΦ in CD displays an unexplored MRI. Our final goal is to perform in vitro testing of biology remain poorly understood. The high degree of field. The present project aims to define the role of mono- response to therapy of currently developed and already plasticity with involvement of different polarization cyte- and MΦ-metabolism in small intestinal CD. approved CFTR modulators in patient-derived nasal epi- states is one of the characteristic features of MΦ. Phe- thelial cells and intestinal organoids. We believe that notypic changes are accompanied with changes in the studying these questions will provide new insights into cells metabolism that impact the effector functions of
Mentors Mentors
Univ.-Prof. Dr. med. Marcus Mall Univ.-Prof. Dr. med. Wolfgang Kübler Univ.-Prof. Dr. med. Britta Siegmund Dr. rer. nat. Rainer Glauben Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Pediatric Respiratory Institute of Physiology Department Department of Department Department of Medicine, Immunology and Critical Gastroenterology, Infectious Diseases Gastroenterology, Infectious [email protected] Care Medicine and Rheumatology Diseases and Rheumatology [email protected] [email protected] [email protected] 110 Clinician Scientists 111
Dr. med. Dr. med. univ. Stefan Habringer Dr. med. Georg Hilfenhaus
In Program From – to Fields of Research In Program From – to Fields of Research 07.2019–06.2022 › Translational hematology 08.2020–07.2023 › Tumor immunology and oncology › Adoptive T cell therapy Contact Contact › B-cell lymphoma › Pancreatic cancer [email protected] [email protected] › Genetic screening › Tumor stroma Clinic › Targeted therapies Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Hematology, Department of Hematology, Oncology and Oncology and Cancer Immunology Cancer Immunology Director Director Univ.-Prof. Dr. med. Ulrich Keller Prof. Dr. med. Sebastian Stintzing
Forward Genetic Screening for Analysis and Therapeutic Adoptive T Cell Therapy in Pancreatic Cancer: Targeting of BCL6-Associated Lymphoma Effects of the Abundant Tumor Stroma on Tumor Rejection
BCL6 is a BTB/POZ zinc finger transcription factor acting (PB) transposon mutagenesis system enables us to screen Pancreatic cancer is a highly aggressive disease with can be targeted in a MHC-restricted fashion. To investi- as a transcriptional repressor in a sequence-specific for functionally relevant cancer genes by activating and limited therapeutic options in advanced stages. In recent gate the stroma-related role in the context of adoptive manner. Without intact BCL6, the GC reaction cannot inactivating all genes across the whole genome. Thereby, years, adoptive T cell therapy has led to impressive T cell therapy an orthotopic mouse model of pancreatic occur, resulting in failure to produce memory B cells and it serves as a complementary approach to the aforemen- responses in patients with hematopoietic malignancies cancer will be used that closely mimics the complex tumor antibody-producing plasma cells. BCL6 represses various tioned patient datasets to answer open questions about and melanoma, however, its clinical efficacy for most microenvironment in humans. The relevance of antigen tumor suppressor genes, but also oncogenes to coun- novel cancer genes in vivo. In this system, short DNA solid tumors still needs to be tested. The complex stroma cross-presentation by stromal cells will be determined. terbalance the risk of transformation. BCL6 transloca- elements carrying promoters and gene traps called trans- and microenvironment of solid cancers is thought to act Furthermore, the interplay of T cell-derived effector tions and overexpression occur in up to 50% of DLBCL posons (ATP2 mouse) are randomly integrated into the immune suppressive, and thus could pose a challenge cytokines and other components of the tumor stroma patients and are present in a subset of patients with genome by a transposase (RosaPb mouse), allowing the for T cell-based therapies. Also, the tumor stroma is an such as tumor vessels will be examined. In addition, adverse prognosis. The IµBCL6 mouse is a lymphoma identification of oncogenes and tumor suppressor genes important target during T cell-mediated tumor rejection. human tumor tissue samples will be used for functional model carrying a translocation similar to the one found in a single unbiased experimental approach. Transposon In this context, cross-presentation of tumor antigens by analyses. Overall, our study will test feasibility of adop- in DLBCL patients, resulting in spontaneous lymphoma insertion sites can be identified with quantitative inser- stromal cells such as macrophages and potentially fibro- tive T cell therapy in pancreatic cancer and explore pos- development. Strategies to target BCL6 are currently tion site sequencing (QiSeq) with very high resolution blasts has been discussed. In addition, T cell-derived sible stroma-associated mechanisms of resistance. being tested, but drug development for targeting tran- as described. We are using PB in the DLBCL-prone IµBCL6 interferon-γ and tumor necrosis factor have been shown scription factors and identifying patients who will profit mouse model to find novel candidate genes relevant for to play important roles by affecting components of the from novel drugs is challenging, especially in high-risk lymphomagenesis. Thereby, we aim at identifying clini- stroma including tumor vessels. Pancreatic cancer is or treatment-resistant patients. In DLBCL, sequencing cally relevant mechanisms of lymphoma development characterized by an abundant and dense tumor stroma samples from large, well-annotated patient cohorts have and progression, biomarkers for treatment response and associated with immunosuppression and therapeutic provided us with a plethora of evidence about genetic resistance, focusing on how to overcome treatment resis- resistance. Thus, stroma-associated aspects are of par- and non-genetic alterations in this disease. The central tance by molecularly targeted therapies. ticular importance for this type of cancer. The goal of challenge is to identify and understand highly relevant this study is to evaluate adoptive T cell therapy in pan- functional alterations and distinguish them from less creatic cancer using T cell receptor gene transfer. Using relevant genetic and non-genetic events. The piggyBac this approach, pancreatic cancer-specific tumor antigens
Mentors Mentors
PD Dr. med. Martin Janz Univ.-Prof. Dr. med. Ulrich Keller Prof. Dr. med. Sebastian Stintzing Univ.-Prof. Dr. rer. nat. Thomas Blankenstein Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Hematology, Oncology Department of Hematology, Oncology Department of Hematology, Oncology Max Delbrück Center for Molecular Medicine and Cancer Immunology and Cancer Immunology and Cancer Immunology Molecular Immunology and Gene Therapy [email protected] [email protected] [email protected] [email protected] 112 Clinician Scientists 113
Dr. med. Paul Jahnke Dr. med. Michael Kaczmarczyk
In Program From – to Fields of Research In Program From – to Fields of Research 01.2021–12.2023 › 3D printing 07.2019–09.2022 › Tumor immunology › Computed tomography › Adoptive T cell therapy Contact Contact › Image quality › Pancreatic cancer [email protected] [email protected] › Standardization › Tumor stroma Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Radiology Department of Psychiatry and Neurosciences Director Director Univ.-Prof. Dr. med. Bernd Hamm Univ.-Prof. Dr. med. Dipl.-Psych. Isabella Heuser-Collier
3D Printing of Tumor Models to Standardize Radiomics Influence of Hormones on Depressive, Stress-Related, Biomarkers in Oncologic Patients and Anxiety Disorders
Radiomics makes quantitative information available from for radiomics. We will use the phantom to evaluate Traumatic experiences and adverse life events are risk blocking target receptors, have shown associations computed tomography (CT) images that provides new effects of imaging technologies on the robustness of factors for numerous somatic and mental disorders. between estrogen and progesterone levels and cognition. diagnostic and prognostic insights into tumor diseases. radiomics features, and we will develop methods to Stress- and trauma-related disorders such as depressive Less is known about the effects of sex hormones on Novel radiomics biomarkers have shown high potential improve the quality of CT data, establish standardization and posttraumatic stress disorder are associated with cognition in humans. Therefore, we systematically inves- for better, personalized tumor therapies in numerous and enable more reliable radiomics analyses. sex-specific differences. Following traumatic experiences, tigate the effects of hormones on cognitive processes studies. However, as the field progresses, the quality of women show higher prevalence rates, as well as higher in depressive, stress-related and anxiety disorders. CT data becomes increasingly important. Radiomics fea- symptom severity and comorbidity rates. In our previous tures are extracted from tumor pixel information, which work we could show that both major depressive and currently varies widely across institutions, scanners and posttraumatic stress disorder are associated with even within the same scanner. This situation represents changes in cortisol and catecholamine metabolism, and a major limitation for the robustness and clinical appli- that early life adversities are associated with cognitive cation of radiomics. Imaging phantoms are reference impairments in later life. Fear conditioning is a crucial objects of known ground truth and represent a standard concept of learning theory, and is frequently applied to instrument in testing, controlling and comparing imaging explain the development and maintenance of mental systems. However, standard CT phantoms test and stan- disorders. Increasing evidence suggests a pivotal role dardize technical system parameters, but do not evaluate of sex hormones in fear conditioning, thus offering a radiomics features. Based on a new technology specifi- possible explanation for sex-related differences. Pre- cally developed for 3D printing of radiopaque objects, clinical studies, using techniques such as assessing our aim is to develop the first reference tumor phantom endogenous hormone levels or by pharmacologically
Mentors Mentors
Univ.-Prof. Dr. med. Bernd Hamm PD Dr. med. Michael Scheel Univ.-Prof. Dr. med. Dipl.-Psych. Univ.-Prof. Dr. med. Christian Otte Clinical Mentor Scientific Mentor Isabella Heuser-Collier Scientific Mentor Clinical Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Radiology Institute of Neuroradiology Charité – Universitätsmedizin Berlin Department of Psychiatry and Department of Psychiatry and Neurosciences [email protected] [email protected] Neurosciences [email protected] [email protected] 114 Clinician Scientists 115
Dr. med. Jakob Kaminski Dr. med. Evelyn Kidess-Sigal
In program From – TO Fields of Research In Program From – to Fields of Research 01.2019–12.2021 › Neuroimaging 09.2017–12.2021 › Oncology › Cognitive Neuroscience › Circulating tumor DNA Contact Contact › Clinical Psychiatry [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Psychiatry and Medical Department, Division of Hepatology Psychotherapy and Gastroenterology Director Director Univ.-Prof. Dr. med. Dr. phil. Andreas Heinz Univ.-Prof. Dr. med. Bertram Wiedenmann
The Neurobiology of Psychotic Disorders Evaluation of the Potential of »Liquid Biopsies« in Representing Mutational Profiles of Metastatic Tissue
My workgroup investigates underlying neurobiological tool for several kinds of symptoms. The understanding In order to administer an individually tailored therapy to expand the diagnostic repertoire in cancer patients mechanisms that lead to impaired learning and neuro- of the effect of non-invasive stimulation techniques will to a cancer patient, currently, a tumor is molecularly by enabling the obtainment of molecular data non-in- cognitive processes in neuropsychiatric diseases. We help to refine the application. I am investigating the characterized by analyzing tissue biopsies. Unfortunately, vasively. Thus, patients may significantly benefit from apply a broad range of techniques in order to elucidate experimental modulation of brain activation and its the obtainment of tissue biopsies is invasive and there- our results, since the analysis of liquid biopsies will neurobiological underpinnings of complex human traits. impact on behavioral and neurobiological outcome mea- fore associated with a risk of complications, and in some enable the administration of tailored therapy for every We investigate large cohorts and estimate differential sures like local activity (fMRI) and effective connectivity cases may not even be possible due to difficult accessi- individual patient corresponding to the molecular char- contributions of brain structure, function as well as (dynamic causal modeling, DCM). DCM is an approach bility. Using Liquid biopsies is a promising alternative, acteristics of the tumor. genetic and epigenetic contributions to cognitive capac- that overcomes the challenge of missing mechanistic as it requires solely obtaining blood samples, which can ity. We explore malleable biomarkers for interindividual insight. DCM exploits generative models that provide be molecularly analyzed. Up to now, it is unknown, to differences in cognitive abilities. We apply state-of-the- parameters which explain how the measured data could which extent the mutational profile of metastatic tissue art in-vivo imaging techniques using functional magnetic have arisen from neurophysiological mechanisms like can be revealed by analyzing Circulating Tumor Cells resonance imaging (fMRI) and positron emission tomog- task-dependent synaptic connectivity between neuronal (CTCs) or Circulating Tumor DNA (ctDNA), and which of raphy (PET). More precisely, I am interested in the patho- populations. Taken together my current work is focusing these liquid biomarkers is most representative when physiology of psychosis and the mesocortical dopamine on the exploration of interindividual differences in cog- comparing different tumor entities. To answer this ques- system that modulates putative glutamatergic prefrontal nitive capacity which allow possible interventions that tion, in the current project we are analyzing blood sam- functions like working memory. I have a particularly are capable of inducing changes in network processing ples from patients suffering from colorectal cancer, head strong commitment to translating my increasing meth- in the human brain. and neck cancer and malignant melanoma with distant odological knowledge towards clinical application. In my metastases. Using a panel consisting of 327 genes fre- research, I focus on alterations in neurocognitive pro- quently associated with cancer, blood and tissue samples cesses using non-invasive brain stimulation (NIBS) tech- are sequenced and the mutational profiles of CTCs and niques such as transcranial magnetic stimulation (TMS) ctDNA are going to be compared to the ones in metastatic or transcranial direct current stimulation (tDCS). Non-in- tissue as well as primary tumor tissue, if applicable. We vasive stimulation techniques are a putative therapeutic strongly believe, that liquid biopsies have the potential
Mentors Mentors
Univ.-Prof. Dr. med. Philipp Sterzer Prof. Dr. Florian Schlagenhauf Univ.-Prof. Dr. med. Prof. Dr. rer. nat. Univ.-Prof. Dr. med. Clinical Mentor Scientific Mentor Bertram Wiedenmann Ingeborg Tinhofer-Keilholz Ulrich Keilholz Clinical Mentor Scientific Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Psychiatry Department of Psychiatry Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin and Psychotherapy and Psychotherapy Medical Department, Department of Radiation Oncology Comprehensive Cancer Center Division of Hepatology and and Radiotherapy [email protected] [email protected] [email protected] Gastroenterology [email protected] [email protected] 116 Clinician Scientists 117
Dr. med. Daniel Kroneberg Dr. med. Dorothee Kübler
In Program From – to Fields of Research In Program From – to Fields of Research 10.2020–09.2023 › Parkinson’s Disease 01.2019-12.2021 › Functional Imaging in › Movement Disorders Movement Disorders Contact Contact › Deep brain stimulation › Deep Brain Stimulation [email protected] [email protected] › Gait assessment › Neuropsychiatry and (Social) Clinic Clinic Cognition Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology Department of Neurology and Experimental Neurology and Experimental Neurology Director Director Univ.-Prof. Dr. med. Matthias Endres Univ.-Prof. Dr. med. Matthias Endres
Network Modulation for the Improvement Cognitive Effects of Dopamine and Subthalamic Nucleus of Gait Function in Parkinson’s Disease Deep Brain Stimulation in Parkinson’s Disease
Disturbances of gait and balance and specifically freezing performance ON and OFF DBS. For each patient, specific Apart from motor disabilities, patients with Parkinson’s study. With a novel Go/NoGo paradigm, we found that of gait (FoG) are clinical features of advanced stages of profiles of network activation and connectivity will be disease (PD) show a variety of cognitive symptoms that young onset PD patients performed worse on compared Parkinson’s disease (PD) that are associated with an modeled from the reconstructed DBS-electrodes based are relevant in terms of prognosis and quality of life. to off dopaminergic medication whereas late-onset PD increased risk of falls, reduced mobility and impaired on normative structural and functional connectomes These include increased impulsivity under dopaminergic patients seemed to benefit from dopamine in terms of quality of life. Deep brain stimulation (DBS) of the sub- and then related to individual modulation of gait per- medication and deep brain stimulation (DBS) in the sub- reduced error commission rates on compared to off thalamic nucleus (STN) is a highly efficacious treatment formance. This will clarify if we need to target different thalamic nucleus, respectively. In order to find a balance dopaminergic medication. By means of simulations in a for motor symptoms of PD such as tremor, rigidity and networks to treat gait disability in contrast to other motor between beneficial motor effects and cognitive side neuro-computational model of the cortex – BG loops, we bradykinesia but with limited effects on gait disability. symptoms of PD.This study aims to optimize DBS therapy effects, a better understanding of the underlying cor- were able to show that these opposite effects can be Therapeutic effects of DBS relate to modulation of dis- towards a more patient- and symptom-oriented approach tex-basal ganglia (BG) interactions and their modulation explained by different patterns of striatal dopamine loss tinct brain networks connected to the stimulation area that may be integrated into future solutions for adaptive by our therapies is crucial. During my Junior Clinician between young and late-onset PD groups: younger PD via basal-ganglia-cortical-pathways. Here, specific struc- DBS. Scientist grant period, I investigated different cognitive patients who dispose of a relatively intact associative tural and functional connectivity patterns have been domains in PD patients on and off dopaminergic medi- striatum show impaired inhibition due to dopamine over- identified that are associated with and predictive of cation and looked at their functional basis with [123I] dosing of the associative striatum. This is important when motor improvement. We will adapt this methodology to FP-CIT SPECT. In a first study, we were able to show that considering that younger PD patients are often candi- study the optimal connectivity profiles of DBS for improv- overall cognitive performance correlated with the degree dates for DBS. The focus of my upcoming projects will ing gait function and particularly FoG in Parkinson’s of dopaminergic degeneration in the associative part of be on the effects of DBS surgery on cognition and prog- disease. To account for the diversity of gait phenomena the striatum. As impulse control disorders especially nostic markers for cognitive outcomes in PD. in PD, sensor based kinematic measurements will provide affect younger patients, we looked at inhibitory control high resolution, multi-parametric assessments of gait with respect to dopaminergic degeneration in a second
Mentors Mentors
Prof. Dr. med. Christoph Ploner Univ.-Prof. Dr. med. Andrea Kühn Univ.-Prof. Dr. med. Matthias Endres Univ.-Prof. Dr. med. Andrea Kühn Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology Department of Neurology Department of Neurology Department of Neurology and Experimental Neurology and Experimental Neurology and Experimental Neurology and Experimental Neurology [email protected] [email protected] [email protected] [email protected] 118 Clinician Scientists 119
Dr. med. Tina Mainka Dr. med. Tazio Maleitzke
In Program From – to Fields of Research In Program From – to Fields of Research 01.2020–12.2022 › Movement Disorders 01.2021–12.2023 › Osteoarthritis › Pain › Cell-based Therapies Contact Contact › Mesenchymal Stromal Cells [email protected] [email protected] › Osteoimmunology Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology Center for Musculoskeletal Surgery and Experimental Neurology Director Director Univ.-Prof. Dr. med. Carsten Perka Univ.-Prof. Dr. med. Matthias Endres
Study of the Pathophysiology of Pain in Dystonia MORCA – Mechanism of Regenerative Cell Action by Neurophysiological and Imaging Methods
Pain is the most frequent non-motor symptom in cervical of questionnaires, neurophysiological markers, partic- Osteoarthritis (OA) is the most common degenerative to better understand molecular pathways by which dystonia in up to 75% of patients. It might occur as the ularly conditioned pain modulation, and imaging meth- joint disease worldwide with a marked prevalence regenerative cells including PLX cells may alter disease first symptom of the disease and oftentimes becomes ods. The results will lead to a better understanding of increase over the past decades. Primary OA is caused activity in a pre-clinical naturally occurring in vivo model chronic. For many patients, pain is more disabling than the pathophysiological mechanisms of pain in dystonic and characterized by a vicious cycle of micro-trauma to of OA (Dunkin Hartley guinea pig model). Potential immu- the sustained or intermittent muscle contractions caus- syndromes and create a foundation for individualized, the cartilage and a low-grade articular inflammation, nomodulatory and regenerative effects of intraarticular ing abnormal movement and/ or postures which is the mechanism-based therapies. that cause chronic pain and functional disability in injections of PLX cells will be traced histologically and main motor manifestation of dystonia. Despite its severe affected patients. Symptomatic OA treatment comprises radiologically as well as through molecular and single impact on the patients’ quality of life and the significant lifestyle changes, physiotherapy and analgesia, which cell analyses. To compare pre-clinical results with clinical socioeconomic implications, the phenotype and the unfortunately cannot effectively slow down or halt dis- reality, human OA cartilage and synovium samples will pathophysiology of pain in dystonia are mostly unknown. ease progression. Due to the progressive nature of the be obtained and included in the analyses. We hope to There is no correlation between motor symptoms and disease, arthroplasty is often the only therapy that can better comprehend, establish and advance novel regen- pain, and non-dystonic muscles might also be painful. replace, yet not restore joint integrity. Placental expanded erative treatment strategies for OA through the work Therapeutic interventions that might relief pain (e.g., (PLX) cells are placenta-derived mesenchymal like adher- conducted during the Clinician Scientist fellowship. A injections of botulinum toxin, deep brain stimulation) ent stromal cells, that are known to exert unique immu- paradigm shift from a symptomatic to a disease modi- do not always improve motor symptoms and vice versa. nomodulatory and regenerative properties in the treat- fying treatment approach for primary OA would have a We can therefore assume, that pain in dystonia is not ment of muscle injury and critical limb ischemia. Admin- lasting impact on affected generations to come. solely generated by dystonic muscles. Recently, it has istered locally, PLX cells are able to regulate the adaptive been proposed that an insufficient descending pain inhib- immune response and the pro-inflammatory cytokine itory system, assessed by conditioned pain modulation, distribution. Infiltration of the synovium and the synovial might contribute to pain in dystonic patients. With this fluid with cells from the adaptive immune system and project, we aim to phenotype the pain syndrome in large pro-inflammatory cytokines are key pathomechanisms cohorts of patients with various forms of focal and gen- of OA, yet PLX cells have not been exploited for intraar- eralized dystonia without and during therapy by means ticular treatment of OA. With the MORCA project we strive
Mentors Mentors
Univ.-Prof. Dr. med. Matthias Endres PD Dr. med. Christos Ganos Univ.-Prof. Dr. med. Andrea Kühn Univ.-Prof. Dr. med. Carsten Perka Univ.-Prof. Dr.-ing. Georg Duda Clinical Mentor Scientific Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Julius Wolff Institute of Biomechanics Department of Neurology Department of Neurology Department of Neurology Center for Musculoskeletal Surgery and Musculoskeletal Regeneration and Experimental Neurology and Experimental Neurology and Experimental Neurology [email protected] [email protected] [email protected] [email protected] [email protected] 120 Clinician Scientists C linicianScientists 121
Dr. rer. nat. Melba Muñoz Roldán, MSc Dr. med. Alexander Heinrich Nave
In Program From – to Fields of Research In Program From – to Fields of Research 01.2019–12.2021 › Mast cells 10.2018–11.2021 › Stroke › Viral infections › Biomarkers Contact Contact › CD8 T cells › Metabolism [email protected] [email protected] › HSV Clinic › MRGPRX2 Clinic Charité – Universitätsmedizin Berlin › Urticaria Charité – Universitätsmedizin Berlin Department of Dermatology, Department of Neurology Venereology and Allergology and Experimental Neurology Director Director Prof. Dr. med. Kamran Ghoreschi Univ.-Prof. Dr. med. Matthias Endres
The Role of Mast Cells in Viral Infections Homeostasis After Stroke – the Effect of Stress-Tests on Metabolic and Cerebral Biomarkers
Mast cells are pleotropic immune cells most abundantly aim to investigate and characterize the role of mast cells Stroke is a major cause of death and long-term disability for 4 weeks in addition to usual care. Blood and imaging found at host-environment interfaces, such as the skin, in viral infections and to determine how herpes viruses worldwide. Despite rehabilitation and optimal secondary analyses are performed before and after the intervention respiratory and gastrointestinal mucosa. Mast cells act modulate the phenotype and function of mast cells. In prevention, many stroke survivors remain functionally to establish new biomarkers for vascular risk prediction as sentinel cells to sense and fight pathogens. In order addition, we investigate the impact of MRGPRX2 and dependent and at a high risk for recurrent vascular and assess potential protective effects of fitness training to do this, they are armed with a plethora of bioactive C5aR blockade in the activation of mast cells in patients events. Impairment of lipometabolism is a risk factor for early after stroke (Nave et al. 2013). In this research proj- mediators that initiate immune cell recruitment, promote with chronic spontaneous urticaria. We use a combina- cardiovascular disease and physical fitness training is ect, we hypothesize that A) investigation of hemostatic the development of adaptive responses and contribute tion of cutting edge technologies, high throughput cul- thought to promote metabolic and cerebral hemostasis. control of lipometabolism in the acute phase of stroke to defense mechanisms of the host against infections. ture methods, cell cultures and mouse models viral Because the etiology of stroke is heterogeneous, the use following a stress test, i.e. oral triglyceride tolerance Activation and subsequent mast cell degranulation are infections. A better understanding of the mechanisms of biomarkers for individual risk prediction is promising, test (OTTT), will improve the individual risk prediction mediated through several receptors including the novel underlying mast cell activation after viral infections will especially when these biomarkers can quantify the ability after stroke. B) Application of anaerobic fitness training human G protein-coupled receptor (GPCR), known as allow the development of novel antiviral strategies as of the individual to maintain homeostasis. We have ini- after stroke in addition to usual care will lead to a better Mas-Related G Protein-Coupled Receptor-X2 (MRGPRX2) well as therapies to treat symptoms in mast cell asso- tiated the prospective observational Berlin Cream and functional outcome and will improve markers of meta- and the C5a receptor. Although mast cells are crucial in ciated diseases. Sugar study (NCT01378468) to evaluate the metabolic bolic homeostasis compared to relaxation sessions. the defense of the host, they also play an active role in changes after stroke and assess the effect of an oral These new markers will include conventional markers of allergy, urticaria, itch and fibrosis. Herpes simplex virus glucose and triglyceride tolerance test on metabolic metabolism as well as novel markers, such as different type 1 (HSV-1) can cause infections in humans ranging homeostasis for individual vascular risk prediction. A types of microvesicles and expression levels of isolated from orolabial lesions to life threating conditions such second study is the randomized-controlled PHYS-STROKE exosomes. The work will lead to more insight into the as herpes simplex encephalitis. Using mouse and human trial (NCT01953549), where subacute stroke patients role of homeostasis as a key concept in understanding skin mast cells as well as animal models of disease, we receive physical fitness training or relaxation sessions the role of biomarker research.
Mentors Mentors
Univ.-Prof. Dr. med. Univ.-Prof. Dr. med. Marcus Maurer Univ.-Prof. Dr. med. Matthias Endres Dr. Bob Siegerink, PhD Ulrike Blume-Peytavi Scientific Mentor Clinical Mentor Scientific Mentor Clinical Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Dermatology, Department of Neurology Center for Stroke Research Berlin Department of Dermatology, Venereology and Allergology and Experimental Neurology [email protected] Venereology and Allergology [email protected] [email protected] [email protected] 122 Clinician Scientists 123
Dr. med. Mir Timo Zadegh Nazari-Shafti Dr. med. Marc Nikolaus
In Program From – to Fields of Research In Program From – to Fields of Research 07.2019–06.2022 › Cardiothroacic Surgery 09.2019–11.2022 › Pediatrics › Myocardial Revascularization › Autoimmune encephalitis Contact Contact › Cardioprotection › Neuroimmunology [email protected] [email protected] › Extracellular Vesicles Clinic Clinic German Heart Center Berlin Department Charité – Universitätsmedizin Berlin of Cardiothoracic and Vascular Surgery Department of Pediatric Neurology Director Director Univ.-Prof. Dr. med. Volkmar Falk Prof. Dr. med. Angela Kaindl
Targeting Inflamed Endothelium with Smart Exosomes Mechanisms of Antibody-Mediated Encephalitis for Cardioprotection in Tumor Disease
With the incident of cardiovascular disease on the rise, cell-based therapies on remodeling is inhibited by the Encephalitis associated with antibodies against the now look for receptor internalization, shifts in cluster the natural clinical course in patients after cardiovascular low retention rate and survival of MSCs after transplan- metabotropic glutamate receptor 5 (mGluR5) is an auto- localization and impact on cell viability after antibody events has become a significant economic burden on our tation. Significant titers of paracrine factors including immune disease characterized by a complex neuropsy- incubation with neuronal cell cultures. After the enceph- society. In the heart, acute ischemia and reperfusion exosomes are only achieved during the first 24-48 hours chiatric syndrome (Ophelia syndrome). It often affects alitis, the very same patient developed a Hodgkin lym- injury leads to remodeling, and ultimately, to impairment after allocation of MSCs (»hit-and-run« mechanism) due young adults and is associated with Hodgkin lymphoma. phoma. Immunohistochemistry on biopsy material might of functionality in affected myocardium. Remodeling is to limited retention and engraftment of cells. While mGluR5 belongs to the family of G protein-coupled recep- now reveal anti-mGluR5 antibody binding. We will com- preceded by tissue inflammation, followed by fibroblast application of MSCs is usually limited to a one-time injec- tors and activates an intracellular signal cascade. In the pare the results to anti-mGluR5 binding on tumors from migration and proliferation in the damaged myocardium. tion during cardiac surgery or percutaneous intervention past, receptor dysfunction has been associated with non-encephalitic Hodgkin patients as controls With this Cell based therapies, including neonatal and adult mes- the application of exosomes may allow for repetitive schizophrenia, autism, fragile-X syndrome, and Parkin- project we want to provide new insight into autoimmu- enchymal stem cells (MSC), have aimed to prevent myo- treatments via intravenous applications. The overall son’s disease. The role of anti-mGluR5 in autoimmune nological pathomechanisms on the metabotropic recep- cardial remodeling. In this setting, the cardioprotective objective of this project is to develop a therapeutic exo- encephalitis though, the underlying pathomechanisms tor mGluR5 as well as on the link between tumor and effect is in part mediated by extracellular vesicles, par- some product that targets inflamed endothelium in the of antibody binding and the link between tumor and autoimmunity. A better understanding of the pathophys- ticularly exosomes. Exosomes contain miRNAs and pro- infarcted myocardium. These smart exosomes (SExs) autoimmunity remain unclear. Recently, we treated a iology may modify treatment strategies and serve teins that can facilitate an anti-fibrotic, angiogenic and should exhibit thecapacity to accumulate in the myocar- young patient with Ophelia syndrome and anti-mGluR5 patients with autoimmune encephalitis in general. immune-modulatory effect after ischemia reperfusion dium after ischemia and revascularization upon systemic antibodies. We generated monoclonal antibodies of this injury. Despite promising pre-clinical trials, clinical stud- delivery. Furthermore, they should allow for repetitive and other patients’ CSF by using single cell cloning. With ies utilizing MSCs in the acute setting of myocardial application via minimally invasive /percutaneous routes. tissue- and cell-based assays we characterize the binding ischemia failed to demonstrate the reduction of remod- Finally they should act cardioprotective in situations of patterns and affinities of these anti-mGluR5 antibodies. eling . It is hypothesized that the positive impact of myocardial ischemia such as acute infarction. To address functional effects of the antibody binding we
Mentors Mentors
Univ.-Prof. Dr. med. Volkmar Falk Prof. Dr. Dr. med. Maximilian Emmert Univ.-Prof. Dr. med. Christof Stamm Prof. Dr. med. Angela Kaindl PD Dr. med. Ellen Knierim Prof. Dr. med. Markus Univ.-Prof. Dr. med. Clinical Mentor Scientific Mentor Scientific Mentor Clinical Mentor Scientific Mentor Schülke-Gerstenfeld Harald Prüß Scientific Mentor Scientific Mentor German Heart Center Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Charité – Department of Cardiothoracic Department of Cardiovascular Department for Cardiothoracic and Universitätsmedizin Berlin Universitätsmedizin Berlin Charité – Charité – and Vascular Surgery Surgery Vascular Surgery Department of Department of Universitätsmedizin Berlin Universitätsmedizin Berlin Pediatric Neurology Pediatric Neurology Department of Department of Neurology [email protected] [email protected] [email protected] Pediatric Neurology and Experimental Neurology [email protected] [email protected] [email protected] [email protected] 124 Clinician Scientists 125
Dr. med. Christian Oeing Dr. med. Florence Pache
In Program From – to Fields of Research In Program From – to Fields of Research 02.2020–01.2023 › Basic Science 04.2019–03.2022 › Neurology › Heart Failure › Immunology Contact Contact › Autophagy › Neuroimmunology [email protected] [email protected] › Metabolism Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Internal Medicine and Department of Neurology Cardiology and Experimental Neurology Director Director Univ.-Prof. Dr. med. Burkert Pieske Univ.-Prof. Dr. med. Matthias Endres
Fine-Tuning the TSC2-MTOR Axis in Diabetic Cardiomyopathy Comprehensive Analysis of the Relation Between EBV-Infection and Intrathecal Ig Production in Multiple Sclerosis
Diabetes mellitus (DM) is linked with heart failure even Multiple sclerosis (MS) is the most frequent chronic perspective, MS can be regarded as a late complication after controlling for coronary artery disease and hyper- inflammatory demyelinating disease of the central ner- of EBV infection, a herpesvirus causing strong activation tension. This type of heart failure is called diabetic car- vous system (CNS). Time of onset typically is in young of B lineage cells during primary infection. Nevertheless, diomyopathy (DM-CMP). DM-CMP has become an increas- adulthood, neurological deficits tend to be irreversible the underlying mechanisms remain unknown. In this ingly recognized entity among clinicians, hence a better with a rapid decline in autonomic living. Early detection translational-mechanistic experimental research project understanding of its pathophysiology is necessary for and anti-inflammatory treatment is the key for preserving we want to investigate the relation between EBV infection diagnosis and treatment strategies. In this project we quality of life. Unfortunate for patients and clinical phy- (the most important environmental risk factor for MS) address the relevance of a novel phospho-site S1365 on sicians, there is no biomarker for MS. The most charac- and intrathecal Ig production (the most important lab- TSC2 in DM. In several murine DM models mTOR is known teristic laboratory finding comprises an intrathecal pro- oratory feature of MS) by addressing 2 research questions: to be hyperactivated. Our mouse model (S1365A and duction of immunoglobulins (Ig) which is not found in 1. How strong is the correlation of infection with EBV, as S1365E knock-in) can potentially alter mTOR signalling in healthy individuals. While intrathecal production of IgG measured by levels of antibodies to Epstein-Barr nuclear the diabetic heart and change disease course via several is detectable in >90% of MS patients, intrathecal produc- antigen-1 (EBNA-1) in serum, with the extent of a quanti- mechanisms including metabolic substrate shift and tion of IgA and IgM occurs in 10% and 20% respectively. tative intrathecal IgG, IgA and IgM production in patients altered autophagic flux. This discovery has not only impli- They all result from the invasion of the CNS by antibody with MS? 2. Is there a difference in the frequency distri- cations beyond the cardiomyocyte and the heart but it producing B lineage cells, but the trigger for and the time bution of intrathecal antibody production to EBV and to also reveals a novel mechanism by which PKG works as of CNS invasion are elusive. Importantly, it is well-estab- other common viruses in patients with MS? The ultimate a strong and drugable command point. lished that the intrathecal immune response in MS is aim of this project is thus to improve treatment of patients polyspecific (i.e., directed against a variety of different with MS through a better understanding of pathogenic target antigens) and frequently comprises antibodies to mechanisms operating in MS.« common viruses such as measles virus, rubella virus, and varicella zoster virus. Compelling evidence for an asso- ciation of infection with the Epstein-Barr virus (EBV) and MS can be found, to the point that from an epidemiological
Mentors Mentors
Univ.-Prof. Dr. med. Univ.-Prof. Dr. med. Prof. Dr. med. Prof. Dr. med. Univ.-Prof. Dr. med. Matthias Endres Univ.-Prof. Dr. med. Friedemann Paul PD Dr. med. Klemens Ruprecht Burkert Pieske Frank Heinzel, PhD David Alan Kass Johannes Backs Clinical Mentor Scientific Mentor Scientific Mentor Clinical Mentor Scientific Mentor Scientific Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Charité – Universitätsmedizin The Johns Hopkins Heidelberg Universität Department of Neurology Department of Neurology and Department of Neurology Berlin, Department of Internal Berlin, Department of Internal Hospital (Baltimore) (Heidelberg) and Experimental Neurology Experimental Neurology and NeuroCure and Experimental Neurology Medicine and Cardiology Medicine and Cardiology Clinical Research Center [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] heidelberg.de [email protected] 126 Clinician Scientists 127
Dr. med. Moritz Peiseler PD Dr. med. Constanze Pfitzer
In Program From – to Fields of Research In Program From – to Fields of Research 03.2021–02.2024 › Immunology 08.2018–02.2023 › Neurological Outcome of Children › Innate Immunity and Grown-Ups with Congenital Heart Contact Contact › Hepatology Disease [email protected] [email protected] › Intravital microscopy › Hypothermia Clinic Clinic Charité – Universitätsmedizin Berlin German Heart Center Berlin Department of Hepatology Department of Congenital Heart Disease and Gastroenterology Pediatric Cardiology Director Director Univ.-Prof. Dr. med. Frank Tacke Univ.-Prof. Dr. med. Felix Berger
In Depth Phenotyping and Functional Profiling of Macrophage »Of Heart and Mind«: A Longitudinal Neuropsychological Evaluation Subsets in Chronic Liver Injury and Regression of Children with Congenital Heart Disease
The liver is an important immune organ and provides Using a combination of novel linage-tracing tools with Neurodevelopmental deficits are the most common, and of Infant Development, which is a pediatric development the critical filter to prevent dissemination of blood-borne state-of-the-art intravital microscopy, we plan to inves- potentially most disabling long-term complications for test and consists of a series of developmental play tasks pathogens. The filter function is mediated by specialized tigate the fate and function of different macrophage patients with congenital heart disease (CHD) and their used to derive a developmental quotient. The patients liver macrophages, Kupffer cells, that are embryonically subsets in liver disease models. Genetic fate mapping treatment. However, only a few studies have investigated will be tested at the age of one, two and three years. In derived tissue resident macrophages. Kupffer cells have will allow us to differentiate bona fide Kupffer cells from the development of the child longitudinally. That is why summary, we would like to evaluate the neuropsycho- a unique intravascular location and an arsenal of spe- monocyte-derived macrophages. By using multicolor we would like to test these patients using different neu- logical development of children after surgical repair of cialized receptors to capture pathogens under flow con- intravital microscopy, we can investigate the function rological and developmental tests. This prospective a TOF, VSD or TGA, compare it to the normal development ditions. Furthermore, as intrahepatic sentinels, Kupffer of these subsets with regards to their critical function: longitudinal study evaluates the neuropsychological out- of children, and determine if there are differences cells initiate or suppress immunity in the liver via cross- capturing of blood-borne pathogens and initiating / sup- come of children who had a heart operation in the new- between these patient groups. Finally, we will study the talk with many other resident and infiltrating immune pressing immune responses in the liver via crosstalk born or infant age. Project 1: Common CHD: This patient neuropsychological development of children after resus- cells. Liver inflammation leads to a sustained influx of with other cells. These investigations will be comple- group includes children with common CHD who required citation and mechanical circulation support. monocyte-derived macrophages that augment the pool mented by using 25-color spectral flow cytometry to an operation in the new-born and infant period, i.e.: of liver macrophages. These bone marrow-derived cells further phenotype the different macrophage populations patients who had an arterial switch operation with trans- infiltrate as pro-inflammatory cells fueling liver inflam- identified. In addition, as a translational approach, we position of the great arteries (TGA), as a common oper- mation or as cells with a repair phenotype. To date, the will investigate liver biopsies of patients with various ation in the new-born period; children who had an oper- functional consequence of this macrophage heteroge- chronic liver diseases. We will isolate and phenotype ation of a ventricular septal defect (VSD) as the most neity and the fate of different macrophage subsets in liver macrophages with multicolor flow cytometry and common CHD; and children with surgical repair of a chronic liver disease is enigmatic. Since patients with correlate the findings with clinical characteristics to tetralogy of Fallot (TOF) as a cyanotic CHD. Project 2: chronic liver diseases are hallmarked with immune dys- better understand macrophage biology in humans. Ulti- Resuscitation and mechanical circulation support: regulation, inefficient pathogen clearance on the one mately, by gaining a better understanding of the func- Included is patients who had a resuscitation (longer >five hand and exaggerated immune responses on the other tional consequences of liver macrophage heterogeneity, minutes) and an implantation of an extracorporeal mem- hand, understanding the contribution of different mac- we hope to identify novel pathways that can the targeted brane oxygenation and ventricular assist device. The rophage subsets in the liver is of critical importance. therapeutically in patients. central measurement instrument is the Bayley Scales
Mentors Mentors
Univ.-Prof. Dr. med. Frank Tacke Univ.-Prof. Dr. med. Andreas Diefenbach Univ.-Prof. Dr. med. Felix Berger PD Dr. med. Katharina Schmitt Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Institute of Microbiology, Infectious German Heart Center Berlin German Heart Center Berlin Department of Hepatology Diseases and Immunology Department of Congenital Heart Department of Congenital Heart and Gastroenterology Disease Pediatric Cardiology Disease Pediatric Cardiology [email protected] [email protected] [email protected] [email protected] 128 Clinician Scientists 129
Dr. med. Dominique Piber Dr. med. Dominika Pohlmann
In Program From – to Fields of Research In Program From – to Fields of Research 09.2020–08.2023 › Psychoneuroimmunology 08.2018–11.2022 › Uveitis › Depression › Immunology Contact Contact › Metabolic disorders › Imaging [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Psychiatry and Department of Ophthalmology Neurosciences Director Director Univ.-Prof. Dr. med. Antonia Joussen, FEBO Univ.-Prof. Dr. med. Dipl.-Psych. Isabella Heuser-Collier
Exploring Inflammatory Pathways Linking Immunological and Morphological Signatures in Non-Infectious Depression and Comorbid Obesity Chorioretinitis to Improve Therapy
Major depressive disorder (MDD) is associated with alter- might be especially suitable candidates for clinical trials Non-infectious chorioretinitis, a form of posterior uveitis better monitoring of inflammatory activity and prediction ations in numerous biological systems, including a dys- of anti-inflammatory agents. Thus, the present BIH-proj- encompasses a group of potentially blinding disorders, of disease progression. The T-cell subpopulation will be function of the immune system. While the cellular source ect comprises two studies: a cross-sectional and a lon- predominantly occurring in the working age group. Bird- characterized and phenotyped by mass cytometry. The of inflammation in MDD is still poorly understood, accu- gitudinal study. The cross-sectional study examines shot-Retinochoroiditis (BSRC) and Punctate Inner Cho- assessment of morphological signatures will be detected mulating data point towards an increased activation of putative differences in the proinflammatory monocyte roidopathy (PIC) are an organ-specific inflammation with by using multimodal imaging techniques, such as optical monocyte cell populations in depressed patients. Indeed, phenotype and molecular signature across patients with distinct morphological and genetic characteristics. Dis- coherence tomography, fluorescence- and indocyanine- several studies, including prior work of our group, demon- MDD, obesity, comorbid MDD and obesity, and healthy ease hallmarks manifest as distinct multiple hypopig- green angiography, fundusautofluorescence, and a new strated that patients with MDD show an expansion of controls. The longitudinal study, embedded in an ongoing mented chorioretinal lesions in BSCR, small punctate non-invasive modality the optical coherence tomography non-classical monocytes (also commonly referred to as RCT, examines whether add-on simvastatin (a lipid-low- lesions and choroidal neovascularization in PIC patients. angiography (Pohlmann D et al., Ocul Immunol Inflamm. »proinflammatory monocyte phenotype«). In addition, ering agent with pleiotropic effects including anti-in- Both diseases show a clinically progressive course with 2017; Pohlmann D et al. Br J Ophthalmology. 2019, Pohl- MDD frequently co-occurs with other inflammation-re- flammatory properties) to standard antidepressant atrophy of the outer neurosensory retina and formation mann D et al. Br J Ophthalmology. 2019). All collected lated conditions, such as metabolic syndrome and obe- treatment alters the proinflammatory monocyte pheno- of fibrotic scars in the final stage. The etiology and patho- data will be brought into an overall context, in order to sity. Interestingly, obese patients are reported to show type and molecular signature in patients with MDD and genesis are largely unknown but considered as driven get a better understanding of these two diseases and a proinflammatory monocyte phenotype, which parallels comorbid obesity. The present BIH-project aims to pro- by an autoimmune response. It is assumed that BSRC is potentially translate to more targeted therapy. previous findings in MDD. However, prior research has vide new insights in the shared cellular and molecular a chronic T-helper 17-cell mediated inflammation, but evaluated the proinflammatory monocyte phenotype in inflammatory pathways of MDD and comorbid obesity, only few studies with single parameters and a small MDD and obesity only in separate studies. Furthermore, which could translate to new antidepressant therapies number of patients were reported. Therefore, the aim given that MDD and obesity have both been linked to for comorbid patients. of my research project is to identify immunological and inflammation, patients with comorbid MDD and obesity morphological biomarkers in BSCR and PIC patients for
Mentors Mentors
Univ.-Prof. Dr. med. Christian Otte Prof. Dr. Psych. Stefan Gold Univ.-Prof. Dr. med. Univ.-Prof. Dr. rer. nat. Andreas Thiel Clinical Mentor Scientific Mentor Antonia Joussen, FEBO Scientific Mentor Clinical Mentor Charité – Department of Psychiatry Charité – Universitätsmedizin Berlin Berlin-Brandenburg Center for and Neurosciences Department of Psychiatry and Charité – Universitätsmedizin Berlin Regenerative Therapies Neurosciences Department of Ophthalmology [email protected] [email protected] [email protected] [email protected] 130 Clinician Scientists 131
Dr. med. univ. Uwe Primessnig, PhD PD Dr. med. Magdalena Sarah Prüß
In Program From – to Fields of Research In Program From – to Fields of Research 04.2019–03.2022 › Interventional cardiology 08.2018–04.2023 › Gastroenterology › Cellular mechanisms of contractile › Chronic Pain Contact Contact dysfunction and arrhythmias › Immune System [email protected] [email protected] › Imaging Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Internal Medicine and Department of Gastroenterology, Cardiology Infectious Diseases and Rheumatology Director Director Univ.-Prof. Dr. med. Burkert Pieske Univ.-Prof. Dr. med. Britta Siegmund
Sudden Cardiac Death, Arrhythmias and Cardiac Contractile Functional Brain Changes and Pain Reduction in Patients Dysfunction in HFpEF with Inflammatory Bowel Disease
Heart failure with preserved ejection fraction (HFpEF) is Brain Changes and Pain Reduction in Patients with Inflam- via activation of the ENS have not been studied yet, we an increasingly common syndrome with poor prognosis, matory Bowel Disease Inflammatory bowel diseases (IBD) aim to analyze the brain-gut axis by performing a pro- high mortality and morbidity. Sudden cardiac death (SCD) are associated with chronic pain in up to 38% of patients. spective clinical phase-III-trial: tDCS will be applied to is the most common mode of death in HFpEF (26% SCD Several chronic pain conditions have previously been IBD patients to ameliorate IBD-associated pain. In par- in I-Preserve and 24.3% in TOPCAT. However, the patho- shown to result in functional and structural changes in allel, the impact of tDCS on CNS structure and function genesis of sudden cardiac death in this patient popula- both the peripheral and the central nervous system (CNS). (fMRI) as well as IBD disease activity and the dynamics tion is not well-understood. The major aims of the project Those so-called maladaptive changes are described as of immune cell activity (mucosal and in peripheral blood are to investigate underlying cellular causes of contrac- the phenomena of hyperexcitability and hypersensitivity. samples) will be studied in patients before and after tile dysfunction and calcium mediated arrhythmias in Recently published work suggests a bidirectional inter- tDCS treatment. Finally, in search of the mechanistic link cardiorenal and metabolic HFpEF. action between the central and the enteric nervous sys- between stimulation of the CNS and mucosal inflamma- tem (ENS). Visceral pain in chronic pancreatitis has been tion, we will switch to a mouse model of colitis-associ- associated with an inflammatory infiltration of pancreatic ated chronic visceral pain. This will allow to address the perineuria that includes macrophages, T-cells, and mast interrelation of CNS, ENS, neurotransmitters production cells. We have previously shown that transcranial direct and mucosal inflammation and to study underlying mech- current stimulation (tDCS), a non-invasive method to anisms by assessing the role of a distinct set of neu- transcranial modulate neuronal plasticity, is efficient to rotransmitters as well as the contribution of inflamma- treat pain in IBD patients (Prüß/Volz et al., Pain 2016). tory cellular infiltrates. With this approach, we aim to Since the impact of tDCS on the CNS of IBD patients as decipher mechanistic insights of the gut-brain-axis and well as putative effects on the mucosal immune system hence identify novel therapeutic targets.
Mentors Mentors
Univ.-Prof. Dr. med. Burkert Pieske Univ.-Prof. Dr. med. Ph. D. Frank Heinzel Prof. Dr. med. Felix Bermpohl Univ.-Prof. Dr. med. Britta Siegmund Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Internal Medicine and Department of Internal Medicine and Department of Psychiatry and Department of Gastroenterology, Cardiology Cardiology Psychotherapy Infectious Diseases and Rheumatology [email protected] [email protected] [email protected] [email protected] 132 Clinician Scientists 133
Dr. med. Tobias Püngel Dr. med. Judith Rademacher
In Program From – to Fields of Research In Program From – to Fields of Research 01.2021–12.2023 › Non-alcoholic steatohepatitis 04.2020–03.2023 › Spondyloarthritis (NASH) & Fibrosis › Acute Anterior Uveitis Contact Contact › Immunology › Arthritogenic Antigens [email protected] [email protected] › Metabolism Clinic › Treatment strategies Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Hepatology Department of Gastroenterology, and Gastroenterology Infectious Diseases and Rheumatology Director Director Univ.-Prof. Dr. med. Frank Tacke Univ.-Prof. Dr. med. Britta Siegmund
In Depth Phenotyping and Functional Profiling of Macrophage Gut-Joint-Eye Axis – Arthritogenic Antigens and Their Relevance Subsets in Chronic Liver Injury and Regression in Acute Anterior Uveitis and Spondyloarthritis
Non-alcoholic fatty liver disease (NAFLD) became the Single-cell RNA sequencing, 3D liver biochip system). Axial spondyloarthritis (axSpA) is a chronic inflammatory triggering inflammation as autoimmune reaction in spe- most common chronic liver disease worldwide and its Among potential inflammatory targets myeloid liver cells disease which primarily affects the sacroiliac joints and cific tissues (eye, gut, joint). The objective of this project prevalence is still increasing. NAFLD is closely associated (Monocytes and Monocyte-derived Macrophages) axial skeleton, though also extra-spinal and extra-artic- is to identify disease-specific clonal expanded T cell with the metabolic syndrome and can progress to non-al- emerged as key players orchestrating disease progres- ular manifestations occur. Acute anterior uveitis (AAU) receptors and possible shared and distinct arthritogenic coholic steatohepatitis (NASH), which can further advance sion. Therefore, we will further elucidate effects of phar- is the most frequent extra-articular manifestation, pres- antigens in axSpA and AAU. The analysis of T cells from to fibrosis and ultimately liver cirrhosis. Strikingly, liver macologically targeting macrophage recruitment on ent in a third of axSpA patients. We initiated a prospec- different tissues (peripheral blood, inflamed joint, ante- fibrosis is the main determinant of liver-related and dysmetabolism in NASH and fibrosis. In a recent study tive cohort of 200 patients with non-infectious AAU rior chamber of the eye) will enable us to compare their overall mortality and in contrast to cirrhotic stages, liver we could demonstrate that targeting several PPAR iso- (GESPIC-Uveitis), who underwent a standardized rheu- T cell receptor repertoire and challenge the arthritogenic fibrosis and NASH are considered as reversible. At pres- forms in different cellular components of the liver (e.g. matological assessment at inclusion as well as an MRI antigene hypothesis. Furthermore, we will analyze ent, therapeutic options beyond lifestyle modifications hepatocytes – PPARα, macrophages – PPARδ, stellate of the sacroiliac joints. In a preliminary analysis, 60% of whether those antigens are part of the gut microbiota. are limited and difficult to sustain – approved pharma- cells – PPARγ) dramatically improved the NASH pheno- the AAU patients had concomitant axSpA (Rademacher In a confirmatory analysis, we will verify our findings in cological therapies are still lacking. During disease pro- type over single PPAR isoform targeting in experimental et al, EULAR 2019). Though the exact pathogenesis the patients of the GESPIC-Uveitis cohort. We thereby gression of NASH and hepatic fibrosis multiple signalling mouse models (Lefere S*, Puengel T* et al, JHEP 2020). remains unknown up to date, both, axSpA and AAU seem aim to get a deeper understanding of the pathogenesis pathways (e.g., disrupted metabolic and inflammatory Based on these findings and as currently still ongoing to result from a complex interplay between a genetic of axSpA and the gut-joint-eye axis. responses) are dysregulated. Latest pathomechanistic clinical trials indicate that single drug treatments demon- background (mainly HLA-B27 positivity), external influ- insights prompted the experimental and clinical explo- strate lacking efficacy in reaching relevant endpoints ences such as mechanic stress, (bacterial) infection and ration of many new potential drug targets. In the current such as fibrosis regression, we will additionally explore microbiota. According to the »arthritogenic antigen project we will further elucidate mechanistic insights of the prospects of rationally designed combination ther- hypothesis« of pathogenesis, peptide antigens presented the cross-links between metabolism and inflammation apies in NASH and fibrosis. by HLA-B27 to CD8+ T cells might initiate autoimmunity in NASH and fibrosis progression. Going into detail, we in SpA. Our hypothesis is, that arthritogenic antigens will investigate effects of metabolism modifying inter- might be part of the microbiome and lead to an activation ventions on macrophage functionality in experimental of antigen-specific T cells in genetically predisposed and human NASH employing up-to-date techniques (e.g., individuums via disturbed gut and or skin barrier, thus
Mentors Mentors
PD Dr. med. Münevver Demir Prof. Dr. med. Alexander Wree Univ.-Prof. Dr. med. Britta Siegmund Prof. Dr. med. Denis Poddubnyy Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Hepatology and Department of Hepatology Department of Gastroenterology, Department of Gastroenterology, Gastroenterology and Gastroenterology Infectious Diseases and Infectious Diseases and Rheumatology Rheumatology [email protected] [email protected] [email protected] [email protected] 134 Clinician Scientists 135
Dr. med. Damian Tobias Rieke Dr. med. Paul Ritschl
In Program From – to Fields of Research In Program From – to Fields of Research 01.2019–06.2022 › Precision Medicine 01.2019–09.2022 › Transplant Immunology › Immune Therapy › Organ Allocation Contact Contact › Head and Neck Cancer › Allorecognition [email protected] [email protected] › Tumor Biology › Colonic Diverticulitis Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Hematology, Department of Surgery Oncology and Cancer Immunology Director Director Univ.-Prof. Dr. med. Johann Pratschke PD Dr. med. Jan Eucker
Development of a Translational Precision Oncology Program The Impact of Donor Derived Microparticles for Head and Neck Cancers Following Solid Organ Transplantation
Outcome is dismal for patients with advanced cancers, Following solid organ transplantation, leukocyte migra- mendous role in initiating the adaptive immune response, including patients with tumors of the head and neck. tion and trafficking through the recipient´s body and antigen recognition in the long-term is attributed to the Tumors are characterized by genomic alterations. Novel subsequent allorecognition are the prerequisites for the indirect pathway. During the past decades, the idea that sequencing techniques allow for a rapid and compre- development of an alloimmune response. Trafficking of secondary lymphoid organs are supposed to be the major hensive identification of these alterations. The integra- leukocytes through blood or lymphatic vessels, as well sites of antigen presentation is a widely accepted con- tion of molecular tumor analyses into an individualized as their migration in lymphoid or solid organs, is critical cept. Key to the following project is the comprehensive treatment plan promises an improved outcome with for antigen presentation initiating either allograft rejec- analysis of passenger leukocytes, their pathway through limited toxicity. However, the complexity of genomic tion or mediating allograft acceptance (tolerance). In the body and the sites of alloantigen recognition by the alterations, difficulties in clinical trial design, availability general, the current understanding of alloantigen rec- recipient. Especially lymphatic vessels and their function of drugs and many more challenges still limit the appli- ognition by the recipient’s immune system ultimately as »leukocyte highway« will be brought into focus. The cation of precision oncology in the clinic. In my clinician shaping the specific graft rejection mechanism implies fact that surgeons do not reconnect lymphatic drainage scientist project, I am working on the integration of two forms of donor antigen recognition that are defined of solid organs during transplantation questions tradi- molecular data into the clinical management of patients by the source of APC: during »direct« presentation tional textbook knowledge but simultaneously offers with advanced cancers with a focus on head and neck donor-derived cells display donor major histocompati- new scientific possibilities to study passenger leukocytes neoplasms. My research focuses on the reproducible bility complex (MHC) molecules to the recipient, whereas and other donor derived antigen carriers like micro par- interpretation of genomic data to identify therapeutic during »indirect« presentation donor-derived antigens ticles. What is the fate of passenger leukocytes after targets, as well as an improved understanding of tumor are acquired by recipient APCs that process and present transplantation? How long do they survive in the recip- biology in immune escape and complex cancer genomes. these peptides to the host. Although the direct pathway ient? Is there a formation of donor derived micro parti- of allorecognition has been described as playing a tre- cles? What is the role of these micro particles?
Mentors Mentors
PD Dr. med. Sebastian Ochsenreither Univ.-Prof. Dr. med. Ulrich Keilholz Prof. Dr. med. Robert Öllinger PD Dr. med. Moritz Schmelzle Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Hematology, Comprehensive Cancer Center Department of Surgery Department of Surgery Oncology and Cancer Immunology [email protected] [email protected] [email protected] [email protected] 136 Clinician Scientists 137
Dr. med. Susanne Rittig PD Dr. med. Anne Rübsam, FEBO
In Program From – to Fields of Research In Program From – to Fields of Research 08.2020–07.2023 › Immunotherapy 11.2017–10.2021 › Neurodegeneration › Multiple Myeloma › Diabetic Retinopathy Contact Contact › Dendritic Cell › Oxidative Stress [email protected] [email protected] › Cancer Vaccine Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Hematology, Department of Ophthalmology Oncology and Cancer Immunology Director Director Univ.-Prof. Dr. med. Antonia Joussen, FEBO Univ.-Prof. Dr. med. Ulrich Keller
Augmenting Dendritic Cell Function for Rational Role and Regulation of Nox4 in Retinal Cells During Diabetes Immunotherapies in Multiple Myeloma
Multiple Myeloma (MM) is a heterogeneous hematologic possibly further impairing their ability to mount immune Anti-VEGF therapies have tremendously improved the role and regulation of Nox4 in cell types other than vas- malignancy with courses varying from asymptomatic responses to dying tumor cells. Our group and others treatment of proliferative diabetic retinopathy (DR) and cular cells, namely retinal neurons, MGCs, and pericytes. stages to aggressive disease. Despite a plethora of have previously demonstrated altered DC phenotype macular edema, the two ocular late manifestations of Thus with this proposed research project, I aim to develop approved therapies the disease largely remains incurable. and impaired function by exposure to various therapeutic diabetes, but there are still no therapies targeting early a complete picture of Nox4 activity in the retina during Hence, novel anti-cancer therapeutic approaches com- agents and we focus on elucidating the influence of fur- stages of the disease to prevent alterations of the neu- diabetes by evaluating the role and regulation of Nox4 bining efficacy, tolerability and minimal treatment bur- ther therapeutic drugs in order to identify optimal part- roretina and thereby preserve visual function. We and as a major source of ROS in the aforementioned cells den are much-needed. Cancer vaccines have shown to ners for DC-based immunotherapies. Another scientific others reported on the early neurodegeneration in DR, under diabetic conditions in vitro and in two models of be mainly well-tolerated and can promote long-term interest is the role of checkpoint molecules in MM. In triggered by pathomechanisms such as inflammation diabetes (type 1 & 2) in vivo. We further want to evaluate specific anti-tumor immune responses. Dendritic cells contrast to a variety of other cancers, immune checkpoint and the ER stress response in retinal neurons and Müller the rationale of Nox4 inhibition in preventing oxidative (DCs) as the most potent antigen-presenting cells are blockade, e. g. using blocking antibodies to the Pro- glial cells (MGCs) subjected to diabetes-related metabolic stress-induced early neurodegenerative changes in DR. vital players in inducing, maintaining and regulating grammed cell death protein 1 or its ligand to date has stress conditions and in streptozotocin (STZ) – induced If such a treatment could be realized, it may be possible these immune responses and therefore represent a cru- failed to achieve clinical efficacy in MM. Here too, an diabetic mice. Numerous reports indicate the importance to arrest DR at the earliest stages of its development. cial component of vaccination. Considerable objective exhausted immune system may be the reason for missing of oxidative stress in the development of the early neu- responses have been achieved with DC-based vaccines. response. Even though DCs are dominant partners of rodegenerative changes in DR. Hyperglycemia-dependent However, this approach alone has not yet met expecta- T cells, the role of DCs in this setting is not well-charac- generation of reactive metabolites lead to excessive tions concerning the clinical outcome. Considering this terized. Furthermore, other immune checkpoints may be reactive oxygen species production (ROS), which are likely low clinical efficacy, approaches combining therapeutic of relevance. One molecule we seek to further analyse to be a key contributor to the development of DR. NADPH cancer vaccine strategies with approved agents are being in DCs is Osteoactivin, which was recently shown to (Nox) enzymes generate reactive oxygen species (ROS) designed. This provides the opportunity to introduce be an immune checkpoint that impairs T-cell activation. and they are widely distributed throughout the retina. cancer vaccines into treatment at an early point of dis- We plan to further elucidate the role of checkpoint Compelling evidence suggests, that in particular Nox4 ease before onset of severe immune exhaustion. However, molecules in DCs for a possible targeted manipulation is an important source of ROS in the retina during DR a critical challenge in using therapeutic agents to pro- of T cell responses in the context of DC-based and thus contributes to the vascular pathology in DR. mote cancer immunotherapy is that they potentially also immunotherapies. Still today, there is a gap of knowledge regarding the influence immune cells in the tumor microenvironment,
Mentors Mentors
Univ.-Prof. Dr. med. Ulrich Keller Prof. Dr. med. Jan Krönke Univ.-Prof. Dr. med. Il-Kang Na Univ.-Prof. Dr. med. Univ.-Prof. Dr. rer. nat. Olaf Strauß Clinical Mentor Scientific Mentor Scientific Mentor Antonia Joussen, FEBO Scientific Mentor Clinical Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Hematology, Department of Hematology, Department of Hematology, Charité – Universitätsmedizin Berlin Department of Ophthalmology Oncology and Cancer Immunology Oncology and Cancer Immunology Oncology and Cancer Immunology Department of Ophthalmology [email protected] [email protected] [email protected] [email protected] [email protected] 138 Clinician Scientists 139
Dr. med. Laura Katharina Schmalbrock Dr. med. Eva Vanessa Schrezenmeier
In Program From – to Fields of Research In program From – TO Fields of Research 01.2020–12.2022 › Acute myeloid leukemia 07.2019-06.2022 › Immunology › Multiple Myeloma › B cells Contact Contact › Drug resistance › SLE [email protected] [email protected] › CRISPR screenings › COVID Clinic Clinic › Vaccination Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Hematology, Medical Department, Oncology and Cancer Immunology Division of Nephrology and Internal Intensive Care Medicine Director Univ.-Prof. Dr. med. Ulrich Keller Director Univ.-Prof. Dr. med. Kai-Uwe Eckardt
Functional Characterization of Genomic Networks in Acute Epigenetic Regulation of Plasma Cell Differentiation Myeloid Leukemia Using CRISPRi/a Screenings in Systemic Lupus Erythematosu
While large sequencing studies have comprehensively kemogenesis with focus on mutations in epigenetic reg- Patients with Systemic Lupus Erythematosus (SLE) show characterized recurrent gene mutations in acute myeloid ulating genes (IDH1, ASXL1). Besides a deeper understand- epigenetically mediated altered differentiation of plasma leukemia (AML), the functional consequences of these ing of the genomic network that promotes leukemogen- cells (PC). PC represent ultimately differentiated B cells mutations and the impact of genetic interactions that esis in the context of these specific mutations, we producing protective antibodies in the bone marrow, but drive leukemogenesis are less well understood. Muta- eventually aim at finding new vulnerabilities that can be in case of autoimmune conditions such as SLE, also patho- tions in epigenetic modifying genes, such as Isocitrate used for pharmacological targeting, thus translating our genic autoantibodies. Plasmablasts (PB) are immature PC dehydrogenase 1 and 2 (IDH1/2) and Additional sex combs findings into the clinic. that circulate in the peripheral blood. In patients with like 1 (ASXL1), occur frequently in AML patients. It is known lupus flares an expansion of the PB population is detect- that these mutations alter methylation status, which able which contains autoreactive PB and correlates with affects cell differentiation and gene expression. In mouse SLE activity. Very recently, increasing interest focusses on models however, these mutations alone did not induce epigenetic regulation of PC differentiation via histone leukemia, pointing to additional genetic alterations that methylation. It has been shown in mice as well as in a play a role in leukemogenesis. Genome wide CRISPR human in vitro model that enhancer of zeste homolog 2 screens are powerful tools to identify and functionally (EZH2) catalyzing the histone methylation of H3K27me3 is characterize genes and vulnerabilities in cancer. In addi- one of the key mechanisms of PC development. We hypoth- tion to CRISPR-Cas9 knock-out screenings, which are esize that patients with SLE differ from healthy controls commonly used in most studies, more recently gain- and in PC differentiation and that this is in part epigenetically loss-of-function CRISPRa/CRISPRi screenings have been mediated through H3K27me3. Further, we propose that a developed, which enable to comprehensively study acti- modification of H3K27me3 during PC differentiation via vation and inhibition of gene expression. Within my proj- inhibition of EZH2 or the demethylating opponent of EZH2, ect, we plan to perform genome wide CRISPR activation jumonji domain containing-3 (JMJD3), can revert aberrant (CRISPRa) and CRISPR interference (CRISPRi) screenings PC differentiation and function in SLE and holds promise to identify novel genes and pathways that promote leu- for therapy.
Mentors Mentors
PD Dr. med. Jan Eucker Univ.-Prof. Dr. med. Lars Bullinger Univ.-Prof. Dr. med. Klemens Budde Univ.-Prof. Dr. med. Kai Schmidt-Ott Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Hematology, Oncology Department of Hematology, Oncology Medical Department, Medical Department, and Cancer Immunology and Cancer Immunology Division of Nephrology and Internal Division of Nephrology and Internal Intensive Care Medicine Intensive Care Medicine [email protected] [email protected] [email protected] [email protected] 140 Clinician Scientists 141
Dr. med. Wibke Schulte Dr. med. Leonille Schweizer
In Program From – to Fields of Research In Program From – to Fields of Research 08.2018–04.2022 › Macrophage Migration 08.2018–10.2021 › Cancer Genetics Inhibitory Factor › Epigenetics Contact Contact › Sepsis [email protected] [email protected] › Emergency General Surgery Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Surgery Department of Neuropathology Director Director Univ.-Prof. Dr. med. Johann Pratschke Univ.-Prof. Dr. med. Frank Heppner
Role of MIF in Human Acute Peritonitis Molecular Characterization of Spinal Paragangliomas
Sepsis, defined as life-threatening organ dysfunction that mediate lethal septic shock, thus suggesting avenues Paragangliomas are rare neuroendocrine neoplasms that ship to non-spinal paragangliomas and other neuroen- caused by a dysregulated host response to infection, is for new therapeutic approaches to sepsis. We hypothe- can develop at various body sites including the head, docrine tumors, we investigate a comprehensive series a leading cause of death in intensive care units worldwide. size that the severity of peritoneal infection and the neck, thorax, and abdomen. Approximately 25% have an of cauda equina paragangliomas using a combination of Management of sepsis includes timely control of the precise nature of intraabdominal inflammation with unfavorable course and patients with metastatic para- whole exome sequencing and genome-wide DNA meth- infection source, which in sepsis resulting from intraab- respect to macrophage activation determine the success gangliomas have limited treatment options and poor ylation profiles. We further aim to identify molecular risk dominal infection often requires emergent surgery. Delay of surgical reconstruction in the acute setting. Our pre- prognosis. Unlike other types of cancer, there is no estab- factors for better predicting clinical outcomes and drug- of surgical intervention and inability to obtain source clinical data indicate that MIF substantially aggravates lished grading system and no reliable predictive and gable targets for future personalized therapy strategies control dramatically increase mortality. However, it sepsis disease progression and suggest that pharmaco- prognostic markers based on morphology and immuno- in patients with malignant tumors. remains controversial whether source control should be logic inhibition of MIF may be of therapeutic value. To histochemistry. Comprehensive epigenetic and genetic followed by complete reconstruction of the gastrointes- further define mechanisms that control favorable surgical characterization of non-spinal paragangliomas revealed tinal tract during emergent surgery or whether limited results and, thus, sepsis outcome we propose two specific a diversity of driver alterations affecting multiple genes and repeated surgical interventions according to a dam- aims: 1. To precisely characterize macrophage responses and pathways and resulted in the establishment of age control strategy pose additional benefit. Macrophage in human acute peritoneal infection/inflammation, and molecularly defined subtypes correlating with clinical migration inhibitory factor (MIF) is an immunoregulatory 2. To establish mechanisms by which MIF aggravates outcome. Moreover, at least one-third of non-spinal cytokine that is of special interest in sepsis pathophys- human disease progression, and to test the value of paragangliomas are associated with inherited cancer iology because functional MIF polymorphisms predict pharmacological MIF inhibition as a potential therapeutic susceptibility syndromes, which is the highest rate mortality in different infections, and experimental stud- target to diminish sepsis-related mortality. among all tumor types. Paragangliomas of the central ies indicate that anti-MIF improves survival even when nervous system instead occur almost exclusively in the administered eight hours after infectious insult. Our cauda equina and are considered non-familial. However, preclinical data indicate that MIF levels are elevated in genetic and epigenetic alterations in spinal paragangli- septic shock, that MIF recruits highly proinflammatory omas have not been investigated so far. In order to gain macrophage subsets to the site of peritoneal infection further insights into the molecular background of cauda and that MIF regulates macrophage activation responses equina paragangliomas and their ontogenetic relation-
Mentors Mentors
PD Dr. med. Michael Knoop Univ.-Prof. Dr. med. PD Dr. med. Arend Koch Dr. rer. nat. Dr. phil. Anne Schöler Clinical Mentor Igor-Maximilian Sauer Clinical Mentor Scientific Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Surgery Charité – Universitätsmedizin Berlin Department of Neuropathology Department of Neuropathology Department of Surgery [email protected] [email protected] [email protected] [email protected] 142 Clinician Scientists 143
Dr. med. Elise Siegert Dr. med. Christoph Tabeling
In program From – TO Fields of Research In Program From – to Fields of Research 04.2019–07.2023 › Immunology 07.2019–09.2022 › Pulmonary hypertension › B cells › Pulmonary circulation Contact Contact › SLE › Asthma [email protected] [email protected] › COVID › Pulmonary th2 inflammation Clinic › Vaccination Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Rheumatology Department of Infectious Diseases and Clinical Immunology and Respiratory Medicine Director Director Univ.-Prof. Dr. med. Gerd-Rüdiger Burmester Univ.-Prof. Dr. med. Norbert Suttorp
Neuromuscular Involvement in Systemic Sclerosis Role of Spleen Tyrosine Kinase (Syk) in Pulmonary Arterial Hypertension (PAH)
The aim of my project is to assess the prevalence and Pulmonary arterial hypertension (PAH) is a fatal condition type mice or mice deficient in eNOS, PKCα or mast cells nature of neuromuscular involvement in Systemic Sclerosis characterized by pulmonary vasoconstriction and pul- with or without inhibition of Syk, protein kinase C (PKC), (SSc). SSc is a rare connective tissue disease characterized monary arterial remodeling leading to increased pulmo- rho kinase and/or nitric oxide (NO) synthase. Pulmonary by the pathophysiological triad of microvascular dysfunc- nary vascular resistance and ultimately right heart failure. vascular hyperresponsiveness was investigated following tion, tissue fibrosis and autoimmune inflammation. Spe- Intense research within the past three decades led to induction of pulmonary Th2 inflammation. Our data iden- cifically, we will screen patients for symptoms of small successful translation of pharmacological compounds, tify Syk as a central regulator of pulmonary vasocon- fiber neuropathy (SFN) and confirm the diagnosis by skin which are able to improve both quality of life and survival striction. Syk was expressed in pulmonary arterial biopsy. Recent studies show that approximately 45% of of PAH patients. However, despite modern PAH-specific smooth muscle cells of both control and PAH lungs. Syk all patients suffer from neuropathic pain. However, there therapy, PAH remains to be a lethal disease and further inhibition diminished pulmonary vasoconstriction in is no study systematically evaluating potential causes of research is required. From previous studies we learned human PCLS and in isolated mouse lungs independent neuropathic pain in SSc. Even though SFN is a well-recog- that in the airways the non-receptor tyrosine kinase of eNOS, PKCα or mast cells. In preconstricted lung vas- nized complication of other connective tissue diseases spleen tyrosine kinase (Syk) promotes inflammation, culature, Syk inhibition rapidly reversed vasoconstriction such as Systemic Lupus Erythematosus, it has not been smooth muscle cell proliferation and contraction (Tabe- in a NO-independent manner. Pulmonary vascular hyper- assessed as a cause for neuropathic pain in SSc, yet. Our ling, C. et al. Allergy 2017 Jul;72(7):1061-1072). However, responsiveness was markedly reduced following Syk hypothesis is that SFN is a common complication of SSc. little is known about the expression and role of Syk in inhibition. Thus, Syk may be a promising target in PAH In a second project we will perform a retrospective analysis the vascular compartment of the lung. Therefore, in this therapy and the effects of Syk inhibition on pulmonary of SSc muscle biopsies according to current neuropatho- ongoing project, we analyze Syk expression and function arterial remodeling and pulmonary hypertension will be logical standards. We will try to identify a morphological in the pulmonary vasculature and its possible involve- further analyzed in this project. Moreover, we attempt pattern that is specific to SSc. We reckon that the origin ment in the pathogenesis of PAH. To date, Syk expression to further characterize the intracellular Syk-mediated of neuromuscular involvement in SSc is not only destruc- was assessed in human (PAH vs. donor) and murine lungs signaling cascade leading to pulmonary arterial smooth tive fibrosis and obliterative vasculopathy, but that the by immunofluorescence and spectral confocal micros- muscle cell contraction. interplay between immune cells and nerve cells is respon- copy. Syk function was analyzed in human precision-cut sible for peripheral tissue damage. lung slices (PCLS) and in isolated perfused lungs of wild-
Mentors Mentors
PD Dr. med. Katrin Hahn Univ.-Prof. Dr. med. vet. Anja Hauser-Hankeln Univ.-Prof. Dr. med. Martin Witzenrath Univ.-Prof. Dr. med. Wolfgang Kübler Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology Department of Rheumatology Department of Infectious Diseases and Institute of Physiology and Experimental Neurology and Clinical Immunology Respiratory Medicine [email protected] [email protected] [email protected] [email protected] 144 Clinician Scientists 145
Dr. Loredana Vecchione, MD PhD Dr. med. Jan Voß
In program From – TO Fields of Research In Program From – to Fields of Research 01.2020–12.2022 › Translational research 08.2020–07.2023 › bone healing › Biomarker discovery in CRC › immune system Contact Contact › Identification of new [email protected] [email protected] therapeutical options in CRC Clinic › Dissecting the biology of CRC Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Hematology, Department of Oral Oncology and Cancer Immunology and Maxillofacial Surgery Director Director Prof. Dr. med. Sebastian Stintzing Univ.-Prof. Dr. med. Dr. med. dent. Max Heiland
Studying the Concordance of Molecular Subtypes of Primary Biomarker for Impaired Bone Healing of the Mandible and Metastatic CRC in Patient Samples and Organoids
Focus on my research is the better understanding of the This prospective research project is a hypothesis-testing CRC biology in order to identify new therapeutical options blinded study design. The project objective is to pro- for the treatment of CRC. To this end, we use CRC organoid spectively validate CD8+ TEMRA cells as a biomarker for models and we compare in vitro data with in vivo data. impaired fracture healing in (A) mandibular corpus frac- We furthermore stratify our models, as well as patients tures and (B) mandibular osteotomies in the setting of samples in different molecular subtypes in order to define mandibular displacement surgery. The project hypothesis subgroups who may benefit from exsisting and new emerg- here is that CD8+TEMRA cell expression acts as a potential ing treatments. prognostic biomarker with high diagnostic precision in terms of differentiating between normal and impaired fracture healing.
Mentors Mentors
Prof. Dr. med. Sebastian Stintzing Univ.-Prof. Dr. med. Ulrich Keilholz Univ.-Prof. Dr. med. Dr. med. dent. Univ.-Prof. Dr.-ing. Georg Duda Clinical Mentor Scientific Mentor Max Heiland Scientific Mentor Clinical Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Hematology, Oncology Charité Comprehensive Cancer Center Charité – Universitätsmedizin Berlin Julius Wolff Institute for Biomechanics and Cancer Immunology Department of Oral and Maxillofacial and Musculoskeletal Regeneration [email protected] Surgery [email protected] [email protected] [email protected] 146 Clinician Scientists 147
Dr. med. Veith Weilnhammer Dr. med. Ran Xu
In program From – TO Fields of Research In Program From – to Fields of Research 01.2019–12.2021 › Neural Correlates of Consciousness 01.2020–12.2022 › Subarachnoid hemorrhage (SAH) › extracellular RNA Contact Contact › brain-heart axis [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Psychiatry and Neurosciences Department of Neurosurgery Director Director Univ.-Prof. Dr. med. Dr. phil. Andreas Heinz Univ.-Prof. Dr. med. Peter Vajkoczy
The Role of Prefrontal Cortex in Conscious Experience Microglia-Associated Inflammation after Subarachnoid Hemorrhage (SAH)
Despite considerable progress, it is still unclear how con- tal brain activity in the inferior frontal cortex (IFC) signals Subarachnoid hemorrhage (SAH), caused by the rupture cells are isolated for RNASeq studies, and further immu- scious experience emerges from brain activity. In the the accumulating conflict between conscious experience of an intracranial aneurysm contributes for a third of all nofluorescence studies and behavior studies are per- search for the neuro-computational underpinnings of and ambiguous visual inputs. In a third experiment, inhib- hemorrhagic strokes and is a devastating disease with formed to dissect the dynamics within the course of SAH. consciousness, the role of prefrontal cortex is particularly itory TMS revealed that a disruption of neural activity in a mortality of approx.. 25% and 40%. This pathology In parallel, blood and CSF samples from SAH patients controversial: Its activity may shape conscious experience IFC leads to a decrease of conflict-driven changes in per- poses a unique role in hemorrhagic stroke, since it occurs are collected in a prospective study which will be ana- by modulating perceptual processes in sensory brain ception, indicating a causal influence of IFC on conscious outside the brain parenchyma at the base of the brain lyzed for potential targets of the immune system. regions. Alternatively, prefrontal cortex may become active experience. A forth experiments will test whether this within the basal cisterns that then leads to intraparen- merely as a consequence of conscious experience, serving effect is also presents in patients who suffered a structural chymal damage in an outside-in fashion. Previous studies subsequent cognitive functions such as introspection or lesions in IFC. from our laboratory have shown that microglia accumu- response preparation. In this project, we investigated role lation and activation within the brain induces neuronal of prefrontal cortex in consciousness using both virtual cell death after experimental subarachnoid hemorrhage, and structural lesions. In a series of three experiments, which in turn may contribute to secondary brain injury. we studied the effects of perceptual conflict on conscious This project aims at further characterizing the functional experience, combining computational modeling, functional phenotype of resident CNS-macrophages/microglia, and magnetic resonance imaging (fMRI) and transcranial mag- studying their association with the pathological hall- netic stimulation (TMS). Human participants reported marks of secondary cellular brain injury following SAH periodic changes in conscious experience that were in an animal model (filament perforation model). MRI in induced by perceptual conflict during bistable perception. vivo and ex vivo studies are undertaken to confirm the Two model-based fMRI experiments showed that prefron- bleeding and study imaging patterns of SAH. Microglia
Mentors Mentors
Univ.-Prof. Dr. med. Dr. phil. Univ.-Prof. Dr. med. Philipp Sterzer Priv.-Doz. Dr. med. Ulf Schneider Univ.-Prof. Dr. med. Peter Vajkoczy Andreas Heinz Scientific Mentor Clinical Mentor Scientific Mentor Clinical Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Psychiatry and Department of Neurosurgery Department of Neurosurgery Department of Psychiatry and Neurosciences [email protected] [email protected] Neurosciences [email protected] [email protected] 148 Clinician Scientists Alumni Clinician Scientist Alumni
Dr. med. Kun Zhang
In Program From – to Fields of Research 09.2016–09.2022 › Calcium Signaling in Heart Failure › Excitation-Secretion Coupling Contact in Cardiomyocytes [email protected] Clinic Charité – Universitätsmedizin Berlin Department of Cardiology Director Univ.-Prof. Dr. med. Burkert Pieske Clinician Scientist Alumni The Heart as an Endocrine Organ: Chromogranin B and the Inositol‑1,4,5-Trisphosphate Receptor in Excitation-Secretion Couplingin Cardiomyocytes
In endocrine cells, a crucial role of chromoganin B (CGB) and the inositol-1,4,5-trisphosphate receptor (IP3R) in exocytosis of vesicles and hormone secretion is known. The heart owns characteristics of an endocrine organ as well. We could show that CGB as a marker of secretory granules is also expressed in cardiomyocytes and demonstrated a pathophysiological pathway of the CGB and IP3R interaction in cardiac hypertrophy and heart failure. While excitation-secretion coupling is well described in other excitable cells such as neurons, this concept is novel and not yet studied in cardiomyocytes. Aim of this project is to examine the functional role of CGB and the IP3R in excitation-secretion coupling in car- diomyocytes and in murine models of heart failure with preserved ejection fraction (HFpEF). Final goal will be to establish a pathway that can serve as a new target in heart failure treatment.
Mentors
Univ.-Prof. Dr. med. Burkert Pieske Univ.-Prof. Dr. med. Frank Heinzel, PhD Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Cardiology Department of Cardiology [email protected] [email protected] 150 Clinician Scientist Alumni 151
PD Dr. med. Güliz Acker Dr. med. Till Althoff
In Program From – to Fields of Research In Program From – to Fields of Research 07.2016–04.2022 › Glioblastoma Multiforme 04.2014–03.2017 › Cardiac Electrophysiology › Vascular Targeting › GPCR/G-protein signaling Contact Contact › Radiosurgery › Cardiovascular mechanotransduction [email protected] [email protected] › Virtual Reality and metabolism Clinic › Moyamoya Disease Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurosurgery Medical Department, with Pediatric Neurosurgery Division of Cardiology and Angiology Director Director Univ.-Prof. Dr. med. Peter Vajkoczy Univ.-Prof. Dr. med. Karl Stangl
Inhibition of the CXCL2/CXCR2 Signaling Pathway in Metabolic Plasticity of Smooth Muscle Cells Glioblastoma Multiforme as a Therapeutic Option in Human Vascular Disease
Glioblastoma multiforme (GBM) is the most common and glioma mouse model that depletion of microglia/ mac- Unlike cardiac or skeletal myocytes, vascular smooth tured cells and mice can be analogously applied to human most malignant astroglial brain tumor with an overall rophages resulted in diminished angiogenesis and muscle cells (VSMCs) are highly plastic and able to switch vascular disease, we are performing a patient study in median survival of around 15 months. Despite intensive reduced tumor volumes. We have also discovered a from a contractile, quiescent state, towards phenotypes collaboration with the German Heart Center Berlin. In research in recent decades on new therapeutic strategies potential new feature of microglia/macrophages in a of increased proliferation, migration and secretory this study we are acquiring vascular samples from no considerable advance in glioma treatment was glioblastoma mouse model by secreting different chemo- capacity (Althoff et al. J Mol Med. 2015). This ability to patients undergoing surgery in terms of ascending aneu- achieved. Thus, novel and innovative therapeutic kines. Due to high overexpression as well as indications dedifferentiate and redifferentiate is a prerequisite for rysm repair, coronary artery bypass graft or heart trans- approaches are required to prolong survival and improve in the literature the potential contribution of CXCL2 to vascular remodeling processes, which in turn are cen- plantation for ischemic and dilated cardiomyopathy, the quality of life for patients with malignant astroglial glioma angiogenesis awakened our interest at most. Thus, trally involved in virtually all vascular diseases. The dif- respectively. Ultimately, we aim to identify strategies tumors. High angiogenesis of GBM is one of the causes the aim of our study it to establish a new therapy with ferentiation state of VSMCs is influenced by a myriad of that target cellular metabolism for the treatment of car- of high malignancy, thus angiogenesis represents one blocking CXCL2 signal way induced angiogenesis in gli- extracellular cues and tightly regulated by two distinct diovascular disease. of the promising therapeutic targets. However, the ther- omas and to analyze the role of this pathway in recurrent G-protein mediated signaling pathways, as we have apeutic effect of antiangiogenic treatments has been so GBM. recently demonstrated (Althoff et al. J Exp Med. 2012). far limited by diverse resistance mechanisms. Beside Using mass spectrometry, we have now discovered that the strong vascularization of gliomas, a high accumula- dedifferentiation of VSMCs is accompanied by a highly tion of microglia/macrophages was shown. In addition, dynamic regulation of key metabolic enzymes, indicating Roggendorf et al. proposed a direct correlation between a fundamental alteration of VSMC metabolic state. Such the grade of gliomas and the number of tumor-associated metabolic switch has been confirmed by us in metabolic microglia and macrophages. Therefore, these immune studies on primary VSMCs using an extracellular flux cells could represent an effective therapeutic target. We analyzer (Seahorse Bioscience) and in in vivo models for have already published that resident microglia are the vascular remodeling. Currently we are studying the main source of brain tumor mononuclear cells, thus these pathophysiological relevance of this VSMC metabolic cells represent a promising novel therapeutic target for plasticity using different murine vascular disease models. patients suffering from this tumor. We observed in our Moreover, to determine whether our findings from cul-
Mentors Mentors
Univ.-Prof. Dr. med. Peter Vajkoczy Dr. rer. nat. Susan Brandenburg Univ.-Prof. Dr. med. Karl Stangl Univ.-Prof. Dr. Stefan Offermanns Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Max-Planck-Institute for Heart and Department of Neurosurgery Department of Neurosurgery Medical Department, Lung Research Bad Nauheim with Pediatric Neurosurgery with Pediatric Neurosurgery Division of Cardiology and Angiology [email protected] [email protected] [email protected] [email protected] 152 Clinician Scientist Alumni 153
PD Dr. med. Georgi Atanasov Dr. med. Lorenz Bastian
In Program From – to Fields of Research In Program From – to Fields of Research 07.2016–06.2019 › Cancer Immunity 08.2015–09.2018 › Acute Lymphoblastic Leukemia › Hepato-Biliary Tumors › Molecular Leukemogenesis Contact Contact › Monocytes/Macrophages › Genotype Informed Treatments [email protected] [email protected] › Immunomodulation Clinic › Biomarkers Clinic Charité – Universitätsmedizin Berlin Universitätsklinikum Schleswig-Holstein Department of Surgery Klinik für Innere Medizin II - Hämatologie, Onkologie Director Univ.-Prof. Dr. med. Johann Pratschke Director Univ.-Prof. Dr. med. Claudia Baldus
The Importance of Immune System and Oncogenic Drivers in the Molecular Pathogenesis Purinergic Pathways in Hepatocarcinogenesis of Acute Lymphoblastic Leukemia
Hepatocarcinogenesis is associated with chronic inflam- CD39-dependent manner and linked to Tregs activities. The prognosis of adult patients suffering from B cell Analyzing a cohort of 90 matched diagnosis – relapse mation, which is linked to immune dysregulation. The With this in mind, we established a tumor model in mice precursor acute lymphoblastic leukemia (BCP-ALL) is still sample pairs, we observed the frequent acquisition of role of purinergic signaling in hepatocarcinogenesis is emulating human hepatocarcinogenesis, and were able poor, especially in case of relapsed disease. Detailed mutations in histone methylation regulators during BCP- poorly understood. Disordered purinergic signaling via to demonstrate presence of functionally active purinergic knowledge of leukemogenic drivers is required for tar- ALL relapse. We perform ChIP-Seq analysis of mutated receptors for danger-associated molecular patterns receptors on human monocytes/macrophages. We pre- geted therapeutic interventions. We integrate high res- primary patient samples and cell line models to delineate (DAMPs), i.e. adenosine triphosphate (ATP) and adenosine viously reported angiogenic monocytes/macrophages to olution profiling of gene fusions, sequence mutations, the impact of these alterations on gene regulation. Using diphosphate (ADP), is associated with carcinogenesis. associate with tumor growth, metastasis, recurrence and copy number alterations as well as gene expression- and CRISPR genome editing, we create functional models of Nucleoside triphosphate diphosphohydrolase-1 (CD39/ clinical prognosis in primary liver malignancies. Conse- DNA methylation profiles together with clinical pheno- the identified mutations to dissect the signaling mech- ENTPD1) is an ectonucleotidase that regulates these quently, we focused especially on cytokine levels, apop- types to characterize novel drivers and resistance factors anisms involved and to validate potential therapeutic extracellular nucleotide/nucleoside concentrations by tosis rate and purinergic receptor profiles, as well as in BCP-ALL. With-in a cohort of 250 BCP-ALL patients we targets. Further oncogenic signaling dependencies are scavenging nucleotides to ultimately generate adenosine. immune cell responses and infiltrates. By performing have established a novel molecular subgroup by a dis- explored in a drug sensitivity profiling of primary BCP- CD39/ENTPD1 is the dominant ectonucleotidase expressed pharmacologic blockade with selective inhibitors of CD39 tinct gene expression and DNA methylation profile. We ALL samples and cell lines with defined genomic back- by regulatory T-cells (Tregs). CD39 drives the sequential activity, and consecutively reducing extracellular ade- identified a combination of sequence mutations in the ground. Together, these analyses provide the framework hydrolysis of both ATP and ADP to AMP. Adenosine pro- nosine concentrations, we demonstrated therapeutic hematopoietic transcription factor PAX5, copy number for a molecular tumor board to guide individual treatment motes immune suppression and tumor progression by effects in wild type tumor mice. The survival rates of loss in the cell cycle regulator CDKN2A and activating decisions in relapsed/refractory BCP-ALL. Together with stimulating vascular endothelial cell proliferation, and treated animals were significantly improved compared RAS/MAPK- or JAK/STAT-pathway mutations as bona-fide our cooperation partners, we are currently developing inhibiting immune cell cytokine synthesis, transendothe- to control groups. In addition, tumor volumes and num- drivers of the disease these patients, thus representing this tumor board within the German Acute Lymphoblastic lial migration, and anti-tumor effector responses. Taken bers were markedly reduced after treatment. A successful an interesting disease model where hallmark signaling Leukemia Study group. together, these properties inhibit anti-tumor immune chemotherapy implies that an immunologic checkpoint pathways each are affected by a single defined alteration. responses and promote angiogenesis. Based on our pre- inhibition of CD39 enzymatic activity may find utility as vious findings implicating the key role of monocytes/ an adjunct therapy for hepatic malignancies. macrophages in hepatobiliary tumors, we hypothesize their function to be mechanistically modulated in a
Mentors Mentors
Prof. Dr. med. Andreas Pascher Univ.-Prof. Dr. med. Marcus Bahra Univ.-Prof. Dr. med. Claudia Baldus Univ.-Prof. Dr. rer. nat. Michael Hummel Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Universiätsklinikum Münster Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Surgery Department, Division of Hematology Institute of Pathology andreas.pascher@ukmuenster. de and Oncology [email protected] [email protected] [email protected] 154 Clinician Scientist Alumni 155
PD Dr. med. Peter Bobbert PD Dr. med. Wolfgang Böhmerle
In Program From – to Fields of Research In Program From – to Fields of Research 04.2011–03.2014 › Adipocytokines 08.2013–09.2016 › Experimental Neurology › Cardiomyopathy › Neurotoxicity Contact Contact › Chemotherapy Induced Neuropathy [email protected] Current Position [email protected] President of Chamber of Clinic Clinic Physicians Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology Director and Experimental Neurology Univ.-Prof. Dr. med. Peter Vajkoczy Director Univ.-Prof. Dr. med. Matthias Endres
The Role of Adipocytokines on the Coagulation System Pathophysiology and Prevention of Chemotherapy- in Patients with Cardiomyopathy Induced Neuropathy
Patients with cardiomyopathy show multiple risk factors such as TF, coagulation factor VIII, fibrinogen and Von Neurotoxic phenomena are among the most common thus established cell- and animal models of chemother- for the development of thromboembolic events. These Willebrand factor. Patients with clinical cardiomyopathy side effects of cytostatic chemotherapy and affect a apy-induced neuropathy for a number of clinically rele- include hemodynamically relevant parameters such as show different expression patterns for adipocytokines. large number of patients. They further increase the bur- vant cytostatic drugs. These models are then used to impaired contractile force and the resulting pathological In this context, it seems necessary to consider not only den of disease for patients and directly affect prognosis further elucidate the role of a deranged intracellular wall movements of the myocardium, as well as differen- systemic serum levels but also local cardiac expression by necessitating treatment changes. Despite the high Ca2+ homeostasis in CIPN. In addition to this line of tially exposed cytokines that may influence blood hemo- processes of adipocytokines in order to describe their relevance for patients, comparatively little research experiments, we use a screen of differentially regulated stasis parameters. Adipocytokines such as adiponectin, effects on hemostasis in the circulation. In this project, efforts are allocated to neurological side effects of che- miRNAs to identify novel disease mechanisms. Under- leptin, resistin, and visfatin are largely released from the first step is to describe a complete picture of the motherapy. In the past, neuroprotective interventions standing the molecular mechanisms underlying CIPN adipose tissue into the systemic circulation. They exert expression of adipocytokines such as adiponectin, leptin, for neurological diseases such as stroke have failed in development will not only improve our understanding a central role in the regulation of energy balance in resistin, and visfatin in patients with nonischemic car- clinical trials due to the unpredictable onset of damage. for the (patho-)physiological states of sensory neurons, humans. In addition, they also possess modulatory prop- diomyopathy. By obtaining endomyocardial biopsies, In contrast, chemotherapy-induced neurotoxicity is ide- but also enable us to develop new strategies for the erties in the field of hemostasis. For example, adiponec- cardiomyopathy is defined particularly by the possibility ally suited for a preventive therapy, as the time point of prevention and treatment of CIPN. tin, classically considered to be anti-inflammatory, shows of describing cardiac inflammatory processes. The damage is well defined and evidence suggests that the inhibitory influences on procoagulant parameters such expression level of adipocytokines is determined on a molecular mechanisms of neurotoxicity differ from the as tissue factor (TF). These effects are differentiated cardiac local as well as on a systemic level. Based on cytostatic mode of action in many chemotherapeutic depending on the molecular structure of adiponectin. In this, the second step focuses on describing the effects agents. We hypothesize that an impaired intracellular contrast, the adipocytokines leptin and resistin, which of the adipocytokines on the regulation of parameters calcium (Ca2+) homeostasis is an important aspect of are described as inflammatory, have procoagulant prop- of coagulation and fibrinolysis. chemotherapy-induced peripheral neuropathy (CIPN) erties due to the increased expression of parameters and a potential therapeutic target. In an initial step, we
Mentors Mentors
Prof. Dr. med. Ursula Rauch-Kröhnert Univ.-Prof. Dr. med. Matthias Endres PD Dr. med. Friedrich Johenning Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Cardiology Department of Neurology Neuroscience Research Center and Experimental Neurology [email protected] [email protected] [email protected] 156 Clinician Scientist Alumni 157
Univ.-Prof. Dr. med. Elena Ioana Braicu, MD MSc PD Dr. med. Eva Janina Brandl
In Program From – to Fields of Research In Program From – to Fields of Research 11.2013–10.2017 › Ovarian cancer 01.2017–04.2019 › Psychopharmacology › Ultrasound imaging › Pharmacogenetics Contact Contact › Transcultural psychiatry [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Gynecology Department of Psychiatry and Psychotherapy Director Director Univ.-Prof. Dr. med. Jalid Sehouli Univ.-Prof. Dr. med. Dr. phil. Andreas Heinz
BERLINER Study – The Role of Circulatory Biomarkers Alone and Psychosocial and Genetic Factors Influencing Antidepressant in Combination with Systematic Ultrasound to Identify the Risk Response in Patients of Turkish Origin of Ovarian Cancer in Pelvic Mass Patients
Ovarian cancer is the main cause of death due to gyne- this study was to develop a new algorithm for the early Genetic factors are known to influence the risk for psy- antidepressant treatment response in migrants in gen- cological malignancies. Ovarian cancer is called the diagnosis of ovarian cancer that will combine CA125, HE4 chiatric disorders as well response to psychopharmaco- eral as well as on pharmacogenetics of antidepressant »silent killer« due to lack of specific symptoms. This fact and other serological and genomic biomarkers with sys- logical treatment (e.g., Brandl et al., 2014, Lett et al., 2016). response in patients of Turkish origin. The project inves- leads to most of ovarian cancer patients being diagnosed tematic transvaginal ultrasound. However, only few findings have yielded independent tigates antidepressant response in patients of Turkish in advanced stages, with only 25% of the cases diagnosed replication, and pharmacogenetic testing has not yet origin with major depression over the first eight weeks in stage I and II, when the disease is limited to the pelvis. As secondary aims we would like to been successfully established in clinical practice (Müller/ of treatment and aims to identify psychosocial as well Early stages patients have a significant improved overall • Identify new predictive biomarkers in Serum and Brandl et al., 2018). Further research is required to achieve as genetic factors associated with treatment response. survival, compared with patients in advanced stages. Urine, as also genetic changes that could predict the a more detailed understanding of genetic underpinnings The results of the project will not only contribute to Therefore finding new effective methods for the early response to the platinum-based chemotherapy and of treatment response. In particular, the interaction pharmacogenetic research but may also help to improve diagnosis of ovarian cancer is mandatory in order to to bevacizumab. between genetic and psychosocial factors influencing psychiatric treatment for this underserved population significant improve survival rates. The most used bio- • Identifycirculatorybiomarkerasalsogenetic- treatment response is poorly understood. Moreover, in the future. marker for assesing the risk in pelvic mass patients, is changestopredictsurgicaloutcome. there are a number of ethnic groups where pharmacog- the cancer antigen 125, CA125. CA125 is increased in 80% enetic factors have not been studied sufficiently in psy- of advanced stages, but only 50% of the early stages, chiatric research. Therefore, this research project inves- furthermore is increased in benign diseases leading to tigates psychosocial as well as pharmacogenetic influ- false positive results. Therefore there is an urgent need ences on antidepressant response in patients of Turkish to identify new serologic biomarkers, and to analyse origin. Migrants with Turkish background have a high risk their diagnostic role alone and in combination with clin- for development of depression and other psychiatric ical parameters such as transvaginal ultrasound. Aim of disorders. They show a high symptom load and more often receive polypharmacy (Brandl et al., 2018), reflect- ing poorer treatment response compared to patients without migration background. However, there is only sparse literature on psychosocial factors influencing
Mentors Mentors
Univ.-Prof. Dr. med. Jalid Sehouli Prof. Dr. rer. nat. Reinhold Schäfer Prof. Dr. med. Univ.-Prof. Dr. med. Dr. phil. Clinical Mentor Scientific Mentor Meryam Schouler-Ocak Andreas Heinz Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité Center Gynecology, Perinatal, Charité Comprehensive Cancer Center Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Pediatric & Adolescent Medicine Department of Psychiatry and Department of Psychiatry and [email protected] Psychotherapy at St. Hedwig-Hospital Psychotherapy [email protected] [email protected] [email protected] 158 Clinician Scientist Alumni 159
PD Dr. med. Claudia Brockmann, FEBO PD Dr. med. Tobias Brockmann, FEBO
In Program From – to Fields of Research In Program From – to 08.2014–09.2018 › Retinal vascular diseases 01.2016–12.2018 › Neurodegeneration Contact Contact › Angiogenesis [email protected] [email protected] › Choroidal pathologies Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Ophthalmology Department of Ophthalmology Director Director Univ.-Prof. Dr. med. Antonia Joussen, FEBO Univ.-Prof. Dr. med. Antonia Joussen, FEBO
Interaction Between Pathological Angiogenesis Influence of the Complement System on the Myofibroblast and Retinal Neurodegeneration Activation During Corneal Wound Healing
In recent years, treatment and prevention of vascular Degenerative eye disorders, which are associated to a retinal diseases has decisively improved, in particular severe loss of visual acuity very often are the result of with regard to age-related macular degeneration, dia- misguided angiogenesis or wound healing/fibrogenesis; betic and veno-occlusive retinopathy. Nevertheless, cur- and thereby are the response to ischemic of inflammatory rent first-line therapy with inhibition of the vascular processes. Today, there are no causal therapeutic endothelial growth factor (VEGF) is limited. Pathological approaches for the treatment of fibrotic eye disorders. vessel growth can be inhibited as long as continuous Hence, the aim of my BIH Charité Clinician Scientist proj- intravitreal anti VEGF injections are given, however, in ect is to investigate the Influence of the complement long-term use it causes irreversible retinal ischemia and system on the myofibroblast activation during corneal atrophy. Based on this background, detailed interaction wound healing. Therefore, we will analyze molecular between inhibition of pathological angiogenesis and mechanisms of human specimens and perform animal retinal neurodegeneration is poorly understood. The aim experiments to identify involved key processes. Thereby of my research project is to analyze the interaction we will contribute to a better understanding of funda- between pathological angiogenesis and retinal neuro- mental pathomechanisms of corneal wound healing. degeneration. Using animal experimental approaches Finally, current treatment regimes shall be optimized molecular mechanisms of mutual influences will be inves- and new therapeutic approaches may be derived. tigated. Furthermore, pathological processes of vascular and primary neurodegenerative retinal diseases will be compared. Thereby fundamental pathomechanisms of degenerative retinal diseases should be better under- stood to develop novel treatment strategies. Finally, results obtained should be compared with outcome of clinical studies.
Mentors Mentors
Univ.-Prof. Dr. med. Univ.-Prof. Dr. rer. nat. Olaf Strauß Univ.-Prof. Dr. med. Prof. Dr. med. Uwe Pleyer, FEBO Antonia Joussen, FEBO Scientific Mentor Eckart Bertelmann, FEBO Scientific Mentor Clinical Mentor Clinical Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Ophthalmology Charité – Universitätsmedizin Berlin Department of Ophthalmology Department of Ophthalmology Department of Ophthalmology [email protected] [email protected] [email protected] [email protected] 160 Clinician Scientist Alumni 161
PD Dr. med. Federico Collettini PD Dr. med. Marcus Czabanka
In Program From – to Fields of Research In Program From – to Fields of Research 04.2015–05.2018 › Image-Guided Ablative Tumor Therapy 04.2011-03.2014 › Glioma angiogenesis › Molecular mechanism of spinal Contact Contact metastasis [email protected] [email protected] › Moyamoya disease Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Radiology Department of Neurosurgery Director Director Univ.-Prof. Dr. med. Bernd Hamm Univ.-Prof. Dr. Peter Vajkoczy
Beyond the Margin of Local Ablation: Perifocal Immune The Role of EphrinB2-EphB4 Signalling for Vascular Resistance Responseand Tumor Progression After Image-Guided Ablative Development in Malignant Glioma Tumor Therapies in a VX2 Liver Tumor Model
While surgery remains the favored treatment option for role in tumor progression following local ablation. Hence, Targeting glioma vasculature with antiangiogenic agents in experimental glioma focusing on pericyte-endothelial resectable liver malignancies, only a minority of patients the overall goal of our project is to characterize the tissue has become a clinically established medical therapy in cell interactions. Using different in vivo glioma models, is amenable to surgery at presentation. This situation rim surrounding the ablation zone following use of dif- order to control glioblastoma multiorme growth and small animal MR imaging and intravital microscopic tech- has led to the development of various minimally invasive ferent ablative modalities and to elucidate the effects tumor associated edema. Despite increasing clinical use, niques the results of our project showed that endothelial tumor ablation techniques for patients with unresectable of local ablation on residual tumor deposits and systemic antiangiogenic agents have not been approved as first EphB4 overexpression led to stabilization of pericyte-en- liver tumors. The most commonly used and best-under- spread in a VX2 liver tumor model. line treatment for malignant glioma due to the lack of dothelial cell interactions and consequently to vascular stood ablative technique is radiofrequency ablation (RFA), superiority proof in diverse randomized controlled trials. resistance against anti-VEGF therapy i.e. glioma vacsu- which has now been officially included into international Despite the initial assumption that antiangiogenic ther- larization was not reduced in response to VEGF inhibition. treatment guidelines and, since 2012, has been the ther- apy may be resistant against resistance mechanisms, In turn, endothelial EphrinB2 knock out induced increased apy of choice in patients with very early hepatocellular glioma studies have shown that malignant glioma develop sensitivity for antiangiogenic treatment. Correspondingly, carcinoma not amenable to liver transplantation. The several mechanisms to induce resistance against anti- EphB4 overexpressiong glioma did not show reduced underlying tumoricidal effect of RFA relies on the gen- angiogenic therapy. A major player for developing vas- tumor growth in response to antiangiogenic treatment. eration of frictional heat, which results in thermal coag- cular resistance against antiangiogenic therapy are The results consequently identify EphrinB2- EphB4 medi- ulation necrosis of the tumor and the surrounding per- pericyte-endothelial cell interactions. The Eph- ated modulation of pericyte-endothelial cell interactions itumoral tissue. However, only limited knowledge is rinB2-EphB4 signalling cascade is the major regulator of as an important factor in the development of vascular available on the perifocal ablation zone beyond the pericyte-endothelial cell interactions in malignant gli- resistance in malignant glioma. ablation margin and immune response observed after oma. In our clinical scientist project we investigated the image-guided tumor therapy. Initial evidence suggests influence of the EphrinB2-EphB4 system on vascular that perifocally expressed immunomodulators have a resistance mechanisms against antiangiogenic therapy
Mentors Mentors
Univ.-Prof. Dr. med. Bernd Hamm Prof. Dr. Eckart Schott Univ.-Prof. Dr. Peter Vajkoczy Clinical Mentor Scientific Mentor Clinical Mentor Charité – Universitätsmedizin Berlin HELIOS Clinic Berlin Charité – Universitätsmedizin Berlin Department of Radiology Medical Department for Internal Department of Neurosurgery Medicine, Gastroenterology, [email protected] [email protected] Hepatology and Diabetes [email protected] 162 Clinician Scientist Alumni 163
Prof. Dr. med. Frederik Damm PD Dr. med. Nadja Ehmke
In Program From – to Fields of Research In Program From – to Fields of Research 04.2014–03.2017 › Hematopoietic Stem Cells 08.2015–07.2018 › Skeletal Dysplasias › Clonal Hematopoiesis and Preleukemia › Bone Development Contact Contact › Lymphomagenesis › Inborn Errors of Metablism [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Medical Department, Institute of Medical Genetics and Division of Hematology, Human Genetics Oncology and Tumor Immunology Director Director Univ.-Prof. Dr. med. Stefan Mundlos Univ.-Prof. Dr. med. Lars Bullinger
Molecular Characterization of Hematopoietic Stem and Progenitor Functional Characterization of the Protein TGDS and Cell Involvement During Leukemo- and Lymphomagenesis the Pathophysiology of Catel-Manzke Syndrome
The hematopoietic system is organized as cell hierarchy patients. Our findings establish the presence of acquired Rare monogenetic skeletal malformations and connective a mouse model will be generated and analyzed with cell having at its top, a hematopoietic stem cell (HSC) and mutations in multipotent hematopoietic progenitors and tissue diseases are models for the development and and molecular biology as well as histological methods. organized in three cell compartments, the hematopoietic show that CLL develop from a pre-leukemic phase and metabolism of the skeleton and connective tissue. The In addition, we intend to use genome sequencing to iden- stem cells compartment, the progenitor compartment propose abnormality in hematopoietic and early B-cell underlying genetic alteration of a large number of such tify the so far unknown molecular basis of skeletal dis- and the mature cells compartment. The hematopoietic differentiation through deregulation of the MAP kinase diseases is unknown at the present time, although knowl- orders similar to Catel-Manzke syndrome (»Catel-Manz- stem cell functions are tightly regulated by a specific pathway as a paradigm for the initial steps of CLL devel- edge of the genetic cause is of great importance to ke-like syndrome«). We expect our results to reveal new microenvironment mainly located in the bone marrow opment (Damm et al., Cancer Discovery 2014). In order affected families. Catel-Manzke syndrome is an autoso- aspects of limb, heart and craniofacial bone development for the HSC, but other microenvironments are involved to gain further insights into the role of progenitor mal recessive skeletal disorder, characterized by retrog- and expand the understanding of proteoglycan metab- in the differentiation of lymphoid progenitors such as involvement of different lymphoid malignancies, we nathia and cleft palate (Pierre-Robin sequence), heart olism, which is involved in a large number of development the thymus for early T cell differentiation. Leukemia (or investigate patients suffering from various types of lym- defect, short stature and a unique hand malformation and aging processes by modulation of various pathways. lymphoma) development results from the accumulation phomas, using a combination of whole-exome and tar- with a bilateral deviation of the index fingers. Recently In addition, we aim to improve the genetic counseling of mutations, generally somatic. We and others have geted deep resequencing. We study the ontogeny, clonal we identified mutations in the gene TGDS as the cause and clinical care of the affected patients and their reported that acquired mutations affecting early pro- hierarchy, their dynamics and evolution during the clin- of Catel-Manzke syndrome. We assume a role of the pro- families. genitors occur in various myeloid malignancies such as ical course. To this aim, flow-sorted cell fractions, single tein TGDS in proteoglycan synthesis or turnover since acute myeloid leukemia, or myelodysplastic syndromes. cells, and different compartments are analyzed. overlapping skeletal disorders are due to alterations in However, the contribution of progenitors to lymphoma- these processes and TGDS shows similarities to an genesis is less understood. We investigated the repar- enzyme involved in proteoglycan synthesis. This project tition of acquired mutations in the hematopoietic dif- aims to characterize the molecular function of TGDS and ferentiation tree of chronic lymphocytic leukemia (CLL) the pathomechanism of the disease. Using CRISPR/Cas,
Mentors Mentors
Univ.-Prof. Dr. med. Lars Bullinger Univ.-Prof. Dr. med. Clemens Schmitt Univ.-Prof. Dr. med. Denise Horn Prof. Dr. rer. nat. Uwe Kornak Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Medical Department, Medical Department, Institute of Medical Genetics and Institute of Medical Genetics and Division of Hematology, Oncology Division of Hematology, Oncology Human Genetics Human Genetics and Tumor Immunology and Tumor Immunology [email protected] [email protected] [email protected] [email protected] 164 Clinician Scientist Alumni 165
PD Dr. med. Philipp Enghard Dr. med. Linda Feldbrügge
In Program From – to Fields of Research In Program From – to Fields of Research 08.2014–07.2017 › Nephrology 01.2017 –12.2019 › Liver Fibrosis › Immunology › Purinergic Signaling Contact Contact › T cells › Macrophage Physiology [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Nephrology and Department of Surgery Medical Intensive Care Director Director Univ.-Prof. Dr. med. Johann Pratschke Univ.-Prof. Dr. med. Kai-Uwe Eckardt
Cellular Urinomics – Flow Cytometric Detection Purinergic Immune Regulation in Acute of Urinary Cell Signatures as Noninvasive Approach and Chronic Liver Injury to Diagnose and Investigate Renal Diseases
Simplified, the pillars of the classic laboratory workup monitoring the amount of urinary T cells in the follow Liver fibrosis is caused by various chronic liver diseases, into the surrounding extracellular space. Purinergic sig- of renal diseases consist of an evaluation of the renal up was able to identify patients with remission and those including inflammatory, toxic and metabolic diseases, naling by extracellular purines such as ATP and adenosine glomerular filtration rate (creatinine, cystatin C), assess- with refractory disease. Aim of our present work is to and can result in liver cirrhosis and organ failure. Liver is one of the pathways that effect both macrophage ment of the function of the filtration barrier (proteinuria) establish different cellular signatures in the urine apply- cirrhosis is among the ten most frequent causes of death phenotype and stellate cell differentiation. ATP is and a microscopic analysis of the urine sediment. Anal- ing flow cytometry. Besides different immune cell subsets in Germany. Liver transplantation remains the only ther- secreted in situations of cell stress, cell death and inflam- ysis of the sediment in particular holds clues to whether we will also detect and quantify renal cells like tubular apeutic option of end-stage liver cirrhosis. Further mation. The CD39 family of ectonucleotidases controls an inflammatory kidney disease is present. However, it epithelial cells and podocytes. We predict that the anal- research is needed to better understand the underlying the concentrations of extracellular ATP and adenosine mainly relies on a semi-quantitative evaluation of ysis of urinary immune cells, tubular epithelial cells and pathophysiology, to refine non-invasive diagnostic tools by hydrolyzing ATP and ADP to AMP which is further unstained cells, is observer-dependent and does not podocytes will enable us to identify different renal dis- and develop effective antifibrotic therapies. Liver fibrosis degraded to adenosine. Members of this family are have a high sensitivity or specificity. Normally the urine eases and separate the elements of renal inflammation, is characterized by excessive formation of scar tissue expressed on macrophages and have also been observed is almost devoid of immune cells and contains only small acute tubular necrosis and glomerular damage. that replaces healthy liver cells, mainly produced by on circulating cellular microparticles. The project aims numbers of epithelial cells. This changes dramatically in activated hepatic stellate cells that transdifferentiate to further define the underlying cellular and molecular different renal diseases. In previous studies we were into myofibroblasts. Different subsets of macrophages mechanisms of purinergic regulation of macrophage able to demonstrate high numbers of urinary CD4+ T cells modulate the activation of stellate cells and thereby function in liver fibrosis. in patients with active lupus nephritis (LN) using flow regulate development and resolution of fibrosis. The cytometry. Applying the amount of urinary T cells as a functions of both macrophages and stellate cells are biomarker in a systemic lupus eythematosus cohort controlled by their microenvironment that is altered by (n=147) we were able to detect patients with acute LN inflammatory and metabolic changes in surrounding cells, with a very high sensitivity and specificity. Interestingly, including the secretion of cytokines and metabolites
Mentors Mentors
Prof. Dr. med. Achim Jörres Univ.-Prof. Dr. med. PD Dr. med. Moritz Schmelzle Univ.-Prof. Dr. med. Clinical Mentor Gerd-Rüdiger Burmester Clinical Mentor Igor-Maximilian Sauer Scientific Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Surgery Charité – Universitätsmedizin Berlin [email protected] Rheumatoloy and Clinical Immunology Department of Surgery [email protected] [email protected] [email protected] 166 Clinician Scientist Alumni C linician Scientist Alumni 167
PD Dr. med. Andreas Fischer Dr. med. Mareike Frick
In Program From – to In Program From – to Fields of Research 04.2011–06.2014 10.2015–06.2019 › Hematopoetic Stem Cells › Clonal Hematopoiesis and Preleukemia Contact Clinic › Myeloproliferative Syndromes [email protected] Charité – Universitätsmedizin Berlin Medical Department, Division of Hematology, Clinic Oncology and Tumor Immunology Univ.-Prof. Dr. med. Bertram Wiedenmann Director Univ.-Prof. Dr. med. Lars Bullinger Director Charité – Universitätsmedizin Berlin Department of Hepatology and Gastroenterology
Studies on the Functional Role of the Protein Kinase PKN1 Investigation of Functional Consequences in the Regulation of the Intestinal Barrier Function of Clonal Hematopoiesis
The intestinal barrier represents an essential interface on the investigation of whether PKN1 is involved in barrier Clonal hematopoiesis – defined by the presence of a allele frequency of at least 2%, the phenomenon is called within the human body, separating the intestinal lumen regulation in intestinal cells. A particular focus here will somatic hematologic-cancer-associated gene mutation clonal hemaptopoiesis of indeterminate potential (CHIP). from the finely regulated interior milieu. Numerous in be to characterize the role that PKN1 plays in mediating – occurs in the peripheral blood of at least 10% of persons At present, caution is needed when predicting clinical vivo and in vitro observations demonstrate that disrup- TNFα induced barrier dysfunction. Specifically, the fol- older than 60 years of age without any history of hema- consequences from a cancer-associated gene mutation, tions of this barrier play a significant role in the patho- lowing goals are pursued: (1) To investigate the effects tologic disorders and defines a premalignant state. The especially with regard to the stem cell compartment. In genesis of chronic inflammatory bowel diseases by lead- of PKN1 activation and inactivation on basic Parameters presence of this common phenomenon is associated the first part of the project, I investigate the effect of ing to an uncontrolled transfer of antigens into the of the epithelial barrier in vitro. (2) To investigate the with an increased risk of hematologic cancers and overall CHIP on the differentiation process of hematopoietic interstitium, which may subsequently lead to the initi- role of PKN1 in steroid-induced tight junction sealing in mortality, which cannot be explained by hematologic stem cells in elderly individuals without cancer using ation of an inflammatory response. Changes in the struc- the intestinal epithelium. (3) To investigate the role of cancers alone. Clonal hematopoiesis is believed to orig- targeted deep sequencing in flow-sorted cell fractions. ture and function of the tight junctions between neigh- PKN1 in TNFα-induced barrier disruption. inate in the stem cell compartment, as mutations occur A second part of my project aims at describing the clinical boring epithelial cells are of particular importance; in the hematopoietic stem cells or in progenitor cells. effects of CHIP in elderly patients with solid cancer however, the responsible molecular mechanisms have The most frequent mutations of clonal hematopoiesis receiving myelotoxic (radio-)chemotherapy, looking at only been incompletely characterized so far. In particular, belong to four functional groups: (1) epigenetic regulators outcome parameters such as frequency of neutopenic the signal transduction pathways that mediate barrier of transcription (e.g. DNMT3A, ASXL1, and TET2), (2) fever, transfusion necessity, chemotherapy dose reduc- disruption induced by proinflammatory cytokines such RNA-processing (e.g. SF3B1, SRSF2, U2AF1), (3) signal trans- tions, etc. Clonal dynamics under the evolutionary pres- as TNFα are not fully known, and thus a therapeutic duction (e.g. JAK2, K-/N-RAS, STAT3), and (4) tumor sup- sure of chemotherapy are also investigated. approach aimed at improving intestinal barrier function pressors and oncogenes (e.g. TP53, BRCC3). Functional for the treatment of inflammatory bowel disease has relevance of these mutations has been demonstrated not yet been successfully developed. This project focuses in mouse models. If the mutation occurs at a variant
Mentors Mentors
Prof. Dr. med. MBA. FACP. AGAF. Daniel Baumgart Univ.-Prof. Dr. med. Lars Bullinger Univ.-Prof. Dr. med. Clemens Schmitt Prof. Dr. med. Frederik Damm Clinical Mentor Clinical Mentor Scientific Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Hepatology and Gastroenterology Medical Department, Medical Department, Medical Department, Division of Hematology, Oncology Division of Hematology, Oncology Division of Hematology, Oncology [email protected] and Tumor Immunology and Tumor Immunology and Tumor Immunology [email protected] [email protected] [email protected] 168 Clinician Scientist Alumni 169
Dr. med. Michaela Golic PD Dr. med. Jan Adriaan Graw
In Program From – to Fields of Research In Program From – to Fields of Research 10.2014–10.2017 › Fetal Programing After 01.2017–09.2020 › Acute Respiratory Distress Syndrome Diabetic Pregnancy › Hemolysis Contact Contact › Uterine Natural Killer Cells in › Blood Transfusion [email protected] [email protected] Preeclamptic Pregnancy Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Obstetrics Department of Anesthesiology and Operative Intensive Care Medicine Director Univ.-Prof. Dr. med. Wolfgang Henrich Director Univ.-Prof. Dr. med. Claudia Spies
Epigenetic Modification in Fetuses of Diabetic Pregnancy Transfusion-Associated Effects of Extra-Cellular Hemoglobin on the Development and Severity of Ventilator-Induced Lung Injury
Intrauterine environment during pregnancy influences Srebf2 gene expression in liver and brain (Golic et al., Mechanical ventilation is used to support millions of nisms by which cell-free hemoglobin and heme might offspring later life health, a phenomenon known as fetal Hypertension 2018). We are currently phenotyping adult critically ill patients each year. However, despite its aggravate VILI. We study whether increased plasma con- programming that has enormous impact on global public offspring of diabetic rat pregnancy with regard to glucose life-saving potential mechanical ventilation can cause centrations of cell-free hemoglobin accelerate the devel- health. Maternal physical and mental state, as well as and fat metabolism and cardiovascular system to address injury and complications. The most important adverse opment and increase the severity of VILI. Both, VILI and nutrition and life style determine intrauterine environ- the pathophysiological relevance of our finding and to effect of mechanical ventilation is the ventilator-induced extracellular hemoglobin independently induce systemic ment during pregnancy. Maternal diabetes during preg- elucidate whether the epigenetic changes are persistent. lung injury (VILI). Among others, patients on the Intensive pro-oxidant and pro-inflammatory effects. Therefore, nancy has an increasing prevalence in western countries We are also interested in characterizing reversible epi- Care Unit are challenged with increased levels of circu- we explore pulmonary and additional extra-pulmonary of up to 10% of pregnancies. It leads to a pathological genetic changes and to analyze the environmental factors lating intravascular cell-free hemoglobin which causes foci of inflammation and apoptosis in VILI with and with- intrauterine environment by inducing fetal hyperglycemia that induce removal of epigenetic modifications. Knowl- vasoconstriction by depletion of endothelial nitric oxide, out exposure to cell-free hemoglobin. Furthermore, we and increases risk for diabetes and obesity in offspring edge about pathophysiological consequences of epigen- oxidative stress, and inflammation. Furthermore, cell- study whether the adverse effects caused by cell-free later life. The molecular mechanisms for this phenome- etic modifications and its removal could enable devel- free hemoglobin contributes to tissue injuries such as hemoglobin might be attenuated by therapy with the non are not well understood, but epigenetic mechanisms opment of new therapeutic strategies. In addition, it renal failure and intestinal mucosa damage after cardiac hemoglobin scavenger haptoglobin. influencing gene expression are suspected. We focus on offers insight into development of diabetes and under- surgery and is associated with an increased mortality deciphering epigenetic changes and its pathophysiolog- standing how environment influences health on a molec- in patients with sepsis. Recently, we demonstrated that ical role in diabetic rat pregnancy. We have shown that ular level. increased plasma concentrations of cell-free hemoglobin rat fetuses of diabetic pregnancy display relevant hyper- and heme after transfusion of stored packed red blood methylation in the promoter region of Srebf2, a tran- cells potentiate a primary injury induced by prolonged scription factor and master regulator of cholesterol hypotension. With this project, we would like to extend metabolism, which is paralleled by downregulation of our knowledge and explore in more detail the mecha-
Mentors Mentors
Univ.-Prof. Dr. med. Wolfgang Henrich PD Dr. med. Ralf Dechend Prof. Dr. rer. nat. Dominik N. Müller Univ.-Prof. Dr. med. Roland Francis Univ.-Prof. Dr. med. Wolfgang Kübler Clinical Mentor Scientific Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Obstetrics and Max Delbrück Center for and Max Delbrück Center for Department of Anesthesiology and Institute of Physiology Molecular Medicine Molecular Experimental and Clinical Operative Intensive Care Medicine [email protected] [email protected] Berlin Experimental and Clinical Research Center [email protected] Research Center [email protected] and HELIOS Clinic Berlin [email protected] 170 Clinician Scientist Alumni 171
PD Dr. med. Leo Alexander Hansmann PD Dr. med. Julian Hellmann-Regen
In Program From – to Fields of Research In Program From – to Fields of Research 01.2016–12.2018 › T cell immunology 09.2013–08.2016 › Neurobiology of Neuropsychiatric › Tumor immunology Disorders Contact Contact › Single cell technologies › Neuropsychopharmacology [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Medical Department, Department of Psychiatry Division of Hematology, Oncology Director and Tumor Immunology Univ.-Prof. Dr. Dipl. Psych. Director Isabella Heuser-Collier Univ.-Prof. Dr. med. Lars Bullinger
Phenotypes, Clonal Relatedness and Functions Retinoic Acid Homeostasis in Major Depression of Multiple Myeloma-Infiltrating T-Cells
Multiple myeloma is characterized by the accumulation types and patterns of disease progression. Parallel single The central research question of this project is to eluci- Furthermore, we will conduct a randomized, placebo-con- of neoplastic plasma cells in the bone marrow and devel- cell sequencing of paired α and β T-cell receptor, cytokine, date a putative link between an altered retinoic acid (RA) trolled clinical trial to assess putative anti-depressant ops from a non-malignant pre-cancer, called monoclonal and transcription factor genes from bone marrow-infil- signaling in the pathogenesis of major depression. RA, effects of minocycline in so far treatment-refractory gammopathy of undetermined significance (MGUS). trating T-cells will identify expanded and most likely the most active metabolite of Vitamin A, plays a key role depressed patients. In the same study, we will system- T-cells influence disease development, therapeutic multiple myeloma-reactive T-cell clones. The T-cell recep- as a morphogen during embryonic development and atically assess an impact of minocycline on RA-homeo- responses, and survival, yet, little is known about their tors of predominant clones will be reconstructed, recom- represents an endogenous neuroprotectant and anti-in- stasis-related parameters over a 6-week time course of clonal restriction, differentiation states, and functions binantly expressed, and screened against peptide-MHC flammatory agent in the adult CNS. Several lines of evi- treatment with minocycline or placebo. Elucidating a at the single cell level. Technologies such as cytometry libraries to identify their possible ligands. Finally, we dence suggest altered cerebral RA signaling in affective role for RA-Homeostasis in the pathogenesis and treat- by time-of-flight (CyTOF) and next generation sequencing will use phosphorylation-specific flow cytometry to disorders. Preliminary own work has demonstrated ment of major depression will be an important step in allow the high-dimensional detection of even rare determine whether bone marrow lymphocyte signaling strong effects on local RA-homeostasis for select anti- the development of more targeted interventions to treat immune phenotypes on the single cell and molecular alterations are cytokine milieu-driven or T-cell intrinsic. depressants and also for the pleiotropic anti-inflamma- depressed patients, particularly those not responding level. We hypothesize bone marrow-infiltrating multiple Determining detailed bone marrow lymphocyte pheno- tory antibiotic minocycline, for which antidepressant to standard treatments. myeloma-reactive T-cells to show unique immune phe- types, clonal relatedness, specificities, and functions, effects have recently been discussed on the basis of its notypes, clonal expansion, and functional aberrations our study will add substantially to the field of multiple potent actions on microglial cells, inhibiting microglial that successively render them incapable of eliminating myeloma biology and possibly lead to new therapeutic activation. Therefore, we will further investigate putative the malignant T-cells during disease progression. strategies in cancer immunology. RA-modulating effects of minocycline and of several 40-dimensional CyTOF phenotyping and functional anal- antidepressants in a preclinical subproject. In parallel, yses of multiple myeloma, MGUS, and healthy bone mar- we will assess altered parameters of RA-homeostasis in row will detect unique disease-associated T-cell pheno- drug-free depressed patients and matched controls.
Mentors Mentors
Univ.-Prof. Dr. med. Lars Bullinger Prof. Dr. med. Jörg Westermann Univ.-Prof. Dr. Dipl. Psych. Univ.-Prof. Dr. med. Christian Otte Clinical Mentor Scientific Mentor Isabella Heuser-Collier Scientific Mentor Clinical Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Medical Department, Division of Medical Department, Division of Charité – Universitätsmedizin Berlin Department of Psychiatry Hematology, Oncology and Tumor Hematology, Oncology and Tumor Department of Psychiatry [email protected] Immunology Immunology [email protected] [email protected] [email protected] 172 Clinician Scientist Alumni 173
PD Dr. med. Bernd Hewing Dr. med. Dipl.-Math. Christian Hinze
In Program From – to Fields of Research In Program From – to Fields of Research 01.2015–12.2017 › Atherosclerosis 07.2017–06.2020 › Single-cell transcriptomics › Inflammation › Spatial transcriptomics Contact Contact › Interventional Cardiology › Single-nuclei transcriptomics [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Medical Department, Medical Department, Division of Cardiology and Angiology Division of Nephrology Director Director Univ.-Prof. Dr. med. Karl Stangl Univ.-Prof. Dr. med. Walter Zidek
IRhom2 in Atherosclerosis Transcriptional Regulation in Healthy and Diseased Kidney Tissue
Tumor necrosis factor (TNF)-alpha is a potent inflamma- the impact of iRhom2 on atherosclerotic plaque devel- Kidneys of higher mammals comprise a complex ensem- kidney drastically complicates the analysis of physio- tory mediator that plays an important role in the devel- opment and on phenotypic and functional characteristics ble of many different T-cell types including renal tubules, logical and pathological renal processes. Each cell type opment of atherosclerosis. It is expressed as a precursor of macrophages as well as the pathophysiological role immune and interstitial cells, to mention but a few. Renal has a distinct role in health and can become an out- transmembrane protein and subsequently converted of iRhom2 in patients with coronary artery disease. Taken tubules are again subdivided into distinct tubular seg- come-determining population in disease. Cell type into its soluble, bioactive form by TNF-alpha converting together, this project aims at characterizing the role of ments serving the excretion of toxins and participating behavior and functions are mainly determined by distinct enzyme (TACE) mediated shedding. Recently discovered iRhom2 in atherosclerosis and thus contributes to better in body water and electrolyte homeostasis. The renal transcriptional gene expression programs. So far, inactive rhomboid protein 2 (iRhom2) is essential for understanding of inflammatory processes in atheroscle- collecting ducts constitute the most distal part of the researchers used a combination of microdissection fol- maturation of TACE in immune cells. A genetic knock-out rosis and the development of novel therapeutic strate- renal tubules and are responsible for urine finetuning lowed by RNA sequencing to uncover renal transcriptional or knock-down of iRhom2 results in a loss of TACE activity gies for the treatment of this disease. including electrolyte and water reabsorption. We were programs in various settings. We were recently able to and, consequently, in a markedly reduced shedding of recently able to uncover the role of a collecting duct-ex- establish single-cell RNA sequencing in our lab. This TNF-alpha in cells involved in atherosclerosis such as pressed transcription factor, grainyhead-like 2 (GRHL2), technology facilitates the investigation of gene expres- macrophages. iRhom2-deficient mice exhibit reduced which mediates collecting duct tightness and barrier sion in individual cells and cell populations. With it, we serum levels of TNF-alpha in response to inflammatory function (Aue, Hinze et al., JASN, 2015; Hinze et al., JASN, want to deepen our understanding of GRHL2 function in stimuli, survive otherwise lethal doses of LPS and are 2018). Lack of collecting duct GRHL2 led to a constant the kidney but also apply it to clinical questions such as protected from the development of inflammatory arthri- loss of electrolytes and free water and a susceptibility in polycystic kidney disease. tis. These findings strongly suggest that the iRhom2/ to prerenal acute kidney injury. We could show that GRHL2 TACE/TNF-alpha signaling axis may contribute to athero- orchestrates a set of genes involved in cell-cell junction sclerosis. However, to date, this hypothesis has not been formation and maintenance in renal collecting ducts. tested experimentally. Therefore, our group evaluates However, the vast heterogeneity of cells forming the
Mentors Mentors
Univ.-Prof. Dr. med. Karl Stangl Prof. Dr. Edward A. Fisher, MD, PhD, MPH Prof. Prof. h.c. Dr. med. Univ.-Prof. Dr. med. Kai Schmidt-Ott Clinical Mentor Scientific Mentor Markus van der Giet Scientific Mentor Clinical Mentor Charité – Universitätsmedizin Berlin New York University School of Medicine Charité – Universitätsmedizin Berlin Medical Department, Department of Medicine, Charité – Universitätsmedizin Berlin Medical Department, Division of Cardiology and Angiology Division of Cardiology Medical Department, Division of Nephrology Division of Nephrology [email protected] [email protected] [email protected] [email protected] 174 Clinician Scientist Alumni 175
Dr. med. Christian Johannes Hoffmann PD Dr. med. univ. Felix Hohendanner, PhD
In Program From – to Fields of Research In Program From – to Fields of Research 01.2016–10.2019 › Molecular Stroke Research 08.2018–07.2021 › Experimental Cardiology › Neuroregeneration After Stroke Contact Contact › Inflammation After Stroke [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology and Department of Cardiology Experimental Neurology Director Director Univ.-Prof. Dr. med. Burkert Pieske Univ.-Prof. Dr. med. Matthias Endres
Influence of Endothelial IL6/Stat3 Signaling on Angiogenesis, Electrical and Mechanical Dysfunction in Atrial Cells ECM Remodeling and Neuro-Plasticity After Stroke During Diastolic Heart Failure
Stroke is the second leading cause of death and the lead- matrix (ECM), promotion of angiogenesis and functional Atrial remodeling (enlargement, contractile dysfunction) sitol-1,4,5-triphosphate (IP3)-receptor mediated Ca2+ ing cause of disability worldwide. Treatment is limited recovery. We hypothesize that paracrine IL6 signaling and atrial arrhythmias are often observed in heart failure release, and the activity of the Na+/Ca2+ exchanger (NCX); to a narrow time window of 4.5 h, but fewer than 10% of within the neurovascular niche can improve neuronal and are associated with worse clinical outcomes. In heart 2) to identify pharmacological targets for the treatment patients benefit from this, and many are left with severe, network rewiring and functional recovery. We generated failure with preserved ejection fraction (HFpEF) atrial of atrial dysfunction in HFpEF. lasting disabilities. A treatment focused on improving a mouse model for cell-specific and inducible expression remodeling is particularly common for further compro- regeneration and functional recovery in the long term of IL6 (FLEX-IL6). The secreted IL6 is subsequently detect- mising left ventricular filling. A variety of mechanisms would be of great benefit, indeed, the brain harbors able by a fused myc-tag. IL6 secretion will be induced 2 including increased left ventricular diastolic pressure endogenous mechanisms to improve neuronal network days after stroke to focus on regenerative mechanisms, and neuro-humoral activation have been linked to atrial rewiring. Interleukin 6 (IL6) is associated with higher risk rather than preventing acute cell death. We will analyze remodeling in HFpEF. However, the cellular mechanisms for atherosclerosis and stroke and increased blood IL6 the effects on functional recovery, angiogenesis, and leading to atrial dysfunction in HFpEF remain elusive. We levels correlate with worse outcome. However, other ECM remodeling. IL6 acts on the CST (tracible by the use echocardiography, MRI, in-vivo hemodynamics and studies have reported IL6 in the acute phase of stroke fused myc-tag), when it is secreted by astrocytes. We state of the art cellular imaging techniques (e.g. FRET is able to reduce lesion size. The pleiotropic effects of will further explore this relationship by using laser cap- imaging, local photoactivation, ratiometric and non-ra- IL6 might be explained by complex signaling mechanisms ture microdissection to excise IL6 positive CST bundles tiometric confocal Ca2+/Na+ live cell imaging) to study that differ according to the cell type involved and the in order to characterize protein expression. Effects on atrial remodeling in HFpEF. Aims of the current project condition of the tissue microenvironment. We have shown network rewiring and CST regeneration will be visualized are: 1) to characterize mechanisms that lead to contractile that downstream IL6 signaling of endothelial Signal by tract-tracing methods, MRI connectivity analysis, and and/or rhythm dysfunction during atrial remodeling in transducer and activator of transcription 3 (Stat3) is of pharmacogenetic inhibition methods (DREADD). a rat HFpEF-model, caused by metabolic syndrome, as high importance for remodeling of the extracellular well as in human myocardium with an emphasis on Ino-
Mentors Mentors
Univ.-Prof. Dr. med. Matthias Endres Univ.-Prof. Dr. med. Christoph Harms Univ.-Prof. Dr. med. Burkert Pieske Univ.-Prof. Dr. med. Frank Heinzel, PhD Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology and Center for Stroke Research Berlin Department of Cardiology Department of Cardiology Experimental Neurology [email protected] [email protected] [email protected] [email protected] 176 Clinician Scientist Alumni 177
PD Dr. med. Petra Hühnchen Dr. med. Philipp Jakob
In Program From – to Fields of Research In Program From – to Fields of Research 07.2015–07.2018 › Neuroscience 01.2015–12.2017 › Regeneration › Cognition › Cardiomyocytes Contact Contact › Neurodegeneration › High-Throughput Screening [email protected] [email protected] › Pain Clinic › Translational research Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology Department of Cardiology and Experimental Neurology Director Director Univ.-Prof. Dr. med. Ulf Landmesser Univ.-Prof. Dr. med. Matthias Endres
Pathomechanisms and Prevention of Chemotherapy Identification of Pro-Proliferative MicroRNAs in Human Induced Cognitive Impairment Cardiomyocytes Using a Functional High-Throughput Screening
Neurotoxic phenomena are among the most common vivo. In a translational effort, we are currently testing The project aims to detect microRNAs (miRNAs) with the using a high-content imaging system. Significant miRNAs side effects of chemotherapy and often result in a major patients with paclitaxel chemotherapy for neurocognitive ability to induce and enhance proliferation in human will be validated in vitro and in vivo. The project is per- limitation for therapy, preventing optimal medical care. deficits in a prospective longitudinal study (CICA- cardiomyocytes (CM) by using high-throughput screen- formed in collaboration with the screening unit of Dr. J. Furthermore, they significantly increase the burden of RO-study) and comparing the results to non-treated ings and high-content imaging techniques. MiRNAs are P. von Kries (FMP, Berlin-Buch) and the stem cell group disease for cancer patients by severely affecting the patients. To further elucidate the underlying pathomech- small non-coding RNAs, which profoundly alter protein of Dr. K. Streckfuß-Bömeke (Universitätsmedizin Göttin- quality of life. Changes of cognitive function associated anisms of PCCI, we are investigating the role of proin- output by interfering with messenger RNAs (mRNA) at gen) and is supported by German Centre for Cardiovas- with chemotherapy (post-chemotherapy cognitive flammatory cytokines in cell culture and animal models the post-transcriptional level. In humans, CM withdrawal cular Research (DZHK) and Deutsche Stiftung für Herz- impairment (PCCI) or »chemobrain«) have gained as well as patients to establish potential biomarkers. from cell cycle is observed early after birth. The marginal forschung (DSHF). increased scientific interest, as the underlying patho- Furthermore, we are characterizing the functional out- number of adult CMs (approx. 1%) undergoing cell cycle physiology remains unclear. We have gathered evidence come of newly identified molecular targets and evalu- and stem/progenitor cells supporting myocardial regen- that very low dosages of systemic chemotherapy such ating novel therapeutics in the prevention of PCCI in erative processes cannot compensate for a myocardial as paclitaxel or bortezomib are sufficient to induce cell animal models, gathering information for a potential loss after cardiac injury. Therefore, the project aims to death in adult neural stem cells via calcium and clinical use. improve cardiac regeneration in patients with myocardial caspase-mediated pathomechanisms. This results in an infarction/ischemic cardiomyopathy by targeting miRNAs impaired hippocampal neurogenesis and distinct cogni- significantly involved in cardiomyocyte pro-proliferative tive deficits in mice. For paclitaxel, we have identified a pathways. High-throughput-screenings using a miRNA-li- molecular target and established an interventional strat- brary were performed in CMs derived from human egy using lithium to inhibit cytotoxicity of adult neural induced pluripotent stem cells (hiPSC-CMs). Proliferative stem cells in vitro and prevent cognitive impairment in capacity of miRNA-transfected hiPSC-CMs was analyzed
Mentors Mentors
Univ.-Prof. Dr. med. Matthias Endres Univ.-Prof. Dr. med. Ulrich Dirnagl Univ.-Prof. Dr. med. Ulf Landmesser Univ.-Prof. Dr. med. Christof Stamm Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology Department of Neurology and Department of Cardiology Department for Cardiothoracic and and Experimental Neurology Experimental Neurology and Vascular Surgery [email protected] BIH QUEST Center [email protected] [email protected] [email protected] 178 Clinician Scientist Alumni 179
Dr. med. Reiner Jumpertz-von Schwartzenberg Dr. med. Julia Kase
In Program From – to Fields of Research In Program From – to Fields of Research 04.2015–03.2018 › Obesity and Energy Balance Regulation 04.2011–03.2015 › Chemoresistance › Human Gut Microbiota › Aggressive B-Cell Lymphomas Contact Contact › Glucose Metabolism › Transgenic Mouse Models [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Endocrinology and Department of Hematology, Metabolic Diseases Oncology and Cancer Immunology Director Director Univ.-Prof. Dr. med. Joachim Spranger Univ.-Prof. Dr. med. Lars Bullinger
Plasticity of the Human Gut Microbiota During Weight Loss A Pan-Omics Approach to Treatment Failure in a Transgenic and its Consequences in Humanized Gnotobiotic Mice Mouse Model of Aggressive B-Cell Lymphomas
This project is geared towards understanding the complex receiving the gut microbiota from individuals after/during Treatment failure is the key determinant of poor outcome mechanisms of treatment resistance.After treatment of constitution of commensal gut microbes in patients with severe weight loss develop a dramatic weight loss within in lymphoma therapy. Unveiling the underlying molecular lymphoma-bearing mice, lasting remissions (reflecting metabolic diseases and their plasticity during weight a very short period after transplantation, a phenomenon mechanisms is critical to overcome drug insensitivity cure) were observed in about half of them. Repetitive loss. During the last years, we collected stool samples which is not seen in mice receiving the microbiota of the and may direct the development of novel therapies. Since treatments of mice harboring relapse lymphomas from overweight and obese individuals during a random- same individuals before weight loss. Additionally, just patient samples are rarely available as matched pairs resulted in progressively shortened remission times and ized weight loss intervention trial. To investigate gut looking at the gut microbiota we were able to develop a at diagnosis and at a resistant state, and cannot be fur- finally led to full-blown resistance, thereby recapitulating microbial communities we performed 16 S sequencing machine learning algorithm that predicts weight loss ther drugchallenged or subjected to functional validation clinical courses of patients with drug-insensitive aggres- and whole genome sequencing of the gut microbiota. We during a weight loss program only based on the gut experiments, we considered transgenic mouse models sive lymphomas. Gene-, RNA-, protein- and metabo- found substantial plasticity in the weight loss group with microbial composition at baseline. In a next step, we of cancer as valuable tools for the molecular dissection lite-analyzing omics technologies were applied to com- profound changes in the relative abundances of specific want to find the top microbial candidates that may pro- of treatment responsiveness. We utilize transcriptomics, pare curable vs. relapse-prone and resistant lymphomas, microbial clades that have been linked to metabolic mote negative energy balance and initiate the translation proteomics, metabolomics, kinomics, whole exome all with or without an additional short-term exposure to health. These changes go along with gene content vari- into a first human intervention trial. sequencing and copy number analysis in a »panomics« CTX to acutely challenge drug-specific response pro- ation indicating a shift in the metabolic propensity of approach to decipher mechanisms of treatment resis- grams. Eµ-myc lymphoma-bearing mice treated in a clin- the of ›obese-type‹ microbiota. To test whether these tance in a Myc-driven lymphoma mouse model with pre- ical trial-like fashion were established as a versatile changes themselves are relevant in body weight regu- viously documented cross-species predictability for model of clinical chemoresistance. Going beyond a tran- lation we performed humanization experiments in germ- human diffuse large B-cell lymphomas.Immunocompe- scriptome-restricted investigation, our pan-omics strat- free mice. For this, we chose to transplant the gut micro- tent recipient mice were transplanted with primary egy aims to dissect underlying mechanisms that will be biota of obese individuals before and after severe weight Eµ-myc transgenic mouse B-cell lymphomas, and exposed further exploited as targets on their own for novel lesion- loss. Out preliminary data suggest that humanized mice to cyclophosphamide (CTX) upon tumor manifestation. based therapies in future cancer precision medicine. Mass spectrometry-based proteomics, metabolomics as well as array-based transcriptomics, genomics, kinomics and copy number alteration analysis were applied, and the data subjected to bioinformatics processing to unveil
Mentors Mentors
Univ.-Prof. Dr. med. Joachim Spranger Prof. Dr. rer. nat. Dominik N. Müller Univ.-Prof. Dr. med. Clemens Schmitt Univ.-Prof. Dr. med. Lars Bullinger Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Endocrinology and and Max Delbrück Center for Medical Department, Division of Medical Department, Division of Metabolic Diseases Molecular Medicine Berlin Hematology, Oncology and Tumor Hematology, Oncology and Tumor Experimental and Clinical Research Center Immunology Immunology [email protected] [email protected] [email protected] [email protected] 180 Clinician Scientist Alumni 181
Prof. Dr. med. Johannes Keller, PhD Dr. med. univ. Barbara Kern, PhD
In Program From – to Fields of Research In Program From – to Fields of Research 01.2016–02.2019 › Bone Metabolism 01.2018–12.2020 › Vascularized Composite Tissue › Fracture Healing › Allotransplantation Contact Contact › Posttraumatic Inflammation › Transplant Immunology [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Center for Musculoskeletal Surgery Department of Surgery Director Director Univ.-Prof. Dr. med. Dr. h.c. Michael Schütz Univ.-Prof. Dr. med. Johann Pratschke
Cellular and Molecular Characterization of Fracture Healing Novel Treatment and Diagnostic Approaches Utilizing the in Traumatic Brain Injury Role of Dendritic Cells in Immune Responsiveness
Impaired fracture healing including malunions still rep- target organs, cells and signaling events involved in Vascularized composite tissue allotransplantation (VCA) problems: the speed of nerve regeneration to regain full resents an ongoing clinical challenge as treatment accelerated fracture healing during TBI. Promising can- including hand, upper extremity, face, and abdominal motor and sensory function, and most importantly, the options remain limited. This is surprising, since bone is didates and signaling pathways are further investigated wall transplants have emerged from a visionary therapy application of immunosuppressants with a myriad of one of two organs that is capable to completely restore using primary cell cultures and cell lines. Finally, phar- option in the past to become an innovative reconstruc- unwanted and life-threatening complications for a non- structure and function without scar tissue formation. In macologic and genetic proof-of-principle experiments tive treatment modality for patients with devastating life saving procedure (Shores et al, J Am Acad Orthop contrast to healing impairments, the clinical phenome- are performed to verify the influence of established tissue defects that are not amendable for conventional Surg, 20100. Dendritic cells (DC) are known to play a key non of traumatic brain injury (TBI) positively affecting candidates in vivo. The cellular and molecular charac- treatment protocols (Swearingen et al, Transplantation role in T-cell activation via presenting antigenic peptides fracture healing is of utmost importance from a basic terization of accelerated fracture healing-complementing 2008). However, patients must undergo life-long immu- in the context of MHC molecules to the T-cell receptor science and clinical point of view. Using an experimental research on delayed healing is basis for a fundamental nosuppression with unwanted effects such as infection, (TCR), as well as by providing co-stimulatory signals approach, we could previously demonstrate that callus understanding of bone healing and its challenges, and renal toxicity, and cancer. Therefore, it is crucial to under- required for T-cell proliferation and differentiation formation is increased in a mouse model combining sur- backbone to any development of new therapeutic strat- stand the underlying mechanisms of skin rejection as (Benichou et al, IImmunotherapy 2011). We hypothesize gically induced TBI and fracture of the femur. As the egies for affected patients. the most immunogenic fraction of VCAs to improve exist- that intragraft DC composition plays a critical role in the underlying mechanisms remain unclear, we are currently ing immunosuppressive therapeutic approaches in VCAs. potent immunogenicity observed in VCA. investigating the cellular and molecular basis for the Our overall objective is, therefore, to critically examine observed phenomenon. First, based on our own prelim- the immunogenicity of mature and immature DCs. Of inary experiments and observations made by other note, studies of DCs in VCA have also the potential to investigators, we test the mechanistic involvement of provide novel treatment approaches for skin and, ulti- leptin and alpha calcitonin gene-related peptide, both mately, solid organ transplantation. Extremity trans- of which are elevated in polytraumatized patients, in plants are currently challenged by two main unsolved the increased callus formation following brain injury. In parallel, extensive gene expression profiling, histological and FACS analyses as well as serum and urine measure- ments are applied to further dissect and identify crucial
Mentors Mentors
PD Dr. med. Philipp Schwabe Univ.-Prof. Dr.-Ing. Georg Duda PD Dr. med. Undine Gerlach-Runge Univ.-Prof. Dr. med. Univ.-Prof. Dr. med. Johann Clinical Mentor Scientific Mentor Clinical Mentor Igor-Maximilian Sauer Pratschke Scientific Mentor Clinical and Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Center for Musculoskeletal Surgery Julius Wolff Institute for Biomechanics Department of Surgery Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin and Musculoskeletal Regeneration Department of Surgery Department of Surgery [email protected] [email protected] [email protected] [email protected] [email protected] 182 Clinician Scientist Alumni 183
Dr. med. Tina Kienitz PD Dr. med. Konrad Klinghammer
In Program From – to Fields of Research In Program From – to Fields of Research 11.2013–11.2016 › Androgens 08.2014–07.2017 › Head & Neck Cancer › Endocrine Cancers › Preclincial Models Contact Contact › Adrenals › Biomarker Research [email protected] [email protected] › Target Identification Clinic Clinic Charité – Universitätsmedizin Berlin Universitätsklinikum Schleswig-Holstein Department of Endocrinology and Klinik für Innere Medizin II – Metabolic Diseases Hämatologie, Onkologie Director Director Univ.- Prof. Dr. med. Joachim Spranger Univ.-Prof. Dr. med. Claudia Baldus
Androgen-Dependent Regulation of Whole Body Sodium Development of Novel Treatment Strategies for Head and Neck Metabolism, Blood Pressure and Cardiovascular Function Cancer Employing Patient-Derived Xenografts
Nowadays, cardiovascular diseases greatly determine intake promoted lymph hyperplasia in rats. This effect Even though therapeutical options have recently response to a given compound with tumor biology we morbidity and mortality in industrialized countries. Epi- was mediated via the tonicity-responsive enhancer bind- improved, the treatment of recurrent and metastatic aim to identify predictive biomarkers. Through the knowl- demiological findings demonstrate sex differences in ing protein (TonEBP) in mononuclear phagocyte system head and neck cancer (HNSCC) remains a challange. So edge of tumor characteristics of the models were are cardiovascular risk: In industrialized countries, men suf- (MPS) cells. TonEBP works as a transcription factor and far there is only Cetuximab as the single approved com- able to select models for novel research projects. Espe- fer from cardiovascular diseases more often and at a enhances vascular endothelial growth factor C (VEGF-C) pound with a targeted approach in this disease and pre- cially with the advent of novel compounds, that have a younger age than women [Gos-Wald A et al. Bundesge- secretion. Interference with this system might contribute dictive biomarkers allowing a treatment stratification a specific target and only function under certain conditions, sundheitsblatt, Gesundheitsforschung Gesundheitss- considerably to the development of sex-specific differ- largely missing. The current research project is based e.g. a mutation of the target, we are able to perform chutz 2013]. Men also have a higher blood pressure than ences in blood pressure control. The androgen receptor on a steadily growing platform of patient derived xeno- biomarker research driven studies. Positive results may women [Stamler J et al. JAMA 1976]. These observations (AR) is expressed in macrophages [Ikeda Y et al. J Endo- grafts from head and neck cancer. Starting in 2012, we create the rationale for clinical trials suggest that androgens contribute to this sexual dimor- crinol 2012]. In sum, the role of androgens in the regu- meanwhile successfully established more than 60 models phism. Sodium intake influences the development of lation of whole-body sodium metabolism is only poorly from various locations and disease stages of HNSCC, arterial hypertension, as well [Elliott P et al. BMJ 1996]. understood. We generated macrophage/monocyte-spe- which display the heterogeneity of this disease. Estab- However, the exact mechanisms responsible for salt-sen- cific androgen receptor knockout mice to investigate lished tumor models are characterized on a molecular sitive hypertension and the relationship between sex, macrophage-mediated androgen action. Since macro- level for whole gene expression, mutational profile and salt intake and endogenous regulation of sodium metab- phages also play a role in the development of obesity, morphology through FFPE section staining. Further, the olism are widely unknown. Experimental data provided glucose and lipid metabolism will be explored in this models are treated with different compounds, which are compelling evidence that macrophages are key elements mouse model, as well. used in clinical routine in the treatment of head and in the regulation of sodium accumulation in the skin neck cancer. Treatment responses are correlated with [Machnik A et al. Nature Medicine 2009]. High sodium clinical courses of patients. Through the correlation of
Mentors Mentors
Univ.-Prof. Dr. med. Joachim Spranger Univ.-Prof. Dr. Michael Bader Univ.-Prof. Dr. med. Ulrich Keilholz Prof. Dr. rer. nat. Ingeborg Tinhofer-Keilholz Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Max Delbrück Center for Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Endocrinology Molecular Medicine Molecular Charité Comprehensive Cancer Center Department of Radiation Oncology and and Metabolic Diseases Biology of Peptide Hormones Radiotherapy [email protected] [email protected] [email protected] [email protected] 184 Clinician Scientist Alumni 185
Prof. Dr. med. Stephan Köhler Univ.-Prof. Dr. med. Peter Krawitz
In Program From – to Fields of Research In Program From – to Fields of Research 07.2015–10.2018 › Affective Disorders 01.2014–12.2016 › GPI-Anchor Deficiencies › Chronic Depression › Bioinformatics Contact Contact › Psychotherapy Research › Interpretation of Whole [email protected] [email protected] Genome Sequences Clinic Clinic Current Position Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Head of the Institute for Genomic Department of Psychiatry and Institute of Medical Genetics and Statistics and Bioinformatics Psychotherapy Human Genetics University Bonn Director Director Univ.-Prof. Dr. med. Dr. phil. Andreas Univ.-Prof. Dr. med. Stefan Mundlos Heinz
Neurobiology of Chronic Depression: Alterations in Emotion Systematic Analysis of Genotype-Phenotype Regulation and Influence of Psychotherapy Correlations in GPI-Anchor Deficiencies
About 20% to 30% of patients with a major depressive we want to evaluate, if emotion regulation (reappraisal) In all eukaryotes, there is a complex in the plasma mem- found pathogenic mutations in the genes PIGV, PIGO, disorder (MDD) have a chronic disease course (MDD last- is altered in CD in contrast to episodic depression in a brane with the key task of anchoring glycoproteins on PGAP2 and PGAP3 in patients with Mabry syndrome and ing for at least two years). Chronic depression (CD) is a fMRI paradigm. Furthermore, we want to investigate, if the cell surface, called the glycosylphosphatidylinositol mutations in PIGT in patients with atypical PNH for the specific subtype of MDD, however, it is barely character- emotion regulation is depending on specific emotional anchor (GPI-anchor). GPI-anchored proteins (GPI-APs) first time. In our project, we aim at identifying novel ized and demonstrates with high rates of treatment activation and if there is an altered regulation of the play a central role in signal transduction, cell adhesion, genes that are involved in the GPI pathway as well as resistance. In contrast to episodic depression, CD often amygdala and the prefrontal cortex. The influence of a and antigen presentation. Defects in the synthesis and regulatory mutations. For this purpose, we use exome has an »early onset« even in adolescence. The develop- specific psychotherapy on emotion regulation in CD is maturation of the GPI-anchor and their consequences sequencing and whole genome sequencing to find patho- ment and persistence of CD are often related to adversity part of a third project. for GPI-APs represent a class of congenital disorders of genic mutations in patients with suspected GPI-anchor and maltreatment experienced during childhood as emo- glycosylation (CDG) that can cause congenital as well as deficiencies of the unknown molecular cause. Flow cyto- tional neglect for example. Patients with CD often demon- acquired disorders. Among the inherited forms is Mabry metric analyses play a key role in the assessment of strate a »lack of social empathy«, interpersonal chal- syndrome, a recessive disorder that is characterized by suspected GPI-anchor deficiencies and bioinformatics lenges, global and prelogical thinking processes and intellectual disability, epilepsies, an elevated alkaline are an essential part of the data evaluation. additionally a reduced affective control. Furthermore, phosphatase and a distinct facial gestalt. Paroxysmal there is growing evidence for a disturbed emotion reg- nocturnal hemoglobinuria, PNH, is an acquired GPI-an- ulation in patients with depression, however, the results chor deficiency, due to somatic loss of function mutations are inconsistent. Especially early childhood trauma in cells of the myeloid lineage. Currently, about 30 genes seems to be associated with an altered activity of emo- are known to play a role in the GPI-anchor synthesis and tion-regulating brain regions (increased amygdala activ- maturation. In several of these genes, disease-causing ity, reduced activity of prefrontal cortex). In our project, mutations could be identified over the recent years. We
Mentors Mentors
Univ.-Prof. Dr. med. Philipp Sterzer Univ.-Prof. Dr. med. Dr. phil. Andreas Heinz Prof. Dr. med. Denise Horn Univ.-Prof. Dr. med. Stefan Mundlos Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Psychiatry and Department of Psychiatry and Institute of Medical Genetics and Institute of Medical Genetics and Psychotherapy Psychotherapy Human Genetics Human Genetics [email protected] [email protected] [email protected] [email protected] 186 Clinician Scientist Alumni 187
PD Dr. med. Felix Krenzien Prof. Dr. med. Peter Kühnen
In Program From – to Fields of Research In Program From – to Fields of Research 01.2016–12.2018 › Liver 09.2013–08.2016 › Metabolism › Surgical › Monogenic obesity Contact Contact › Oncology › Rare endocrine diseases [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Surgery Institute of Experimental Pediatric Endocrinology Director Univ.-Prof. Dr. med. Johann Pratschke Director Univ.-Prof. Dr. med. Heiko Krude
New Regulators of Liver Regeneration Rare Endocrine Diseases
Primary and secondary malignancies of the liver repre- The development of obesity in industrial and also in low- References: sent the second most common cause of cancer deaths and middle income countries is a severe burden for health 1. Kühnen P, Clément K, Wiegand S, Blankenstein O, Gottes- worldwide. It is well established that liver surgery is care systems, because obesity is a major risk factor for diener K, Martini LL, Mai K, Blume-Peytavi U, Grüters A, oncologically superior to systemic therapy and loco-re- the development of cardiovascular diseases and type 2 Krude H. Proopiomelanocortin Deficiency Treated with a gional treatment alternatives in primary liver malignan- diabetes mellitus. The leptin melanocortin signaling path- Melanocortin-4 Receptor Agonist. N Engl J Med. 2016 Jul cies. Evolving evidence even suggests liver resection way is playing a pivotal role for the regulation of satiety. 2. Clément K, Biebermann H, Farooqi IS, Van der Ploeg L, increase survival rates in patients with localized tumor Gene mutations within this pathway are leading to hyper- Wolters B, Poitou C, Puder L, Fiedorek F, Gottesdiener K, spread. Thus, extended liver resections are increasingly phagia and early onset obesity. Here, the activation of Kleinau G, Heyder N, Scheerer P, Blume-Peytavi U, Jahnke applied to a broader spectrum of patients, e.g. patients neurons expressing the gene pro-opiomelanocortin I, Sharma S, Mokrosinski J, Wiegand S, Müller A, Weiß K, at a high age or with impaired regeneration capacities (POMC) via leptin receptors (LEPR) is stimulating to the Mai K, Spranger J, Grüters A, Blankenstein O, Krude H, due to underlying chronic liver disease, e.g. non-alcoholic production of melanocyte-stimulating hormone (MSH), Kühnen P. MC4R agonism promotes durable weight loss fatty liver disease (NASH). Preoperative possibilities to which in turn activates the G-protein coupled receptor in patients with leptin receptor deficiency. Nat Med. 2018 dissect patients who benefit from liver surgery from melanocortin-4 receptor (MC4R). This is leading to satiety May patients who will face serious complications, e.g. post- and modification of energy expenditure. Within the CSP 3. Clément K, van den Akker E, Argente J, Bahm A, Chung operative liver failure, are still limited. Therefore, a better project, I have started an investigator-initiated phase 2 WK, Connors H, De Waele K, Farooqi IS, Gonneau-Lejeune understanding of liver regeneration and non-invasive proof of concept trial, in which patients with mutation in J, Gordon G, Kohlsdorf K, Poitou C, Puder L, Swain J, Stewart diagnostic are urgently needed, as it would help to the gene pro-opiomelanocortin (POMC) and leptin receptor M, Yuan G, Wabitsch M, Kühnen P; Setmelanotide POMC increase the safety of liver surgery and to offer liver gene (LEPR) have been treated with a MC4R agonist 1, 2, 3. and LEPR Phase 3 Trial Investigators. Efficacy and safety resection to a higher number of critically ill patients. This study drug led to restoration of the impaired pathway of setmelanotide, an MC4R agonist, in individuals with and reduction of body weight. Based on this study-data, severe obesity due to LEPR or POMC deficiency: single-arm, phase 3 trials have been performed and this MC4R agonist open-label, multicentre, phase 3 trials. Lancet Diabetes has been approved by the FDA in 2020 as the first drug Endocrinol. 2020 Dec for the treatment of genetic obesity.
Mentors Mentors
PD Dr. med. Moritz Schmelzle Univ.-Prof. Dr. med. Univ.-Prof. Dr. med. Heiko Krude Clinical Mentor Igor-Maximilian Sauer Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Surgery Charité – Universitätsmedizin Berlin Institute of Experimental Department of Surgery Endocrinology [email protected] [email protected] [email protected] 188 Clinician Scientist Alumni 189
PD Dr. med. Annette Künkele PD Dr. med. Florian Kurth, MSc
In Program From – to Fields of Research In Program From – to Fields of Research 10.2015–09.2018 › Immunotherapies 02.2014–03.2017 › Infectious Diseases › CAR-T-cell Therapy › Parasitology Contact Contact › Neuroblastoma › Malariology [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Pediatrics, Medical Department, Division of Oncology and Hematology Division of Infectiology and Pneumonology Director Director Univ.-Prof. Dr. med. Angelika Eggert Univ.-Prof. Dr. med. Norbert Suttorp
A CAR-T-Cell Approach for Solid Tumor Attack Using Delayed Haemolysis Following Artemisinin Therapy of Malaria Neuroblastoma as a Model
Targeting tumors by adoptive T-cell therapy is a promising culture model to investigate which CAR constructs enable Malaria remains the most important vector-borne infec- with the European network for tropical medicine and innovative approach that hijacks the immune system to T-cells to invade solid tumors, b) structurally CAR con- tious disease in humans. Its importance has been rec- travel health (Tropnet). Thereby the incidence and pos- direct effector mechanisms against metastatic and resis- struct optimization to regulate activation and target ognized also recently by the award of the 2015 Nobel sible risk factors of PADH will be identified. Primary tant tumor cells. One form uses chimeric antigen recep- binding, and c) an analysis of the influence of oncogenic Prize in medicine to the malariologist Tu Youyou. Arte- human hepatocytes will be used to metabolize artemis- tors (CARs) to target tumor-associated antigens, which MYCN activity on the tumor microenvironment and CAR- misinins have become the most important class of anti- inins in an In-vitro model. Metabolites with the potential while successful against leukemia and lymphomas has T-cell effector function, which also tests the efficacy of malarials during the last decade. They are superior to to induce auto-immune mediated hemolysis will thereby not yet made strides against solid tumors. I am interested combining drugs targeting MYCN with CAR-T-cell therapy. all other antimalarials in terms of efficacy, safety, and be identified. Simultaneous analysis of the cyto- in optimizing CAR-T-cell therapy for solid tumors to In order to dissect the mechanisms leading to either tolerability. Episodes of severely delayed hemolysis have chrome-profile of the employed hepatocytes will allow remove the current difficulties that the solid tumor envi- tumor eradication or relapse, I will use a syngeneic mouse recently been observed in non-immune patients treated assessing inter-individual differences in the pharmaco- ronment presents for this innovative harnessing of model for the transferred T-cells and the host. The CD171- with Artemisinins for severe malaria. More than 80% of kinetic properties of Artemisinins with respect to differ- immune potential against cancer cells. During my post- CAR will be introduced into CD8+ T-cells derived from a these patients required red blood cell transfusion and ent cytochrome-isoenzymes. Changes in membrane doc time in Seattle, I developed a CAR specific for CD171, mouse expressing a single TCR with tumor unrelated re-hospitalization. Post-Artemisinin delayed hemolysis properties of red blood cells after malaria will be ana- an antigen expressed in several solid tumors including specificity (OT1/Rag-/-). This way T-cell-derived spe- (PADH) has also been reported in a cohort of African lyzed using flow cytometry. Results will be used to deci- neuroblastoma, the most common extracranial tumor in cies-specific cytokines such as interferon gamma can children with severe malaria. The pathophysiological pher the underlying mechanism of erythrocyte loss in childhood with an overall survival of less than 50% in only act on the tumor stroma and cancer cell recognition background, exact incidence and risk factors of PADH PADH. Results of this integrative multi-pronged research high-risk patients. My current research interest is to by T-cells occur exclusively through the CD171-CAR. are still poorly understood. The research program aims project shall help to improve the drug safety of Artemis- increase the persistence and efficacy of CAR-T-cell-based at addressing these open questions within the following inins as the most important class of antimalarials. immunotherapy for children with neuroblastoma using sub-projects: The epidemiology and clinical presentation the CD171-CAR. I will focus on a) a 3D neuroblastoma cell of PADH will be assessed in a clinical study in cooperation
Mentors Mentors
Univ.-Prof. Dr. med. Angelika Eggert Univ.-Prof. Dr. med. Thomas Blankenstein Univ.-Prof. Dr. med. Norbert Suttorp Univ.-Prof. Dr. med. Abdulgabar Salama Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Max Delbrück Center for Molecular Medicine Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Pediatrics, Molecular Immunology and Gene Therapy Medical Department, Institute of Transfusion Medicine Division of Oncology and Hematology Division of Infectiology and [email protected] [email protected] Pneumonology [email protected] [email protected] 190 Clinician Scientist Alumni 191
PD Dr. med. Gunnar Lachmann PD Dr. med. Thomas Liman, MSc
In Program From – to Fields of Research In Program From – to Fields of Research 01.2018–03.2021 › Hemophagocytic Lymphohistiocytosis 02.2014–01.2017 › Cerebrovascular disease in critically ill patients › Endothelial function Contact Contact › Immune dysfunction in critically ill › Neuroepidemiology [email protected] [email protected] patients Clinic › Immune stimulation during immune Clinic Charité – Universitätsmedizin Berlin suppression Charité – Universitätsmedizin Berlin Department of Anesthesiology and Department of Neurology Operative Intensive Care Medicine and Experimental Neurology Director Director Univ.-Prof. Dr. med. Claudia Spies Univ.-Prof. Dr. med. Matthias Endres
Biomarkers for Adult Hemophagocytic Lymphohistiocytosis Biomarkers of Endothelial Function in Stroke – the Prospective in Critically Ill Patients Cohort with Incident Stroke Study Berlin (PROSCIS-B)
Hemophagocytic Lymphohistiocytosis (HLH) is a rare diagnosis. The project aims to find a highly sensitive and Endothelial dysfunction (ED) is an early component of stroke within the »Prospective Cohort with Incident life-threatening hyperinflammatory syndrome with a highly specific biomarker panel to significantly improve atherosclerosis, which plays a major role in the devel- Stroke Study Berlin (PROSCIS-B) and correlation with mortality rate of 68%. It often remains undiagnosed due the currently available diagnostic possibilities, to get opment of cardiovascular and cerebrovascular diseases. stroke severity and stroke volume. Evaluation of cerebral to sepsis-like symptoms. Early and reliable diagnosis of further insights into its pathophysiology, and subse- ED is an established independent predictor for the occur- MRI markers for cerebral small vessel disease (»white HLH in the intensive care unit (ICU) is pivotal for patient quently to reduce mortality. In particular and driven by rence of cardiovascular disease, such as myocardial matter lesion«) with visual rating scales and volumetric outcome. It is known that adult HLH is triggered mainly previous studies, we analyze CRP, PCT, IL-1β, IL-6, IL-8, infarction or cardiovascular death, but whether ED also analyzes in correlation with the above-mentioned bio- by infectious diseases, malignancies, immune deficiency IL-10, TNF-α, IFN-γ, SIL-2R, ferritin, glyco-sylated ferritin, plays a role in cardiovascular risk after first ischemic markers of endothelial dysfunction. To test the hypoth- and autoimmune diseases, leading to an impaired func- EBV and CMV viral load, the microRNAs miR-205-5p, miR- stroke, is currently unclear. Endothelial dysfunction also esis whether biomarkers mentioned above are indepen- tion of cytotoxic T lymphocytes and natural killer cells. 194-5p and miR-30c-5p, perforin and CD107a. play a causal and integral role in the development of a dent risk factors for poor functional and cardiovascular This results in an excessive immune activation of mac- vascular diseases of the small cerebral arteries, so-called outcomes at one to three years after first stroke. rophages and T-cells with extreme cytokine production »small vessel disease« that is associated with poor out- of interferon γ (IFN-γ), and tumor necrosis factor α (TNF- come after stroke. Novel biomarkers of endothelial dys- α) – the so-called cytokine storm. These highly activated function should be investigated in a good-characterized macrophages and the »cytokine storm« infiltrate lym- prospective stroke cohort study (»PROSCIS-B«; clinical- phoid and non-lymphatic tissues and lead to hemophago- trials.org NCT01363856). The following aims are defined cytosis and multiple organ failures. Within this project, within the CS program: Determination of novel biomark- we plan to build up a biobank and systematically inves- ers of endothelial dysfunction as stromal- derived factor tigate this life-threatening hyperinflammatory syndrome 1 (SDF-1), antiendothelial autoantibodies and endothelial in the ICU in order to detect biomarkers for an early microparticles (EMP) in the acute phase of ischemic
Mentors Mentors
Univ.-Prof. Dr. med. Claudia Spies Univ.-Prof. Dr. med. Hans-Dieter Volk Univ.-Prof. Dr. med. Matthias Endres Prof. Dr. med. Thomas Keil, MSc Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Anesthesiology and Institute of Medical Immunology Department of Neurology Institute for Social Medicine, Operative Intensive Care Medicine Berlin-Brandenburg Center for and Experimental Neurology Epidemiology, and Health Economics Regenerative Therapies [email protected] [email protected] [email protected] [email protected] 192 Clinician Scientist Alumni 193
Dr. med. Agustin Liotta PD Dr. med. Alawi Lütz
In Program From – to Fields of Research In Program From – to Fields of Research 08.2014–12.2017 › Anesthetics 11.2013–10.2016 › Critical care › Neurophysiology › Sleep medicine Contact Contact › Neurometabolism › Chronobiology [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Anesthesiology and Department of Anesthesiology and Intensive Operative Intensive Care Medicine Care Medicine Director Director Univ.-Prof. Dr. med. Claudia Spies Univ.-Prof. Dr. med. Claudia Spies
Impact of Anesthetics on Cerebral Energy Metabolism During Prevention of Delirium in Critically Ill Patients Light and Deep Anesthesia: Possible Implications for Postoper
Anesthesia is a state of pharmacologically induced studied. We aim to characterize the effects of anesthetics Delirium is the most frequent psychiatric syndrome in effects of these modifications on patients’ outcome. unconsciousness, amnesia, and analgesia that allows on the oxidative phosphorylation and function of neu- the intensive care unit (ICU). The development of delirium Within the second part of the project, a prospective surgery and intensive care treatment – undoubtedly a rons during different anesthetic regimes in vitro (i.e. in critically ill patients is independently associated with observational cohort study will investigate the incidence key element of modern medicine. However, deep anes- brain slices) and in vivo in rats. Combining oxygen-mea- a 3-fold increase in risk of death within six months after of delirium in patients treated in one of the modified thesia is associated with postoperative delirium and surements, electrophysiology and flavin adenine dinu- ICU admission. Moreover, up to 40% of patients suffer ICU rooms and patients in the standard rooms on the lasting cognitive decline. The underlying mechanisms of cleotide (FAD)-imaging with computational modeling, we from long-term cognitive impairment after critical illness same ICU. We will further evaluate the impact on sleep these postoperative complications are largely unknown. want to predict possible targets of anesthetics in the (similar to scores for patients with mild Alzheimer’s dis- quality (polysomnography), circadian rhythm (cortisol, The depth of anesthesia can be classified by typical EEG mitochondrial enzymatic system. Understanding mito- ease). Within an interdisciplinary project, supported by melatonin, »clock genes), global cognitive function and patterns. Burst suppression (BS) and isoelectricity char- chondrial function during deep anesthesia will increase the Federal Ministry of Economy, 2 ICU rooms were com- general outcome parameters. acterize deep anesthesia and correlate with hypome- our knowledge on the pathophysiology of postoperative pletely redesigned. The major goal of the redesigning tabolism in the brain. Similar EEG-patterns also occur neurological complications. Furthermore, comparing process was to create an ICU bedroom that produces during situations with energy mismatch such as hypoxia gaseous and intravenous anesthetics has clinical rele- measurable improvements in the physical and psycho- or traumatic brain injury, suggesting similar but revers- vance for appropriate therapeutic choice. Last, the use logical states of patients, visitors and staff. Beside inter- ible effects of anesthetics on cerebral metabolism. In of multiparametric measurements and computational ventions aimed at noise reduction, workflow optimization the clinical routine, the use of deep anesthesia to reduce modeling could lead to find new biomarkers and improve and infection control, we conducted modifications to metabolism and evoke neuroprotection is controversial monitoring during surgery and clinical situations in which improve lighting conditions in the room. The first part as anesthetics impair mitochondrial function. Impor- deep anesthesia is performed such as status epilepticus of the Clinical Scientist project compares acoustic and tantly, the relationship between mitochondrial dysfunc- or high intracranial pressure. photobiological characteristics of the modified as well tion and depth of anesthesia was not yet systematically as the standard ICU rooms and evaluates the potential
Mentors Mentors
Univ.-Prof. Dr. med. Claudia Spies Univ.-Prof. Dr. Uwe Heinemann † Dr. rer. nat. Richard Kovacs Univ.-Prof. Dr. med. Claudia Spies Univ.-Prof. Dr. rer. nat. Achim Kramer Clinical Mentor Scientific Mentor Scientific Mentor (after Sept. 2016) Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Anesthesiology and Neuroscience Research Center Institute of Neurophysiology Department of Anesthesiology and Institute of Medical Immunology Operative Intensive Care Medicine Intensive Care Medicine [email protected] [email protected] [email protected] [email protected] 194 Clinician Scientist Alumni 195
PD Dr. med. Anna-Karina Maier-Wenzel Dr. med. Lukas Maurer
In Program From – to Fields of Research In Program From – to Fields of Research 04.2011–03.2014 › Posterior Lamellar Keratoplasty 01.2017–12.2019 › Invasive Neuromodulation › Intraocular Pressure Elevation › Metabolic Phenotyping Contact Contact › Corneal Angiogenesis and › Electrophysiology [email protected] [email protected] Lymphangionesis Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Ophthalmology Department of Endocrinology and Metabolic Diseases Director Univ.-Prof. Dr. med. Antonia Joussen, FEBO Director Univ.-Prof. Dr. med. Joachim Spranger
Evaluation of Surgical Technique of Posterior Lamellar Probing and Manipulating Neuronal Circuits in Obesity Keratoplasty and Postoperative Complications
Corneal endothelial disorders like Fuchs endothelial to the final outcomes (Maier et al., Graefes, 2015). Addi- The prevalence of obesity and type 2 diabetes (T2DM) of the neuronal information processing with respect to dystrophy and bullous keratopathy were treated by pen- tionally, we evaluated, if the localization of the surgical has reached epidemic proportions worldwide. Primarily obesity and recent advances in dissecting the neurocir- etrating keratoplasty (PKP) since years. Prolonged visual approach influences the postoperative outcomes (Maier reward-related overconsumption of highly palatable, cuitry involved in the regulation of food intake and rehabilitation of over a year, high astigmatism, suture-re- et al., Am J Ophthalmol, 2015). Postoperative complica- energy-dense foods beyond homeostatic needs is con- metabolism by optogenetic studies, cumulating evidence lated complications and graft rejection are common tions like graft detachment, graft rejection, and post- sidered a central aspect in the multifactorial pathogen- suggests that obesity might be understood in a similar complications after PKP. Alternative surgical techniques operative intraocular pressure elevation occur also after esis of obesity and the accompanying metabolic distor- way as the circuit disorder involving malfunctioning of like Descemet Stripping endothelial keratoplasty (DSEK) DMEK. We analyzed the rate and localization of graft tions. Recent cumulative evidence indicates that dys- the cortico-striato-hypothalamic system. We, therefore, or Descemet membrane endothelial keratoplasty (DMEK) detachment (Maier et al., Cornea, 2016). Additionally, we functional information flow cortico-striatal networks aim in our experimental design to investigate local field have been developed over the last decade and allow the investigated the incidence of postoperative intraocular involved in metabolic regulation, as well as reward pro- potential oscillations within this system characterize transplantation of posterior corneal layers instead of pressure elevation and analyzed causes and risk factors cessing, may be of primary importance for the patho- information processing and to apply deep brain stimu- the complete cornea. Whereas in the DSAEK procedure (Maier et al., Graefes, 2014, Maier et al., J of Glaucoma, physiology of obesity. Progress in the exploration of lation (DBS) in order to manipulate neuronal activity as the technique with graft preparation and graft unfolding 2017). Corneal angiogenesis and lymphangiogenesis are functional anatomy in a number of neuropsychiatric a potential therapeutic approach in obesity. is well standardized and reproducible, the technique of associated with a higher risk of graft rejection after cor- disorders revealed dysfunctional neuronal processing DMEK surgery remains challenging. Especially, the main neal transplantation. We study the role of different fac- within cortico-striatal circuits. This aspect and the emer- step of the surgical technique of DMEK, the unfolding of tors like ECM molecules in the development of these gence of deep brain stimulation as a suitable approach the lamella to attach the graft to the posterior stroma, blood and lymphatic vessels (Maier et al., IOVS, 2017). to probe and manipulated neuronal activity prompted poses difficulties. During this step, the most manipula- the concept of circuit disorders for diseases as for exam- tions to the graft occur. We investigated if the more dif- ple Parkinson’s disease, obsessive-compulsive disorder, ficult unfolding correlates to donor characteristics and addiction, and depression. Due to multiple similarities
Mentors Mentors
Univ.-Prof. Dr. med. Univ.-Prof. Dr. med. Joachim Spranger Univ.-Prof. Dr. med. Andrea Kühn Antonia Joussen, FEBO Clinical Mentor Scientific Mentor Clinical and Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Endocrinology and Department of Neurology Department of Ophthalmology Metabolic Diseases and Experimental Neurology [email protected] [email protected] [email protected] 196 Clinician Scientist Alumni 197
PD Dr. med. Philipp Mergenthaler Prof. Dr. med. Alexander Meyer
In Program From – to Fields of Research In Program From – to Fields of Research 11.2016–10.2019 › Clinical Neuroscience 01.2017–02.2020 › Machine Learning › Energy Metabolism › Data Science in Medicine Contact Contact › Regulation of Neuronal Cell Death › Medical Computer Science [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology German Heart Center Berlin and Experimental Neurology Department of Cardiothoracic and Vascular Surgery Director Univ.-Prof. Dr. med. Matthias Endres Director Univ.-Prof. Dr. med. Volkmar Falk
Targeting Intravital Protein Interactions in Neuronal Energy Big Data Analytics in Health Care – Medical Data Science Metabolism of Stroke to Improve Patient Safety During Intensive Care
This project addresses the pressing need to develop novel (Mergenthaler et al., Proc Natl Acad Sci USA 2012) and Machine learning applications have become ubiquitously treatment approaches for acute neuro-degeneration provides a prototypic mechanistic example of the inter- popular – from smart mobile phone applications via such as it occurs in stroke. Thus, by investigating the dependence of these major cellular pathways (Mergen- smart homes to entire smart industries. This family of pathophysiological basis for acute neurodegeneration thaler et al., Trends Neurosci 2013). The main hypothesis data-driven methods thrives especially in settings where on a molecular level, this project will mitigate the future of this project is that regulation of the interaction of a large number of concurrent signals go well beyond the challenges imposed by the care for patients suffering HKII and its associated multiprotein complex links capacity of human reasoning. Critical care units are a from these diseases. The high energy demand of the metabolism to programmed cell death in neurons. Pro- highly challenging environment that confronts physicians brain predisposes it to a variety of diseases if energy tein:protein interactions can be highly dependent on the with a demanding caseload and requires rapid deci- supplies are interrupted, such as in stroke. Neurons are physiological context and may be regulated differently sion-making. The handling of a continuous stream of particularly intolerant of inadequate energy supply and in different T-cells. Therefore, in addition to verifying massive amounts of noisy data, such as laboratory die or degenerate in either an acutely or chronically dis- the HKII protein interactions in living cells, I am using results, clinical and physiological measurements as well turbed metabolic environment. Therefore, the goal of live human induced pluripotent stem cell (hiPSC)-derived as imaging and increasingly »omics« information can this project is to unravel the role of the tight connection neurons and human brain organoids to express HKII and easily go beyond the information processing capacity of between glucose metabolism and the regulation of cell its putative interactors with fluorescent protein tags at the human operator (intensive care physician) and may death pathways for neuronal viability or acute neuronal near-endogenous levels. In vitro differentiation of hiPSCs lead to treatment delays or clinical errors. Our work degeneration after ischemic injury. I have previously will permit examining these interactions in human applies deep machine learning methods in a critical care characterized a multiprotein complex centered around neurons. scenario to provide timely and highly accurate decision the mitochondrial glycolytic enzyme hexokinase II (HKII), support to clinical staff. We aim to push the translation which acts as a sensor of the metabolic state of neurons into the clinical routine by performing rigorous clinical validation.
Mentors Mentors
Univ.-Prof. Dr. med. Andreas Meisel Univ.-Prof. Dr. med. Ulrich Dirnagl Univ.-Prof. Dr. med. Volkmar Falk Univ.-Prof. Dr. med. Titus Kühne Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin German Heart Center Berlin Charité – Universitätsmedizin Berlin Department of Neurology Department of Neurology and Department of Cardiothoracic and Institute for Imaging Science and with Experimental Neurology Experimental Neurology and Vascular Surgery Computational Modelling in BIH QUEST Center Cardiovascular Medicine [email protected] [email protected] [email protected] [email protected] 198 Clinician Scientist Alumni 199
Dr. med. Daniel Nörenberg PD Dr. med. Sebastian Ochsenreither
In Program From – to Fields of Research In Program From – to Fields of Research 04.2017–03.2020 › Lymphoma Genetics 01.2014–12.2016 › Tumorimmunology › Lymphomagenesis › Clinical oncology Contact Contact › Clonal Hematopoiesis and Preleukemia [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Medical Medical Department, Division of Department, Division of Hematology Hematology, Oncology and Tumor Director Immunology Univ.-Prof. Dr. Anontio Pezzuto Director Univ.-Prof. Dr. med. Lars Bullinger
Genetic Characterization of Primary Mediastinal B-Cell Lymphoma Development of High Affinity T-Cell Receptors Against Cyclin A1 for the Elimination of Stem Cells in AML
Accounting for approximately 10% aggressive lymphomas largest PMBL cohort (n>350) through national and inter- In analogy to healthy hematopoesis, the population of tified by tetramer titration using extrapolation of the and ~2% of newly diagnosed Non-Hodgkin lymphoma national collaborations comprising clinically well-anno- leukemic blasts in acute myeloid leukemia (AML) is based saturation curve. Functional avidity of the clones (pep- (B-NHL) cases, primary mediastinal B cell lymphoma tated patients. Using a combination of whole-exome, on leukemic stem cells (LSC), which are characterized by tide concentration associated with half maximal effector (PMBL) is a relatively rare disease. It mainly affects young targeted deep resequencing, and gene expression anal- unlimited proliferative capacity and resistance to con- function, EC50) is determined by peptide titration. The and otherwise healthy women. Although important treat- ysis, we aim to identify key oncogenic drivers and dereg- ventional tumor therapies. In many cases, elimination TCR originating from the clones with the highest func- ment improvements could be achieved in the last years, ulated signaling pathways in PMBL. Based on the previous of LSC can only be achieved by cell-mediated toxicity tionality are cloned in a retroviral vector system (MP71) a significant proportion of patients remain refractory to molecular analyses, functional consequences of candi- after allogenic stem cell transplantation (HSCT). A poten- in TCR-P2A-TCR configuration. Miss pairing with endog- standard immunochemotherapy or relapse within a short date driver mutations will be analyzed in PMBL cell lines tial alternative to HSCT is the transfer of LSC-specific enous TCR chains is omitted by partial murinization of time period. As PMBL has previously not been distin- using the CRISPR/Cas technology. T-cells. We have recently described Cyclin A1 as can- the constant region and the addition of a second cysteine guished from DLBCL, there is a large knowledge gap cer-testis- antigen, which is selectively expressed in LSC. bridge. Expression of the transgenic TCR is enhanced by regarding its underlying genetic alterations and the Aim of the actual project is the development of vectors codon- optimization of the construct. All constructs, prognostic and predictive importance of recurrent gene for the expression of high affinity T-cell receptors (TCR) which induce specific functionality against endogenously mutations. As shown by our recent work, unraveling against Cyclin A1 in autologous patient T-cells. T-cell processed Cyclin A1 in the target cells, are potential can- genetic aberrations underlying PMBL lymphomagenesis clones are generated by repetitive stimulation in vitro didates for a therapeutic application in a clinical phase has the potential to identify new targets for tailored with a HLA A2-restricted epitop of Cyclin A1. Main problem I trial. therapy approaches. A thorough description of the muta- for the isolation of high affinity TCR against selfantigens tional spectrum in PMBL and the identification of key is the potential negative selection in the thymus. The oncogenic drivers will thus facilitate rational therapeutic latter can be circumvented by isolating T-cell clones approaches. Until now, we have collected the world’s against a HLA A2- restricted epitope from T-cells of HLA A2-negative donors because thymal selection is HLA-de- pendent. Alloreactive T-cell clones reactive against HLA A2 independent of the presented epitope are excluded on clonal level. The intrinsic affinity of the TCR is quan-
Mentors Mentors
Univ.-Prof. Dr. med. Lars Bullinger Prof. Dr. med. Frederik Damm Univ.-Prof. Dr. med. Ulrich Keilholz Prof. Dr. Wolfgang Uckert Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Max Delbrück Center for Molecular Medical Department, Medical Department, Charité Comprehensive Cancer Center Medicine, Department Cell Biology/ Division of Hematology, Oncology Division of Hematology, Oncology Gene Therapy [email protected] and Tumor Immunology and Tumor Immunology Humboldt University Berlin [email protected] [email protected] [email protected] 200 Clinician Scientist Alumni 201
Dr. med. Lena Oevermann PD Dr. med. Alexander Paliege
In Program From – to Fields of Research In Program From – to Fields of Research 10.2015–09.2018 › GvHD 02.2014–01.2017 › Acute Kidney Injury › Hemoglobinopathies › Kidney Transplant Rejection Contact Contact › Microbiota › Anti-Inflammatory Mediators [email protected] [email protected] › Biomarker Current Position Clinic › Immunreconstitution Clinic Consultant for Internal Medicine Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin and Nephrology Department of Pediatrics, Medical Department, University Clinic Dresden Division of Oncology and Hematology Division of Nephrology and Internal Intensive Care Medicine Director Univ.-Prof. Dr. med. Angelika Eggert Director Univ.-Prof. Dr. med. Klemens Budde
An Immune Reconstitution and Biomarker Platform for Regulation of Intrinsic Anti-Inflammatory Mediators Hematopoietic Stem Cell Transplantation in Children During the Rejection of Kidney Transplants
Graft versus host disease (GVHD), infections and graft are currently evaluating mesenchymal stromal cell-de- Kidney transplantation is the preferred treatment modal- mation and foster tissue repair. The regulation of annexin rejection are major complications following hematopoi- rived exosomes as a new therapeutic approach for GvHD. ity for patients with end-stage renal disease and A1 during renal transplant rejection has not been char- etic stem cell transplantation (HSCT) in children. Severe Moreover, we will focus on the investigation of the human improves quality of life and overall survival. Advances acterized. The aim of the first part of the project is to GvHD is associated with a high mortality rate and remains intestinal microbiota and its significance in GvHD, aiming in organ allocation, surgical techniques, and immuno- study the expression of annexin A1 in kidney biopsies one of the main reasons for mortality after allogeneic to find the optimal preparation strategy before HSCT suppressant combination strategies have effectively from patients with transplant rejection and to identify HSCT. Graft rejection remains an obstacle to successful and perform fecal microbiota transplantation in the reduced rejection rates and improved 1-year-graft sur- cellular sources and potential targets for anti-inflam- transplantation for children with non-malignant diseases, future. Functional analyses of both projects will be car- vival to values above 95%. These advances, however, have matory annexin A1 signals. The second part of the project such as ß-thalassaemia or sickle cell disease. Within this ried out in a minor mismatch GvHD mouse-model (in not translated into a proportionate increase of long-term will determine the utility of annexin A1 as a biomarker project, we established a biobank for an enduring asser- cooperation with O. Penack). Findings will be validated graft survival. The etiology of premature allograft dete- for the detection of renal transplant rejection. vation of materials including blood, urine, feces, cere- in multicenter studies including further pediatric and rioration is multi-factorial and includes nephrotoxic brospinal fluid, bone marrow and tissue biopsies. Our non-pediatric HSCT centers. Comparing impacts of dif- effects of immunosuppressive drugs and chronic sub- patient cohort consists of all pediatric patients under- ferent transplantation settings on the clinical outcome clinical rejection. Novel methods for the detection of going HSCT in the Department for Pediatric Hematology/ will support transplantation strategy optimization focus- transplant rejection and the development of immuno Oncology/SCT at the Charité and their family donors ing on individualized immunosuppressive drug choice suppressant drugs with reduced toxicity are therefore (currently included: 70 patients, 20 family donors). To and dosing. Identification of new therapeutic strategies necessary to improve long-term outcome after kidney connect clinical courses and experimental results, all includes the investigation of GvHD pathophysiology and transplantation. The glucocorticoid-inducible protein data will be collected and saved in our database. During will allow earlier – pre-transplant, if possible – thera- annexin A1 has been identified as the central mediator the first two years after HSCT, immune reconstitution is peutic options and thereby help to reduce the incidences of endogenous anti-inflammatory signaling pathways. It characterized using flow cytometry (NAVIOS, DuraClone of GVHD, infections and graft rejection after HSCT. may, therefore, promote the resolution of renal inflam- technology) allowing a detailed characterization of T-, B, dendritic- and natural killer cells and their subsets. Our project aims at a better prediction, prevention and inno- vative therapeutic approaches for GvHD. Therefore, we
Mentors Mentors
Univ.-Prof. Dr. med. Angelika Eggert Prof. Dr. med. Nina Babel Univ.-Prof. Dr. med. Klemens Budde Univ.-Prof. Dr. med. Sebastian Bachmann Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Pediatrics, Division of Institute of Medical Immunology and Medical Department, Institute of Vegetative Anatomy Oncology and Hematology Marien Hospital Herne, Division of Nephrology and Internal [email protected] Ruhr University Bochum Intensive Care Medicine [email protected] Center for Translational Medicine [email protected] [email protected] 202 Clinician Scientist Alumni 203
PD Dr. med. Tobias Penzkofer Dr. med. Sylvie Picker-Minh
In Program From – to Fields of Research In Program From – to Fields of Research 01.2017–08.2020 › Prostate Cancer 10.2015–09.2018 › Microcephaly › Quantitative Imaging › Brain Development Contact Contact › Radiomics/Deep Learning › Rare Diseases [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Radiology Department of Pediatrics, Division of Neurology Director Univ.-Prof. Dr. med. Bernd Hamm Director Prof. Dr. med. Angela Kaindl
Prostate Cancer: Large-Scale Radiomics Analysis of Prostate Identification and Characterization of »Novel« MRI for Non-Invasive Risk Stratification Microcephaly Genes
Prostate cancer is the most common cancer in western tured reporting of prostate MR examinations, to date no Reduced brain volume manifesting as microcephaly (MC) tein synthesis. Ptrh2 furthermore has a key role in the men and the third leading cancer cause of death in Ger- established quantitative method exists to rate prostate is often associated with intellectual disability (ID) and regulation of anoikis, a process defined as cell death many. One in seven men will be diagnosed with prostate mpMRIs. Recently new analysis methods were introduced, further comorbidities. With this project, we aim to char- caused by loss of cell attachment to the extracellular cancer during his lifetime. The imbalance of incidence that can provide such measures from imaging data: acterize further genetic causes of MC and ID and to better matrix. Our research group also showed that Ptrh2 plays and mortality illustrates the core dilemma of current Radiomics, which systematically assesses subjectively understand underlying pathomechanisms. In a first part a role in cell size regulation of neurons, skeletal muscle approaches in prostate cancer diagnosis: only a few of or objectively acquired image descriptors or deep learn- of the project, we aim to identify novel microcephaly cells, liver and pancreas cells. We have generated Ptrh2 the diagnosed prostate cancers lead to relevant mor- ing which creates classifications based on multilayer genes by a process of clinical screening and genetic anal- knockout mice and analyzed the role of PTRH2 in brain bidity and mortality. At the same time, many of the treat- neural networks. The aim of the project is to investigate ysis of patients with a novel ID/MC phenotype. In a second development in vivo and in vitro. ment options carry the risk of substantial side effects, if image analysis methods based on radiomics and deep part of the project, we focus on the functional analysis preventing a broad treatment regime for this form of learning can be used to establish new imaging biomarkers of novel microcephaly genes identified in our research cancer. Consequently, there is a need for a – ideally to non-invasively determine the aggressiveness of pros- group. Here, we address the infantile multisystem neu- non-invasive – risk stratification method to distinguish tate cancers. This would allow for risk stratification and rologic, endocrine and pancreatic disease (IMNEPD), successfully between highly aggressive prostate cancers, follow-up of prostate cancer patients, avoiding the recently first described by our research group and linked leading to clinically significant disease and indolent potential side effects of invasive diagnostic methods to homozygous mutations in the peptidyl-tRNA hydrolase forms, that need no treatment. Multiparametric magnetic and ultimately preventing unnecessary aggressive 2 (PTRH2) gene. IMNEPD is a multisystem disease with resonance imaging (mpMRI) is the most promising modal- treatments. neurological features of intellectual disability, postnatal ity to that end, especially after the introduction of the microcephaly, and cerebellar atrophy. Ptrh2 is an evo- PI-RADS reporting system. Although this system proved lutionarily well-conserved protein, which prevents accu- its usefulness in the subjective assessment and struc- mulation of peptidyl-tRNAs and thereby maintains pro-
Mentors Mentors
PD Dr. med. Patrick Asbach Univ.-Prof. Dr. med. Kurt Miller Prof. Dr. med. Angela Kaindl Univ.-Prof. Dr. Christian Rosenmund Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Radiology Department of Urology Department of Pediatrics, NeuroCure Clinical Research Center Division of Neurology [email protected] [email protected] [email protected] [email protected] 204 Clinician Scientist Alumni 205
Dr. med. Daniel Pilger, MSc Dr. med. Wolfram Christian Poller
In Program From – to Fields of Research In Program From – to Fields of Research 07.2017–09.2020 › Corneal Dystrophy 09.2015–02.2018 › Atherosclerosis › Corneal Surgery › Inflammation and Glycosaminoglycans Contact Contact › Oculoplastic Surgery › Nanoparticle Imaging [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Ophthalmology Medical Department, Division of Cardiology and Angiology Director Univ.-Prof. Dr. med. Antonia Joussen, FEBO Director Univ.-Prof. Dr. med. Karl Stangl
Femtosecond Laser Assisted Versus Manual Descemetorhexis Glycosaminoglycans as Targets for Non-Invasive Imaging of Unstable Atherosclerotic Plaques
Posterior lamellar keratoplasty such as Descemet mem- Atherosclerotic plaque ruptures cause life-threatening plaques. Previous experiments demonstrated that i.v.-in- brane endothelial keratoplasty (DMEK) and Descemet complications including myocardial infarction and stroke. jected citrate-coated very small superparamagnetic stripping automated endothelial keratoplasty (DSAEK) Methods to identify unstable plaques prior to rupture iron-oxide nanoparticles (VSOP) are rapidly taken up by has become the standard treatment for conditions like are therefore highly desirable. Proteoglycans (PG) and atherosclerotic lesions, thereby enabling plaque visual- Fuchs` endothelial dystrophy. In DMEK surgery, the their glycosaminoglycan (GAG) chains are key compo- ization in the MRI. Experiments in cell culture models patient’s dysfunctional endothelial layer is replaced with nents of the extracellular matrix in atherosclerotic and rodents led to the hypothesis that VSOP primarily a donor Descemet membrane (DM). A key step during plaques and are involved in disease progression. It is binds to GAG components of unstable plaques. To prove DMEK surgery is the descemetorhexis (DR), the excision currently unknown whether plaque instability correlates this hypothesis, we will analyze the potential of VSOP- of the recipient’s DM. The surgeon penetrates the anterior with a specific PG/GAG pattern. This project aims at the based MRI to identify unstable atherosclerotic plaques chamber and makes a circular incision into the patient’s identification of instability-associated PG/GAG and their in comparison with established invasive methods includ- DM prior to removing it. Femtosecond laser technology use as targets for non- invasive imaging. We will com- ing intravascular ultrasound (IVUS) and optical coherence is an important technological advance in ophthalmic paratively analyze PG/GAG composition, GAG structure tomography (PCT). These experiments will be performed surgery. In combination with computer-controlled optical and their chemical modifications in stable and unstable in Göttingen minipigs under high-fat diet and strepto- delivery systems, femtosecond lasers are capable of human atherosclerotic lesions from the coronary and zotocin-induced diabetes. producing precise surgical incisions without damaging carotid arteries. Glycoanalytical techniques (HPLC, CE-LIF, surrounding tissues. Thus far, femtosecond lasers have MALDI-imaging) as well as histological- and expression been mainly used in cataract surgery. We have developed analyses (RT-PCR, Western Blot, IHC, TEM, FISH) will be a novel method, femtosecond laser-assisted DR, to facil- applied to identify instability-associated PG/GAG as itate DMEK surgery. In a clinical trial, we are investigating novel targets for non-invasive imaging of unstable possible benefits and the safety of this new procedure in DMEK surgery.
Mentors Mentors
PD Dr. med. Necip Torun Univ.-Prof. Dr. med. Univ.-Prof. Dr. med. Verena Stangl Univ.-Prof. Dr. med. Matthias Taupitz Clinical Mentor Antonia Joussen, FEBO Clinical Mentor Scientific Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Ophthalmology Charité – Universitätsmedizin Berlin Medical Department, Department of Radiology Department of Ophthalmology Division of Cardiology and Angiology [email protected] [email protected] [email protected] [email protected] 206 Clinician Scientist Alumni 207
Dr. med. Josefine Radke PD Dr. med. Nathanael Raschzok
In Program From – to Fields of Research In Program From – to Fields of Research 04.2015–09.2018 › Primary Central Nervous 07.2016–06.2019 › Liver transplantation System Lymphoma › Ex vivo liver machine perfusion Contact Contact › Lymphomagenesis › Liver regeneration [email protected] [email protected] › Brain Tumors Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neuropathology Department of Surgery Director Director Univ.-Prof. Dr. med. Frank Heppner Univ.-Prof. Dr. med. Johann Pratschke
Molecular Genetic Analysis and Preclinical Modeling Defatting of Steatotic Liver Grafts by Ex Vivo of CNS Lymphoma Machine Perfusion with DNP
Despite extensive research, the molecular alterations different genes involved in e.g. immune escape and Liver transplantation is the treatment of choice for biological membranes. It is hypothesized that DNP is a leading to primary central nervous system lymphoma response (e.g. HLA-DR, PD-L1, TLRs). Additionally, we seek patients with advanced liver cirrhosis, non-metastatic suitable agent for liver defatting by ex vivo machine (PCNSL) and the reasons why PCNSL are confined to the to elucidate the protein landscape of PCNSL by mass early hepatocellular carcinoma, and severe metabolic perfusion under normothermic or sub-normothermic CNS have not been fully elucidated. With regard to the spec. So far, reverse phase protein array (RPPA) revealed or autoimmune hepatic disorders. While the need for conditions. Liver fat is metabolized by the increased genetic alteration of PCNSL, available data are restricted high expression of many cancer related (phospho-)pro- liver grafts is continuously rising, the number of available cellular activity that is needed to compensate for the to whole exome and Sanger sequencing. Our research teins in PCSNL, e.g. BTK or MAPK which could be possible donor organs is increasingly limited by the scarcity of decreased efficiency of the uncoupled respiratory chain. effort shall gain more insight into the molecular land- targets for tyrosine kinase inhibitors. For further vali- suitable donor organs. Steatotic liver grafts from donors In a first work package, the already established lab- scape of PCNSL. So far, we assembled a unique collection dation, preclinical modeling, and drug target develop- with fatty liver disease pose a certain risk of primary scaled liver perfusion system was be optimized in order of 36 CNS lymphoma specimen and used WGS, RNAseq ment, we use 3 different diffuse large B-cell lymphomas non-function to the recipient. Defatting by ex vivo to enable liver perfusion over a period of 6 hours without and DNA methylation arrays (850K arrays) to identify (DLBCL) cell lines (U2932, OCI-Ly3 and OCI-Ly7) to perform machine perfusion has already been proposed as a strat- serious damage to the organ at normothermic. In work important, prognostically relevant genetic and epigenetic differently in vitro anticancer experiments, e.g. chemical egy for conditioning of steatotic liver grafts. A significant package 2, a protocol for liver defatting with DNP is cur- alterations and to distinguish between »driver muta- inhibition of MYD88 homodimerization. reduction of the liver fat could already be achieved by rently developed, with optimal DNP concentration and tions« (e.g. MYD88, CD79B, CARD11, KMT2D, and CDKN2A/B) ex vivo perfusion of steatotic rat and pig livers with perfusion time. In work package 3, the safety and feasi- and kataegis events (e.g. PIM1, BTG2, OSBL10). The results defatting agents, but successful transplantation of defat- bility of ex vivo liver defatting and the expected superior have been compared to the signatures of DLBCL without ted grafts has not yet been shown. This project aims to outcome after transplantation will be proven in rats in CNS manifestation (pDLBCL) to identify differences establish a concept for defatting of steatotic liver grafts comparison to non-treated steatotic grafts. between both entities. Our RNAseq results have already by ex vivo machine perfusion with 2,4-Dinitrophenol shown separate clustering of PCNSL and pDLBCL and (DNP) in a rat liver transplantation model. DNP is a mito- clear differences in terms of expression levels of many chondrial protonophore that shuttles protons across
Mentors Mentors
Univ.-Prof. Dr. med. Frank Heppner Univ.-Prof. Dr. rer. nat. Michael Hummel Univ.-Prof. Dr. med. Johann Pratschke Univ.-Prof. Dr. med. Clinical Mentor Scientific Mentor Clinical Mentor Igor-Maximilian Sauer Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neuropathology Institute of Pathology Department of Surgery Charité – Universitätsmedizin Berlin Department of Surgery [email protected] [email protected] [email protected] [email protected] 208 Clinician Scientist Alumni 209
PD Dr. med. Dr. med. dent. Carsten Rendenbach PD Dr. med. Thomas Schachtner
In Program From – to Fields of Research In Program From – to Fields of Research 07.2017–09.2020 › Biomechanics 02.2016–01.2019 › Transplant Medicine › Biomaterials › Transplant Immunology Contact Contact › Mandible Reconstruction › Immunology of Infection [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Oral and Maxillofacial Surgery Medical Department, Division of Nephrology and Internal Director Intensive Care Medicine Univ.-Prof. Dr. med. Dr. med. dent. Max Heiland Director Univ.-Prof. Dr. med. Kai-Uwe Eckardt
Optimizing Free Flap Mandible Reconstruction Adoptive T-Cell Therapy with Enrichment of Central Memory T-Cells in Solid Organ Transplant Recipients with CMV Infection Resistant to Antiviral Therapy
Mandible reconstruction with osseous free flaps is chal- performed in order to validate these biomaterials for We demonstrated feasibility, efficacy, and safety of adop- in the presence of partial IL-2R inhibition with enrichment lenging, especially in patients with oral squamous cell potential use in craniomaxillofacial surgery. Additionally, tive T-cell therapy with CMV-specific cytotoxic T-cells of CD4+/CD8+ TCM-like cells). Here, we aim to: (1) start a carcinoma and osteoradionecrosis. Currently, titanium mechanobiological optimizations for mandible fixation (CMV-CTL) in solid organ transplant recipients with CMV clinical trial to prove the hypothesis of prolonged efficacy is the standard material for osteosynthesis in trauma systems will be performed in future work packages in disease. Adoptive T-cell therapy, however, showed not of TCM-enriched autologous CMV-CTL, (2) follow the fate and reconstructive surgery. In head and neck cancer cooperation with the Julius-Wolff-Institute for Biome- to be long-lasting. We hypothesize that our 2nd gener- of our adoptively transferred T-cells by monitoring the patients, the metallic characteristics and available plate chanics and musculoskeletal regeneration. ation CMV-specific CTL product enriched for central TCR-repertoire by next-generation sequencing (NGS), (3) designs with high bone-areas and extreme stiffness are memory T-cells (TCM) by partial blocking of IL-2R signaling understand the mechanisms stabilizing the phenotype unfavorable, as they cause severe imaging artifacts in is more long-lasting and effective than our 1st generation of TCM, and (4) extend our studies to other viruses. tumor aftercare examinations, interference with radio- product enriched for effector memory T-cells (TEM). This therapy and high rates of soft tissue complications, e.g., hypothesis will be measured by the ability of these 2 plate removal and thus a second surgery is usually nec- preparations to augment the impaired CMV immune func- essary. Despite high precision planning, osseous non- tion and decrease high CMV-loads in immunocompro- union in the interosteotomy gaps is a common problem. mised solid organ transplant with repeated or persistent With the current project, we evaluate various aspects of active CMV-infection resistant to antiviral therapy. CMV mandible reconstruction in order to improve patient seropositive patients will be randomly allocated to two outcome. Experimental artifact reduction in CT and MRI study arms: Arm A: TEM-enriched autologous CMV-CTL imaging, biomechanical characteristics in load-bearing product (low proportion of TCM and high numbers of situations in vitro and finite element analyses and mag- antigen-specific, induced regulatory T-cells). Arm B: nesium degradation in a long-term animal study are TCM-enriched autologous CMV-CTL product (generated
Mentors Mentors
Univ.-Prof. Dr. med. Dr. med. dent. Univ.-Prof. Dr.-Ing. Georg Duda Univ.-Prof. Dr. med. Prof. Dr. med. Petra Reinke Univ.-Prof. Dr. med. Max Heiland Scientific Mentor Kai-Uwe Eckardt Scientific Mentor Hans-Dieter Volk Clinical Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Julius Wolff Institute for Biomechanics Charité – Universitätsmedizin Berlin Medical Department, Division of Charité – Universitätsmedizin Berlin Department of Oral and Maxillofacial and Musculoskeletal Regeneration Medical Department, Nephrology and Internal Intensive Institute of Medical Immunology Surgery Division of Nephrology and Internal Care Medicine and BIH Berlin Center Berlin-Brandenburg Center for [email protected] Intensive Care Medicine for Advanced Therapies Regenerative Therapies [email protected] [email protected] [email protected] [email protected] 210 Clinician Scientist Alumni 211
PD Dr. med. Michael Scheel PD Dr. med. Jan-Friedrich Scheitz
In Program From – to Fields of Research In Program From – to Fields of Research 04.2011–03.2014 › Functional MRI 01.2014–05.2017 › Heart&Brain Interaction › Diffusion Tensor Imaging › Cardiac Imaging and biomarkers Contact Contact › Neurodegenerative Diseases (troponin) in acute stroke [email protected] [email protected] › Neuroinflammatory Diseases › Takotsubo Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Radiology Department of Neurology Director and Experimental Neurology Univ.-Prof. Dr. med. Hamm, Bernd Director Univ.-Prof. Dr. med. Bick, Ulrich Univ.-Prof. Dr. med. Matthias Endres
Simultaneous FMRI and Cortical EEG – Predictors of Acute (Cardiac) Complications Electrophysiology of the BOLD Effect after Ischemic Stroke
Functional MRI and EEG are one of the most used tech- The main focus of my research group 'Integrative Car- autonomic function, and modern epidemiological meth- niques in neuroscientific research today. Basis for most dio-Neurology' is to study the mechanisms and long-term ods using large-scale clinical cohorts (like BeLOVE) to fMRI effects is the Blood-Oxygen-Level-Dependent consequences of cardiac complications after stroke. In further advance our knowledge about stroke-associated (BOLD) effect. While extensively used the electrophysi- particular, we focus on stroke-associated myocardial cardivascular complications. ology of the BOLD effect in humans is not well under- injury (troponin elevation). During my CSP period, we Recent key publications: stood. The project »Simultaneous fMRI and cortical EEG – have shown that myocardial injury after ischemic stroke 1) Stroke-heart syndrome: clinical presentation and Electrophysiology of the BOLD effect« will further elu- 1) occurs in ~50% of patients, 2) is associated with poor underlying mechanisms. Scheitz JF, Nolte CH, Doehner W, cidate the electrophysiological basis of the BOLD effect functional outcomes and short-term mortality, 3) is linked Hachinski V, Endres M. Lancet Neurol. 2018;17:1109-1120. from an EEG point of view. to a lower frequency of obstructive coronary heart dis- 2) Post-Stroke Cardiovascular Complications and Neuro- ease than in NSTE-ACS, 4) is linked to stroke lesions within genic Cardiac Injury: JACC State-of-the-Art Review. Spo- the insular cortex, 5) is associated with the occurence sato LA, Hilz MJ, Aspberg S, Murthy SB, Bahit MC, Hsieh of newly detected atrial fibrillation, and 6) associated CY, Sheppard MN, Scheitz JF; World Stroke Organisation cerebral small vessel disease, impaired cognitive func- Brain & Heart Task Force. J Am Coll Cardiol. 2020;76: tion and future MACE. These observations led to the 2768-2785. concept of a distinct 'stroke-heart syndrome', a patho- physiological framework for post-stroke cardiac compli- cations. Together with our interdisciplinary partners we apply multimodal brain and cardiac MRI, methods of computational neuroscience, diagnostic measures of
Mentors Mentors
Univ.-Prof. Dr. med. Jens Dreier Prof. Dr. med. Christian Nolte Univ.-Prof. Dr. med. Matthias Endres Clinical, and Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Radiology Department of Neurology Department of Neurology and Experimental Neurology and Experimental Neurology [email protected] [email protected] [email protected] 212 Clinician Scientist Alumni 213
PD Dr. med. Ludwig Schlemm Dr. med. Katharina Schmack
In Program From – to Fields of Research In Program From – to Fields of Research 01.2016–06.2021 › Stroke 02.2015–01.2018 › Psychosis › Biomarker › Visual Perception Contact Contact › Neuro-Imaging › Computational Psychiatry [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology Department of Psychiatry and and Experimental Neurology Psychotherapy Director Director Univ.-Prof. Dr. med. Matthias Endres Univ.-Prof. Dr. med. Dr. phil. Andreas Heinz
Routine Laboratory Parameters and Clinical Outcome in Patients The Neurobiology of Delusions – with Ischemic Stroke with Unknown Time of Symptom Onset: Linking Perceptual Inference and Dopamine a Biomarker Study
It is of paramount importance to further improve the thrombolysis. Using the concept of DWI-FLAIR mismatch Delusions are a core symptom of psychotic diseases such inference has remained unclear. Therefore, the current clinical care of patients with acute ischemic stroke. Reli- in magnetic resonance imaging (MRI), one can obtain an as schizophrenia. They refer to beliefs that are not sup- project is aimed at establishing an empirical link between able blood biomarkers for the prognosis of clinical out- accurate estimate of the age of acute ischemic infarcts. ported by evidence but are nonetheless held with strong dopamine, perceptual inference, and delusions. To this come after ischemic stroke are highly desirable, but For this reason, the prospective clinical trial WAKE-UP conviction. Delusions can cause great suffering to the end, we will conduct behavioral and functional imaging currently lacking. In more than 25 percent of all cases was started in 2012 to investigate if patients with acute affected persons and their environment. For instance, experiments in individuals with schizophrenia and of ischemic stroke, the exact time of symptom cannot ischemic stroke with unknown time of symptom onset affected persons frequently experience intense fear healthy participants. By the use of mathematical models, be ascertained in the emergency setting. It is suspected benefit from an MRI-based decision for, or against, i.v. because they feel persecuted and observed, although we will then the mechanisms underlying perceptual infer- that ischemic strokes with unknown time of symptom thrombolysis. We will analyze the relationship between outside observers cannot find any indication of such a ence. We will test whether these inferential mechanisms onset (which often occur during sleep) form a separate readily available routine laboratory biomarkers and clin- threat. There is convincing scientific evidence that delu- are altered in delusions or can be influenced by drugs sub-entity with regards to etiology, pathogenesis and ical outcome (including hemorrhagic complications) in sions are associated with excessive signaling of the neu- that stimulate or inhibit dopamine signaling in the brain. prognosis. A comprehensive quantitative characteriza- the WAKE-UP cohort according to treatment status (i.v. rotransmitter dopamine, but it is not well understood If successful, this project will contribute to an under- tion of the relationship between routine laboratory thrombolysis yes/no), and evaluate the usefulness of how such an excess in dopamine signaling might lead to standing of the role of dopamine in perceptual processes parameters and clinical outcome has not yet been per- these parameters as prognostic biomarkers. Additionally, the formation of delusions. Influential theories postulate that are compromised in delusions. formed for this stroke subtype. At the moment, the only we will systematically analyze the currently available alterations in the brain’s inferencing machinery that approved specific therapy for acute ischemic stroke scientific data about blood biomarkers and ischemic controls perception, such that expected and insignificant besides thrombectomy consists of intravenous applica- stroke with unknown time of symptom onset. stimuli are automatically perceived as surprising and tion of tissue-specific plasminogen-activator within 4.5 significant and the cognitive effort to make sense out of hours of symptom onset. So far, an unknown time of such aberrant salience results in the formation of delu- symptom onset is considered a contraindication for i.v.- sions. However, the role of dopamine in such perceptual
Mentors Mentors
Univ.-Prof. Dr. med. Matthias Endres PD Dr. med. Dr. phil. Martin Ebinger Univ.-Prof. Dr. med. Dr. phil. Univ.-Prof. Dr. med. Philipp Sterzer Clinical Mentor Clinical Mentor Andreas Heinz Scientific Mentor Clinical Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology Department of Neurology Charité – Universitätsmedizin Berlin Department of Psychiatry and and Experimental Neurology and Experimental Neurology Department of Psychiatry and Psychotherapy Psychotherapy [email protected] [email protected] [email protected] [email protected] 214 Clinician Scientist Alumni 215
PD Dr. med. Felix Alexander Schmidt Dr. med. Rosa Schmuck
In Program From – to Fields of Research In Program From – to Fields of Research 10.2018–09.2021 › Pupillary Function 08.2014–07.2017 › Cancer Stem Cells › B-mode ultrasound › Tumor Associated Stromal Cells Contact Contact › RAPD › Pancreatic Cancer [email protected] [email protected] › Optic neuritis Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology and Department of Surgery Experimental Neurology Director Director Univ.-Prof. Dr. med. Johann Pratschke Univ.-Prof. Dr. med. Matthias Endres
B-Mode Ultrasound as a Novel Non-Invasive Quantitative Cancer Stem Cells and Tumor-Associated Stromal Cells Imaging Biomarker for the Functional Assessment of the in Pancreatic Cancer Afferent Visual Pathway
This project addresses the clinical need of quantifying (PLR) and provided normal values for ultrasound derived Pancreatobiliary carcinomas demonstrate an unfavor- benign bystander cells remains unanswered. Therefore, objectively a relative afferent pupillary defect (RAPD), PLR parameters for 100 subjects in 4 different age groups able prognosis and a poor response to chemotherapy. the interaction between CAFs and cancer cells is going the pathognomonic clinical sign of optic nerve damage (Schmidt et al. PlosOne 2017). PLR assessment with ultra- Cancer stem cells (CSCs) may define the malignant poten- to be studied in a novel approach by measuring the cell due to optic neuritis (ON). The ultimate goal of this project sound in our study was well tolerated, rapidly acquired tial of a neoplasm through tumor initiation and chemo- viability of tumor components (cancer cells and CAFs) in is to establish ultrasound as a novel non-invasive objec- and had a good test-retest reliability. The goals of this therapy resistance. The aim of the project is the geno- direct and indirect co-cultures. tive imaging biomarker for the functional and quantita- research project are to directly compare the ocular ultra- typic, phenotypic and functional characterization of the tive assessment of afferent visual pathway damage. ON sound approach with infrared video pupillometry for tumor stem cell fraction in pancreato biliary malignoms. is a common symptom of demyelinating CNS conditions RAPD assessment and to compare B-mode ultrasound Special focus is set on the Notch-signaling pathway as such as multiple sclerosis and neuromyelitis spectrum with visual evoked potentials and optical coherence a potential therapeutic target. The hypothesis is then to disorder, leading to severe visual impairment and reduced tomography, two established methods that measure be evaluated in vitro, in vivo and in a representative vision-related quality of life. Early detection and quan- subclinical damage of the optic nerve. In a longitudinal cohort of patients with pancreato biliary malignoms. The tification of ON are essential for treatment decisions to study, we want to establish the value of B-mode ultra- main focus will be the analysis of patient-derived tumor improve clinical outcome. Of note, objective quantifica- sound for monitoring disease activity and for outcome cell lines and co-culture with tumor-associated stromal tion of RAPD may also have implications for clinical trials prediction in patients with ON. As the PLR is influenced cells as better treatment options require a fundamental with visual endpoints. Future trials could benefit from a by the autonomous nerve system, we also want to collect understanding of the tumor’s microenvironment and the reliable and reproducible RAPD evaluation method such PLR data from neurological patients with known auton- complex interaction between tumor and other cell types, as the B-mode ultrasound approach. In a recent study omous nerve dysfunction such as patients with multiple especially stromal cells. Furthermore, the question to we performed the first systematic evaluation of B-mode system atrophy. what extend tumor-associated stromal cells hold a gen- ultrasound for assessment of the pupillary light reflex uine malignant potential or whether those cells act as
Mentors Mentors
PD Dr. med. Klemens Ruprecht Univ.-Prof. Dr. med. Friedemann Paul Univ.-Prof. Dr. med. Johann Pratschke Prof. Dr. med. Marcus Bahra Univ.-Prof. Dr. med. Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Igor-Maximilian Sauer Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology Experimental and Clinical Research Department of Surgery Department of Surgery Charité – Universitätsmedizin Berlin and Experimental Neurology Center (ECRC) Department of Surgery [email protected] [email protected] [email protected] [email protected] [email protected] 216 Clinician Scientist Alumni 217
Dr. med. Joanna Barbara Schneider PD Dr. med. Vera Schreiter
In Program From – to Fields of Research In Program From – to Fields of Research 03.2017–06.2021 › Epigenetic 01.2014–12.2016 › Teranostics › Stem cells › Urogenital imaging Contact Contact › Regeneration › Hybrid imaging [email protected] [email protected] › Muscle atrophy Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Division of Neuropediatrics Institute of Radiology Director Director Univ.-Prof. Dr. med. Angela Kaindl Univ.-Prof. Dr. med. Bernd Hamm
Epigenetic Changes and Repair of the DNA Breaks in Skeletal PSMA Theranostic of Prostate Cancer: Radionuclide Therapy Muscle in Critical Illness Myopathy and Functional Molecular Hybrid Imaging by MRI and PET
Critical illness myopathy (CIM) is a devastating acquired and characterize the epigenetic modifications in muscle The aim of this project is to develop new strategies for skeletal muscle disease characterized by atrophy, flaccid stem cells derived from severely ill patients within the personalized theranostic management of prostate cancer paralysis and respiratory failure. It develops in very ill first days after admission to the ICU. We analyze the by using prostate-specific membrane antigen (PSMA). patients during the course of critical illness and is a epigenome and transcriptome as well as the DNA dou- PSMA is a transmembrane protein which can serve as a frequent complication of intensive care unit (ICU)-treat- ble-breaks process of activated satellite cells and early specific target structure for hybrid imaging of prostate ment. It is a very peculiar aspect of CIM that skeletal myoblasts derived from acute onset CIM patients. cancer with the new tracer Ga-68 HBED-CC PSMA as well muscle atrophy and weakness last for a prolonged period as for new treatments of prostate cancer such as radio- of time, often life-long, although all identified risk factors nuclide therapy using lutetium-177. This project deals like inflammation, hyperglycemia, medications etc. have with the evaluation of parameter specification such as been removed. We hypothesize that the acute onset of biodistribution and biokinetics of the new tracer Ga-68 severe critical illness with its dramatic hormonal, met- HBED-CC PSMA for imaging prostate cancer. Further, the abolic and nutritional disturbances leads to epigenetic potential of multimodal functional molecular hybrid changes in skeletal muscle stem cells or early myoblast. imaging such as PET/CT and PET/MRI of prostate cancer The epigenetic changes lead to an impaired ability of the and effects on personalized medicine are investigated. muscle to regenerate and a long-lasting myopathy asso- New therapeutic strategies in radionuclide therapy of ciated with critical illness that typically extends far prostate cancer with lutetium-177 are evaluated focusing beyond the duration of the ICU stay. Furthermore, the on the use of radiosynthesizers and radioprotectors to epigenetic changes lead to an increase of DNA double enable higher therapeutic doses of lutetium-177 to be breaks in the muscle cells. This project aims to identify delivered for the treatment of prostate cancer.
Mentors Mentors
Univ.-Prof. Dr. med. Angela Kaindl Univ.-Prof. Dr. med. Simone Spuler Univ.-Prof. Dr. med. Bernd Hamm Prof. Dr. med. Winfried Brenner Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Division of Neuropediatrics and Max Delbrück Center for Institute of Radiology Department of Nuclear Medicine Molecular Medicine Berlin [email protected] [email protected] [email protected] Experimental and Clinical Research Center [email protected] 218 Clinician Scientist Alumni 219
Dr. med. Stefanie Schreiter PD Dr. med. Michael Schumann
In Program From – to Fields of Research In Program From – to Fields of Research 03.2018–02.2021 › Schizophrenia 08.2013–07.2016 › Epithelial polarity and epithelial › Pharmacogenetics and -epigenetics barrier function Contact Contact › Functional Neuroimaging › Small intestinal enteropathies [email protected] [email protected] including celiac disease Clinic Clinic › Crohn´s disease Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin › Development of Colitis-associated Department of Psychiatry and Department of Gastroenterology, carcinoma Psychotherapy Infectious Diseases and Rheumatology Director Director Univ.-Prof. Dr. med. Dr. phil. Andreas Univ.-Prof. Dr. med. Britta Siegmund Heinz
Phenomics and Genomics of Clozapine Pharmacotherapy Celiac Disease
Clozapine is generally prescribed if at least two trials of such as agranulocytosis, diabetic ketoacidosis, metabolic My project focusses on celiac disease (CD), a polygenetic fication of treatment-refractory CD, a rare, but severe antipsychotic agents have not led to satisfactory clinical syndrome or obsessive-compulsive symptoms. Prescrib- immune disorder that is triggered by the ingestion of complication of CD. This includes in collaboration with improvement, thereby implying that patients on Clozap- ing Clozapine in clinical practice, therefore, requires glutens, proteins that occur in wheat, barley and rye. Professor Michael Hummel (Molecular Pathology, Charité) ine generally suffer from more severe and/or persistent balancing adverse reactions risk profile likelihoods with Once initiated a small intestinal immune response a molecular pathology technique that evaluates the T-cell symptoms than patients suffering from schizophrenia clinical response probabilities. This need highly contrasts against glutens is mounted that leads to intestinal villous diversity in small intestinal samples by means of spectrum disorders (SCZ) on other antipsychotic agents. with the current state of knowledge as it is unknown atrophy and crypt hyperplasia, resulting in malabsorp- next-generation sequencing of the variable region of the Unraveling the (functional) genetic variation underlying who will respond to Clozapine and to what degree a spe- tion of nutrients, weight loss and chronic diarrhea. In T-cell receptor. Furthermore we started a register for this severe SCZ phenotype, therefore, has the potential cific patient may develop side effects. Based on preclin- terms of basic science I study the impact of the inflam- patients suffering from refractory CD with the help of to deepen our understanding of the biological under- ical studies, we hypothesize that epigenetic and gene matory environment on polarity of GI epithelia as well the German competence network for inflammatory bowel pinnings of SCZ beyond the boundaries of DSM-based expression mechanisms influence treatment outcome as the consecutive defect of the epithelial barrier. We disorders to better understand typical disease courses consensus criteria. We here hypothesize that targeting after CLZ initiation. We will, therefore, investigate meth- hope to elucidate the mechanism by which gluten uptake of refractory CD. this phenotype in genome-wide association studies and ylation patterns/levels and gene expression profiles is upregulated, since we believe it might be a (presumably next-generation sequencing studies will signal genetic before and after initiation of CLZ pharmacotherapy. Fur- reversible) trigger point in the pathophysiology of CD. risk loci implicated in this severe SCZ phenotype. In the thermore, we will try and identify other predictive factors Another focus is the establishment of methods to visu- future, this may lead to early detection of severe SCZ, for treatment outcome following CLZ pharmacotherapy alize barrier defects in epithelial monolayers as well as which in turn will enable tailoring of pharmacotherapeu- initiation. The overarching goal is to create a prediction mucosal tissue specimen. Clinical scientific approaches tic strategies to such SCZ sub-types. Though Clozapine model for clozapine response. This model includes include the establishment of clinical tests for the diag- is one of the most effective antipsychotic medications, genetic, epigenetic and clinical data. nosis of celiac disease (including a POCT, point-of-care- it goes along with life-threatening adverse drug reactions, testing, for CD) and clinical tests to optimize the classi-
Mentors Mentors
Univ.-Prof. Dr. med. Dr. phil. Univ.-Prof. Dr. med. Stephan Ripke, PhD Univ.-Prof. Dr. med. Britta Siegmund Prof. Dr. med. Birgit Sawitzki Andreas Heinz Scientific Mentor Clinical Mentor Scientific Mentor Clinical Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Psychiatry and Department of Gastroenterology, Institute of Medical Immunology Department of Psychiatry and Psychotherapy Infectious Diseases and Psychotherapy Rheumatology [email protected] [email protected] [email protected] [email protected] 220 Clinician Scientist Alumni 221
Dr. med. Yuliya Sharkovska Dr. med. Bruno Valentin Sinn
In Program From – to Fields of Research In Program From – to Fields of research 01.2016–03.2020 › Cortical Development 07.2016–11.2019 › Breast Cancer › Hyperoxia-Induced Immature › Chemotherapy Contact Contact Brain Injury › Immunotherapy [email protected] [email protected] › Premature Birth and Cognitive Clinic Impairment Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neonatology Institute of Pathology Director Director Univ.-Prof.Dr. med. Christoph Bührer Univ.-Prof. Dr. med. David Horst
The Role of Neonatal Hyperoxia in Neonatal Brain Evaluation and Integration of Molecular Assays to Address Development and Genesis of Neurobehavioral Disorders Clinical Problems in Breast Cancer
Very preterm birth has been associated with an increased in WT mice providing 48 h exposure to fourfold increased Greater availability of personalized treatment strategies translation into clinical practice. First, we will evaluate risk to develop cognitive and social-emotional disorders. oxygen concentration (80% O2) from P5 to P7, followed for breast cancer requires a better prediction of therapy the use of RNA sequencing on formalin-fixed paraffin Premature infants are often exposed to supraphysiologic by recovery in room air until young adult ages. With the response to select treatment for individual patients. A samples. Using paired pre-therapeutic and intermediate concentrations of oxygen. While arterial oxygen tension current project, we aim to analyze the consequences of large number of patients does not respond well to che- biopsies obtained during neoadjuvant therapy, we will in utero is maintained at low levels between 24 and 28 neonatal hyperoxia on following aspects of neonatal motherapy, especially those with hormone receptor- and then characterize molecular changes that occur under mm Hg, premature birth into room air causes a sever- brain development in immature animal model:1) the neu- HER2-negative disease. Many biological determinants of chemotherapy with or without immune checkpoint inhi- al-fold increase in arterial oxygen tension in preterm robiological mechanisms through which hyperoxia affect response remain unknown and there are no reliable bition. This will allow us to define therapy-induced alter- infants to 65 mmHg and higher, even without supple- cortical neurogenesis and may lead to the development markers to predict the outcome. In addition to chemo- ations associated with therapy response. In addition, we mental oxygen. The exposure to this hyperoxic ex utero of cognitive disorders in preterm children, 2) the neuro- therapy, immunotherapies yield promise in the treatment will test pre-defined gene signatures of immunological environment may affect the immature brain during neu- protective effects of erythropoietin on hyperoxia-in- of breast cancer and reliable measures of tumor-immu- activity as markers for response to immune checkpoint ronal differentiation and maturation processes. In duced brain injury, with the aim of improving neurobe- nological activity are required to select patients. Tissue inhibition. We will include the newly discovered markers humans, the period of fastest brain growth is observed havioral and cognitive outcomes after preterm birth. in pathology is fixed in formalin and embedded in paraffin into customized targeted assays to extend the analysis during the last 3 months of a full-term pregnancy. In and numerous annotated clinical trial cohorts are avail- to a larger number of samples and future clinical trials. newborn mice and rats, in contrast, this brain growth able. The use of high-dimensional techniques like spurt occurs between postnatal days 2 and 10. Therefore, next-generation sequencing can be challenging due to rodents have been used as an experimental model to formalin-induced alterations. At the same time, the investigate the mechanisms of vulnerability in the devel- accessibility of this tissue by modern techniques is crucial oping brain. We are applying an established neonatal for translational research and for the successful trans- hyperoxia model in newborn VGAT–Venus transgenic and lation of gene assays into clinical practice. In this project, we aim to study the mechanisms of sensitivity and resis- tance to neoadjuvant chemotherapy with or without immune checkpoint inhibition. We will develop robust assays for formalin-fixed paraffin tissue to facilitate the
Mentors Mentors
PD Dr. med. Thomas Schmitz Univ.-Prof. Dr. Victor Tarabykin Prof. Dr. med. Carsten Denkert Univ.-Prof. Dr. rer. nat. Michael Hummel Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neonatology Institute of Cell Biology and Department of Pathology Institute of Pathology Neurobiology [email protected] [email protected] [email protected] [email protected] 222 Clinician Scientist Alumni 223
Dr. med. Cornelia Skowronek Dr. med. Kaspar Josche Streitberger
In Program From – to Fields of Research In Program From – to Fields of Research 07.2017–12.2020 › Parkinson Syndromes 01.2016–12.2018 › Neuroprotection › Immunoneuropathology › Prognostication After Cardiac Arrest Contact Contact › Autonomic Nervous System › Cold Shock Protein [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology Department of Neurology and Experimental Neurology and Experimental Neurology Director Director Univ.-Prof. Dr. med. Matthias Endres Univ.-Prof. Dr. med. Matthias Endres
Phosphorylated α-Synuclein in Skin Biopsies: A New Biomarker Hypothermia and Neuroprotection: A Role for Cold-Shock-Proteins? for Neurodegenerative Parkinson Syndromes
Synucleinopathies are neurodegenerative diseases as highly sensitive and specific protocol for patients suf- The aim of this research study is the investigation of could function as a possible marker for neuronal cell Parkinson Syndromes (e.g. Parkinson’s Disease (PD) and fering from Parkinson Syndromes, including standardized cold-shock protein RNA-binding-motif-protein 3 (RBM3) damage and/or for the monitoring of hypothermia treat- Multiple System Atrophy (MSA)). Pathological α-Synuclein skin punch biopsy location, the most sensitive pSNCA and its neuroprotective role. The expression of RBM3 is ment. Within our study, we also focus on the investigation (SNCA) phosphorylation induce misfolding and deposi- antibody, and the right target fiber type. Moreover, we -unlike most other proteins- induced by hypothermia. of RBM3 expression in human brain tissue. Our goal is tion of insoluble intracellular pSNCA aggregates. Differ- will improve the understanding of pSNCA dependent RBM3 is discussed to be a promotor of global protein to quantify and localize RBM3 within the human brain in ential diagnosis of Parkinson Syndromes is based on neurodegeneration in the peripheral nervous system synthesis as well as specific proteins with neuroprotec- correlation with pathological quantification/markers of clinical criteria. However, a definite discrimination can (PNS), by correlating functional features of affected nerve tive effects of which only a few are known. First described neuronal cell damage giving us insights into possible only be assessed post-mortem by means of different fibers types (autonomic vs. somatosensory) with their by Derry et al. in 1995 it is expressed ubiquitously in neuroprotective effects of RBM3 in the adult human brain. cerebral pSNCA aggregate localization (neurons vs. glial histopathological pattern to assess differences in mor- human cells and its pathophysiological function is so In cooperation with the research group »Clinical and cells). In contrast to MSA, PD includes affection of periph- phology, distribution, and quantification of pSNCA in far only partially understood. Our goal is to investigate experimental Epileptology« we aim to establish human eral nervous system. For the first time, our group could PNS vs. CNS. This project will provide a new in vivo diag- the role of RBM3 and its neuroprotective function during brain slice cultures to analyze RBM3 regulation under discriminate PD and MSA by detection of pSNCA in dermal nostic tool for PD and will contribute to adjusting the hypothermia using a multimodal approach in cooperation hypothermia and hypoxia. The characterization of the sympathetic nerve fibers in vivo. All PD patients revealed guidelines and diagnostic consensus criteria. with the research group »Hypothermia and Neuropro- RNA expression and RBM3 protein synthesis could pro- a positive pSNCA immunoreactivity and all MSA patients tection« at the DHZB, the Department of Neuropathology vide the groundwork for subsequent studies investigating were pSNCA negative. However, other groups report on and the Department of Nephrology and Intensive Care the optimum neuroprotection through hypothermia. different methods with significantly variable sensitivity Medicine. Our core projects include the characterization and/or specificity that prevent a successful use in a clin- of RBM3 serum concentration in patients treated with ical routine so far. Putative reasons are different biopsy mild therapeutic hypothermia after cardiac arrest and locations, diverse staining protocols, pSNCA antibodies resuscitation. Changes in the course of hypothermia and nerve fiber type. In this project, we will implement dermal Serine 129 pSNCA in sympathetic nerve fibers as a new biomarker for early and definite differential diag- nosis of PD in clinical routine. We will state a definite,
Mentors Mentors
Prof. Dr. med. Christoph Ploner Prof. Dr. med. Werner Stenzel Prof. Dr. med. Christoph Ploner PD Dr. med. Christoph Leithner Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology Department of Neuropathology Department of Neurology Department of Neurology and Experimental Neurology and Experimental Neurology and Experimental Neurology [email protected] [email protected] [email protected] [email protected] 224 Clinician Scientist Alumni 225
PD Dr. med. Benjamin Strücker PD Dr. med. Thi Minh Tam Ta
In Program From – to Fields of Research In Program From – to Fields of Research 01.2015–02.2018 › Tissue engineering 01.2018–03.2021 › Neurobiology of Depression › Regenerative medicine › Global Mental Health Contact Contact › Experimental surgery › Psychiatric Genomic Consortium [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of General, Visceral and Department of Psychiatry Transplantation Surgery Director Director Univ.-Prof. Dr. Dipl. Psych. Isabella Heuser-Collier Univ.-Prof. Dr. med. Johann Pratschke
Decellularization and Recellularization of Parenchymal Organs Influence of Periphrale Cytochrom P-450 2C19 Activity on Depression: A Functional Study in Two Distinct Ethnic Groups
Decellularization removes cells and antigenic material Various independent findings indicate a direct role of an additional Southeast Asian population (Vietnamese) from organs and tissue to obtain the extracellular matrix altered Cytochrome P450 activity, especially CYP 2C19 in is ideal. Our project investigates for the first time the (ECM). The ECM consists of less or even non-immunogenic depression pathogenesis which is independent of phar- functional link between the CYP 2C19 enzyme activity proteins (e.g. collagen, fibronectin, laminin etc.) and con- macokinetic effects. This involvement is apparently and depressive symptoms by the measurement the func- serves the three-dimensional micro-architecture of an mediated by an impact on the metabolism of endogenous tional enzyme activity in the peripheral blood in Viet- organ. Furthermore, it contains organ specific growth substrates. Translational approaches and initial clinical namese and German patients with depression. The activ- factors and thus can serve as an ideal biomatrix for the findings on CYP2C19 showed the presence of a »fast« ity measurements on patient-specific cells, in contrast repopulation with cells from a different origin. By apply- metabolism (UM) in humans are associated with depres- to the exclusive genotyping, is also influenced by epi- ing decellularization of a (xenogeneic) organ and recel- sive behavior and reduced hippocampal volumes. Besides genetic regulation, induction or inhibition. This func- lularization of this ECM with human cells, the in vitro drugs lifestyle factors such as smoking, nurture and tional approach can also provide valuable evidence of generation of functional, autologous tissue appears medicinal herbs can also influence the CYP 2C19 enzyme potentially usable »druggable targets« which leads to possible. The aim of our project is the implantation of activity. Interestingly various traditional plantbased the development of personalized treatment for the decellularized and recellularized organs (e.g. liver, pan- drugs, which are widespread in Asia have a strong inhi- patients suffering from depression. creas, blood vessels etc.) in vivo. To achieve this objective bition effect on CYP2C19 enzyme activity. Such influence many issues like the re-assembly of an organ-specific factors are entirely neglected by genotyping. In addition micro-anatomy, the re-establishment of a functional to variables such as sex, age, substance consumption endothelial barrier etc. have to be overcome. Further- and eating habits, there is a high degree of ethnic vari- more, interactions between cells used for recellulariza- ability, particularly in the activity of CYP2C19 isozymes. tion and the decellularized ECM will be analyzed. To evaluate the recent findings, the proposed study of
Mentors Mentors
Univ.-Prof. Dr. med. Johann Pratschke Univ.-Prof. Dr. med. Igor-Maximilian Sauer Univ.-Prof. Dr. Dipl. Psych. PD Dr. med. Julian Hellmann-Regen Clinical Mentor Scientific Mentor Isabella Heuser-Collier Scientific Mentor Clinical Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of General, Visceral and Department of General, Visceral and Charité – Universitätsmedizin Berlin Department of Psychiatry Transplantation Surgery Transplantation Surgery Department of Psychiatry [email protected] [email protected] [email protected] [email protected] 226 Clinician Scientist Alumni 227
PD Dr. med. Dorothea Terhorst-Molawi Dr. med. Christoph Treese
In Program From – to Fields of Research In Program From – to Fields of Research 09.2015–10.2019 › Drug Delivery 08.2014–07.2017 › Gastrointestinal Oncology › Dendritic Cells, Macrophages › Metastasis Contact Contact and MasT-cells › Therapy prediction [email protected] [email protected] › Skin Immunology Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Dermatology, Department of Gastroenterology, Venerology and Allergology Infectious Diseases and Rheumatology Director Director Univ.-Prof. Dr. med. Ulrike Blume-Peytavi Univ.-Prof. Dr. med. Britta Siegmund
Laser-Assisted Dermal Drug Delivery Development of Prognostic and Predictive Biomarkers
Intradermal drug-delivery represents an attractive mode delivery. Furthermore, we are planning to apply this Despite radical tumor resection with extended lymph- are developing an experimental platform to analysis of application because of the skin’s easy accessibility method in patients with different skin diseases. The use adenectomy, approximately 40% of patients with gastric biomarkers on the level celllines in vitro and in orthotopic and its high and dense network of immune cells. By of this new laser technology, therefore, represents a cancer develop a disease relapse after initial curative cellline derived xenograft models (CLDX) in vivo. Fur- using a fractionated ER:YAG laser, we can generate micro- scientific approach to tackle the clinical challenge of treatment. Where in early tumor stage patients are thermore, we are creating patient derived xenografts pores of different depth in the skin, which allows the finding the best route of application and optimizing the treated only by surgery, patients with local advanced (PDX) and collecting tumor samples from a large gastric deposition of molecules with high precision. Dermal therapeutic effect. stages get an escalated therapy with chemotherapy and cancer population. In a second step we would like to dendritic cells (DCs) expressing the XCR1 chemokine surgery. This additional treatment leads to survival ben- identify new prognostic makers by performing next gen- receptor, also known as CD103+ or CD8α+ DCs, excel in efit of 10% for these patients. In a retrospective analysis eration sequencing in a large gastric cancer cohort. On the presentation of extracellular antigens to CD8+ T-cells. we could show in 76 patients with gastric cancer that the base of the experimental platform describe above By creating laser-generated micropores through the 12,8% of the patients had a complete response under we would like to prove the quality of these biomarkers. epidermis, we targeted a model protein antigen fused the preoperative treatment and 89% of them were alive The development of predictive biomarkers is performed to XCL1, the ligand of XCR1, to dermal XCR1+ DCs and after 5 years. In contrast to these patients 11.5% had a in collaboration with the Max Plank Institute for molec- induced antigen-specific CD8+ and CD4+ T-cell responses. disease progression under this treatment and a decreased ular genetic (AG Prof M. Schweiger). In this project we In a murine tumor model, we have shown that laser-as- survival of only a few month. To improve the survival of are collecting biopsies of patients with gastric cancer sisted drug delivery induces a strong local as well as a patients with gastric cancer we need on the one hand before and after the first cycle of chemotherapy. By ana- systemic anti-tumor response, which seems to be supe- prognostic biomarkers to identify high-risk tumors in lyzing the samples with RNA-Seq and correlating the rior to classical needle-based drug delivery. We are now early tumor stages for escalating the therapy. On the reaction profils with the histopathologic remission after aiming to better understand the molecular mechanisms other hand we need also predictive biomarkers to iden- three cycles of therapy we hope to find specific reaction of this enhanced effect of laser-assisted dermal drug tify therapy responder and non-responders for treating profils to predict the response to chemotherapy. patients only with effective chemo-therapy. In this proj- ect we analyze the role of the prognostic oncogene MACC1 (metastasis-associated in colon cancer-1) for gastric cancer. On the basis of MACC1 as a model biomarker we
Mentors Mentors
Univ.-Prof. Dr. med. Marcus Maurer Univ.-Prof. Dr. rer. nat. Birgit Sawitzki PD. Dr. med. Severin Daum Univ.-Prof. Dr. rer. nat. Ulrike Stein Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin ECRC – Translationale Onkologie (CBB) Department of Dermatology, Institute for Medical Immunology Department of Gastroenterology, [email protected] Venerology and Allergology Infectious Diseases and [email protected] Rheumatology [email protected] [email protected] 228 Clinician Scientist Alumni 229
PD Dr. med. Falk von Dincklage PD Dr. med. Maximilian von Laffert
In Program From – to Fields of Research In Program From – to Fields of Research 04.2011–06.2014 › Anesthesiology 09.2015–08.2018 › NSCLC and Tumor Heterogeneity › Clinical Neurophysiology › Anaplastic Lymphoma Kinase in NSCLC Contact Contact › Pain Research › Acne Inversa/Hidradenitis Suppurativa [email protected] [email protected] › Medical Informatics Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Anesthesiology and Institute of Pathology Operative Intensive Care Medicine Director Director Univ.-Prof. Dr. med. David Horst Univ.-Prof. Dr. med. Claudia Spies
Investigation of Nociception and Anti-Nociception Comparative Analysis of Tumor Heterogeneity in Non-Small Cell Lung Cancer During Genereal Anesthesia (NSCLC) by Phosphoproteomics and Next Generation Sequencing (NGS)
In current clinical practice, dosing of analgesics during British Journal of Anaesthesia 2018). Also, we showed in Heterogeneity in tumors might have different faces. In intratumoral heterogeneity of Non-Small Cell Lung Cancer general anesthesia is performed based on the patient’s a clinical study that higher analgesic doses during general general, the role of different clones and sub-clones in (NSCLC) on the (phospo)proteomic level in comparison responsiveness to noxious stimulation. If a patient moves anesthesia seem to be associated with lower rates of different areas of one tumor is discussed. However, dif- with mutational profiles (NGS-based). Thereby, we focus or exhibits an increase in blood pressure or heart rate chronic pain, which might be explained by a better sup- ferent diagnostic test facing the protein level (e.g. immu- on the question if future molecular NSCLC-diagnostics in response to a surgical stimulus, the analgesic dose is pression of pain sensitization processes that might be nohistochemistry/IHC) on the one hand and the DNA-level should consider (a) aspects of heterogeneity (e.g. biop- increased as the clinical responses are considered signs triggered through intraoperative nociception (von Dinck- (e.g. Fluorescence in-situ Hybridization/FISH) on the other sies of different tumor regions) and (b) functional rele- of a neuronal processing of the painful sensory input, lage et al., European Journal of Pain 2018). Thus, if future hand might produce discrepant results. Is this tumor vance of certain mutations (e.g. further investigation on which is termed nociception. Accordingly, if a patient studies confirm this connection between persistent heterogeneity, as well? In a first step, we addressed this the proteomic level), as the molecular complexity of the shows no clinical responses to noxious stimulation, the nociception during general anesthesia and triggering of question focusing on the Anaplastic Lymphoma Kinase, mutational landscape is discussed as mechanisms of analgesic dose is considered sufficient, as the absence chronic pain, the current clinical practice of dosing anal- a treatable target in Lung Cancer. Underlined by our Next resistance in targeted (personalized) cancer therapy. In of responses is considered indicative of absent nocicep- gesics according to clinical responsiveness might have Generation Sequencing (NGS) – data, discrepant results the clinical context (e.g. tumor board) our data might, in tion. However, we were able to demonstrate in an exper- to be changed and alternative surrogate measures for by means of IHC and FISH might be due to technical perspective, help to identify and predict therapy resis- imental setting using functional magnetic resonance nociception during general anesthesia might be required. (methodological heterogeneity) or biological (proteo-ge- tance, as well as propose alternative therapy options. imaging (fMRI), electroencephalography (EEG) and spinal nomic heterogeneity) reasons. Within the next step, we pain reflexes (NFR) during general anesthesia that noci- broaden our view (going away from focusing one target ception persists in the spinal cord and the brain through- only), as recent data based on NGS, described tumor out the common clinical doses of anesthetics (von Dinck- heterogeneity on the genetic level by Whole Exome lage et al., Neuroimage 2018). Furthermore, we showed Sequencing. However, data on the proteomic level are that the assumption that absence of clinical responses missing so far. Thus, in this study, we investigate the is a sure sign of a sufficient analgesic dose is not valid as we demonstrated a persistence of nociception in spi- nal cord and brain even though the subjects showed no clinical responses to the stimuli (von Dincklage et al.,
Mentors Mentors
Univ.-Prof. Dr. med. Claudia Spies PD Dr. med. Jan Baars Univ.-Prof. Dr. Dr. h.c. Manfred Dietel Univ.-Prof. Dr. med. Frederick Klauschen Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Anesthesiology and Department of Anesthesiology and Institute of Pathology Institute of Pathology Operative Intensive Care Medicine Operative Intensive Care Medicine [email protected] [email protected] [email protected] [email protected] 230 Clinician Scientist Alumni 231
Dr. med. Carl Weidinger Dr. med. Friedrich Wittenbecher
In Program From – to Fields of Research In Program From – to Fields of Research 07.2015– 06.2017 › Gastroenterology 01.2018–03.2021 › Immune Reconstitution in › Immunology Allogeneic Hematopoietic Stem Contact Contact › Metabolism Cell Transplantation [email protected] [email protected] › Clinical Single Cell Sequencing Clinic Clinic › Secondary Immune Defects Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Medical Department, Division of Department of Hematology, Gastroenterology, Infectiology and Oncology and Cancer Immunology Rheumatology Director Director Univ.-Prof. Dr. med. Lars Bullinger Univ.-Prof. Dr. med. Britta Siegmund
The Role of Mesenteric Fat in Intestinal Inflammation Mobilization of Donor Immunological Memory and its Fate After Allogeneic Hematopoietic Stem Cell Transplantation
Creeping fat represents a disease characterizing finding Loss of the adaptive immunological memory and ham- sponding recipients and determine their contribution to in Crohn’s disease (CD) but its impact on intestinal inflam- pered immune reconstitution after allogeneic hemato- immune reconstitution and protection. Modern single mation and epithelial barrier function is unknown. Pre- poietic stem cell transplantation (alloHSCT) substantially cell RNA sequencing (scRNAseq) technologies will enable vious data indicate that bacterial translocation induces increase the risk for severe infections post alloHSCT, clonal tracking of immune cells from donor to recipient a unique immunologic and endocrine milieu within the which account for significant morbidity and mortality in on single cell level and elucidate immune cell trajectories mesenteric fat of CD patients resulting in immune cell transplanted patients. Transfer of donor memory cells in reconstitution post alloHSCT. In connection with clin- infiltration as well as production of specific cytokines along with the stem cell graft importantly contributes ical data, these studies could help to develop treatment and adipokines thereby influencing intestinal inflamma- to the post-transplant immune protection of the recip- strategies such as niche protection or specific adoptive tion. The present project aims to define how intestinal ient. The graft quality with respect to memory cells and cell therapy to improve post-transplant immune barrier defects shape the homeostasis of mesenteric fat, the impact of G-CSF on the immune cell distribution in competence. how these alterations confer to an alternative intestinal the graft remain insufficiently understood. Especially barrier and how creeping fat modulates epithelial resis- the role of G-CSF in mobilizing specific memory cells tance as well as intestinal immune cell composition and might be relevant, as these cells may possess distinct immunity. A fat-depleting mouse model will serve to antigen specificities. In order to gain further insight into answer these questions and the data will subsequently the effect of G-CSF on memory cells, we will characterize be correlated with results obtained from a CD patient memory T and B cell subset composition and function- cohort as well as from a patient with acquired generalized alities in stem cell donors before and after G-CSF treat- lipodystrophy and combined CD (AGLCD), who lacks mes- ment. Regarding the fate of the transplanted memory enteric fat tissue and suffers from severe CD. cells, we will analyze memory cell subsets in the corre-
Mentors Mentors
PD. Dr. med. Severin Daum Univ.-Prof. Dr. med. Britta Siegmund PD Dr. med. Anne Flörcken Univ.-Prof. Dr. med. Il-Kang Na Clinical Mentor Clinical and Scientific Mentor Clinical Mentor Scientific Mentor Medical Department, Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Division of Gastroenterology, Medical Department, Division of Medical Department, Medical Department, Infectiology and Rheumatology Gastroenterology, Infectiology and Division of Hematology, Oncology and Division of Hematology, Oncology and Rheumatology Tumor Immunology Tumor Immunology [email protected] [email protected] [email protected] [email protected] 232 Clinician Scientist Alumni 233
PD Dr. med. Tobias Wollersheim Dr. med. Thomas Heinrich Wurster
In Program From – to Fields of Research In Program From – to Fields of Research 01.2016–12.2018 › Pathophysiology and Preventive 01.2018–12.2020 › Cardiovascular Imaging Strategies of Neuromuscular Organ › Positron Emission Tomography/ Contact Contact Failure in Critically ill Patients Magnetic Resonance (Imaging) [email protected] [email protected] › Metabolism in Critically ill Patients Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Anesthesiology and Department of Cardiology Operative Intensive Care Medicine Director Director Univ.-Prof. Dr. med. Ulf Landmesser Univ.-Prof. Dr. med. Claudia Spies
Prevention of Neuromuscular Organ Failure Molecular PET/MR-Imaging in Coronary Artery Disease in Critically Ill Patients
My research focus as a Clinician Scientist is the preven- cation is not yet recommended. From the data of earlier Atherosclerotic plaque rupture in coronary arteries can itron Emission Tomography (PET), usually combined with tion of ICU-acquired muscle weakness via advanced, investigations, we could determine the key factors influ- lead to myocardial infarction and in some cases to sud- computed tomography (PET/CT) for anatomical detail, is muscle activating physiotherapy methods. The current encing the effectiveness of enhanced physiotherapy den cardiac arrest. Plaques prone to rupture are consid- a non-invasive imaging modality, which provides molec- therapeutic options allow for the survival of severe dis- options in the prevention of neuromuscular organ failure. ered as »vulnerable plaques« and feature distinct char- ular information. Dependent on the tracer used, specific eases. Serious neuromuscular sequelae are an increasing Considering these findings, a specific therapy will be acteristics, such as a large necrotic core covered by a pathological processes, such as micro-calcification problem that significantly worsens the acute and long- further developed under standardized conditions using thin fibrous cap, macrophage, and positive vascular (18F-fluoride) can be studied. Recently developed PET/ term outcomes in terms of reduced physical functional, an established sepsis-mouse-model. Furthermore, recent remodeling. A substantial number of these «high-risk MR scanners with the opportunity of simultaneous reduced quality of life, and increased mortality. We have investigations lead us to the point that neuromuscular lesions« do not cause flow-limiting stenosis and there- assessment of structure and biology offer great potential shown that systemic inflammation and immobilization failure already occurs during perioperative setting. fore can detract from common non-invasive diagnostic in cardiovascular imaging. The aim of our project is to are major risk factors, inducing pathophysiological pro- Therefore, we just initiated an observational trial to con- stress testing and invasive x-ray coronary angiography. evaluate the potential of PET/MR imaging in coronary cesses that lead to an ICU-acquired weakness. Decreased firm these findings of the first description of Perioper- Intravascular imaging techniques, such as intravascular artery disease. protein synthesis, increased protein degradation, and ative Acquired Weakness (POAW). My work is embedded ultrasound (IVUS) and optical coherence tomography metabolic dysregulation in the form of a pronounced within the BIH Twinning Research Grant project »Inflam- (OCT) demonstrated great potential in the assessment insulin resistance are detected very early in the course mation-induced skeletal muscle atrophy in critically ill of plaque morphology. However, the application is limited of critical illness. We could recently show that a daily patients«. Additional research interests: glucose metab- due to invasiveness. Cardiac magnetic resonance imaging exercise program with electric muscle stimulation can olism, glucose monitoring, insulin therapy, nutritional (MRI) on the other hand is a non-invasive imaging modal- maintain muscle mass, as well as improve glucose metab- support, caloric needs, indirect calorimetry, extracor- ity that provides excellent soft-tissue contrast. CMR olism in skeletal muscle. However, these successes are poreal membrane oxygenation. assessment of atherosclerotic altered coronary arteries inconsistent and patient-specific, so that a broad appli- can depict plaque burden and plaque composition. Pos-
Mentors Mentors
Prof. Dr. med. Steffen Weber-Carstens Univ.-Prof. Dr. med. Jens Fielitz Univ.-Prof. Dr. med. Ulf Landmesser Univ.-Prof. Dr. med. Marcus Makowski Clinical Mentor Scientific Mentor Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Ernst Moritz Arndt Universität Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Anesthesiology and Greifswald Department of Cardiology Department of Radiology Operative Intensive Care Medicine Department of Molecular Cardiology [email protected] [email protected] [email protected] [email protected] 234 Clinician Scientist Alumni Alumni Junior 235
PD Dr. med. Sebastian Zschaeck
In Program From – to Fields of Research 08.2018–07.2021 › Functional Imaging › Normal Tissue Effects of Radiotherapy Contact › Tumor Hypoxia [email protected] Clinic Charité – Universitätsmedizin Berlin Department of Radiation Oncology and Radiotherapy Director Junior Prof. Dr. med. Dr. h.c. Volker Budach Digital Clinician Characterization of the Tumor and its Surrounding Microenvironment During Treatment to Improve Future Cancer Therapies Scientists
Radiation therapy combined with chemotherapy (CRT) in almost all solid tumors, promoting chemo- and is the standard of care for locally advanced head and radio-resistance and metastasis. The underlying bio- neck squamous cell cancer (HNSCC) and as a preoperative logical mechanisms for the association of INT with or definitive treatment for esophageal squamous cell patient outcome and tumor hypoxia remain unclear so carcinoma (ESCC) patients. Metabolic imaging using far. The aim of this research project is to validate INT in 18F-Fluorodeoxyglucose (FDG) positron emission tomog- combination with tumor parameters in a prospective raphy (PET) is commonly used for staging and re-staging cohort of ESCC patients undergoing CRT and unravel the in these patients but the imaging information is not yet biological underpinnings of this phenomenon. For the routinely used to provide additional prognostic or pre- latter, one patient will receive functional imaging dictive information during treatment. Therapy-induced together with analyses of radiation-induced immune FDG uptake of tumor surrounding irradiated normal tis- response in HNSCC and additionally cell culture of a sue (INT) has been shown to have a high prognostic primary tumor, mucosa and immune cells in ESCC impact in both diseases. Additionally, INT cutoff values patients. mRNA NanoString analyses will be performed generated in hypothesis-generating cohorts were able in the already evaluated HNSCC and ESCC cohorts with to discriminate patients at high or low risk for local the aim to identify candidate genes for consecutive cell recurrence and death in independent HNSCC and ESCC co-culture experiments. validation cohorts. When using additional imaging trac- ers INT showed a strong inverse correlation with tumor hypoxia. Hypoxia is a known adverse prognostic factor
Mentors
PD Dr. med. Pirus Ghadjar Prof. Dr. rer. nat. Clinical Mentor Ingeborg Tinhofer-Keilholz Scientific Mentor Charité – Universitätsmedizin Berlin Department of Radiation Oncology Charité – Universitätsmedizin Berlin and Radiotherapy Department of Radiation Oncology and Radiotherapy [email protected] [email protected] 236 Junior Digital Clinician Scientists Junior Digital Clinician Scientists 237
Dr. med. Nikolaus Behr Dr. med. Johannes Eschrich
In Program From – to Fields of Research In Program From – to Fields of Research 08.2020–07.2022 › Neuro-Oncology 08.2020–07.2022 › Artificial Intelligence › Molecular Diagnostics › Gastrointestinal Oncology Contact Contact › Bioinformatics › Cancer Pathology [email protected] [email protected] › Digital Medicine Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology Department of Hepatology and and Experimental Neurology Gastroenterology Director Director Univ.-Prof. Dr. med. Matthias Endres Univ.-Prof. Dr. med. Frank Tacke
Methylation-Based Classification of Cell-Free DNA Image-Based Prediction of Clinically Actionable Features for AI-Driven Pan- Cancer Diagnostics. in Tumor Biopsies of Liver Cancer Using Deep Learning
Histopathological examination of tumor tissue is the based on the machine-learning model random forest. Artificial intelligence already facilitates many aspects of relevant differentiation of the mentioned tumor entities, gold standard for the diagnosis of cancer. Recently, Nanopore sequencing allows a cost-effective and our daily lives. However, there are comparatively few we are working on the predication of relevant molecular molecular pathological assignment of tumor tissue has time-efficient reading of the base sequence by voltage established applications in clinical medicine so far. As biomarkers, like BRAF, Her2neu, V600E, IDH1/2, FGFR2. In also become possible by recognizing the methylation changes during the transport of DNA through a nanopore. a resident in internal medicine and gastroenterology, I addition, we are developing models to predict clinically patterns of the tumor genome. This involves the identi- We have already created a first version of the cancer am particularly interested in improving the care of relevant information such as response to specific therapy fication and classification of tumor entity-specific hyper- classifier with public methylation data of brain-derived patients with cancer of the digestive tract. Our project options or recurrence-free survival. In parallel, we are and hypomethylated promoter regions of oncogenes and and some first non-cerebral tumors. The goal is to extend focuses on cancer of the liver but is also applicable to performing laboratory experiments to enrich our data- tumor suppressor genes. This method has reached appli- this with further public data up to about 150 additional other tumor entities. The two most common malignant base of liver cancer patients with complex molecular cation maturity as a diagnostic procedure for both brain tumor entities. This should enable a minimally invasive, primary liver tumors are so-called hepatocellular and features. Our project has the potential to improve clinical tumors and non-brain tumors. Specimen extraction (PE) cross-organ, methylation-based classification of cholangiocellular carcinomas. These entities represent workflows of liver cancer diagnosis and treatment. is usually performed by an invasive surgical procedure. cancers. the second most common cause of cancer related death Patients could be preselected according to the machine Especially in brain tumors, brain stem or tumor diseases worldwide. Recent advances in molecular medicine have learning biomarker predications and thus the load of with leptomeningeal spread, this is difficult or not pos- identified innovate systemic treatments that are specific molecular assays and radiological imaging could be sible due to possible cerebral side effects, unjustifiable for certain mutations and should therefore be restricted reduced. Finally, more patients could benefit from per- risks or lack of solid tumor mass. A so-called »liquid to patients with these molecular features. However, in sonalized molecular treatment and thus outcomes could biopsy« (LB), the extraction of cell-free tumor DNA certain cases available biopsies do not allow molecular be improved. (cftDNA) from plasma or cerebrospinal fluid (CSF) pro- analysis, e.g. due to a lack of material, high costs or vides an alternative to neurosurgical PE. In this project, missing technological infrastructure. Thus, further ana- for the first time, methylation patterns of cftDNA will be lytics tools allowing to improve diagnostic sensitivity determined from CSF and used to classify brain metas- and specificity are needed in these patients. In our opin- tases and differentiate meningeosis neoplastica. This is ion, this unmet medical need can be addressed by using made possible by the use of innovative technologies deep learning-based image analysis of standard histo- such as nanopore sequencing and a cancer classifier pathological tumor samples. Besides the clinically highly
Mentors Mentors
Univ.-Prof. Dr. med. Matthias Endres PD Dr. med. Philipp Euskirchen Dr. Naveed Ishaque, PhD Prof. Dr. med. Christoph Roderburg Univ.-Prof. Dr. med. Frank Tacke Univ.-Prof. Dr. med. Dipl.-Phys. Clinical Mentor Clinical Mentor Digital Mentor Clinical Mentor Clinical Mentor Frederick Klauschen Digital Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology Department of Neurology Berlin Institute of Health Department of Hepatology and Department of Hepatology and Institute of Pathology and Experimental Neurology and Experimental Neurology Gastroenterology Gastroenterology [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] 238 Junior Digital Clinician Scientists Alumni Junior Digital Clinician Scientist Alumni 239
Dr. med. Nicolas Wieder
In Program From – to Fields of Research 08.2020–07.2022 Alzheimer's Disease Contact [email protected] Clinic Charité – Universitätsmedizin Berlin Department of Neurology and Experimental Neurology Director Junior Univ.-Prof. Dr. med. Matthias Endres Digital Clinician Identifying Alzheimer’s Disease-Relevant Genes at the Intersection of Genomic Risk and Neuronal Lipotoxicity Scientist Alumni
Complex diseases are caused by an interaction of genetic of our time and the contribution of lipids, and FFAs in and environmental risk factors. Large-scale sequencing particular, to disease progression has been recognized projects (genome wide association studies, GWAS) con- before. The identification of the ɛ4 allele of apolipopro- tinue to illuminate the genetic architecture of complex tein E (APOE) gene as the most significant genetic risk diseases such as type 2 diabetes (T2D) and Alzheimer’s factor for AD strongly supports these observations. To disease (AD); however, it remains challenging to connect specifically address the question how environmentally the vast number of emerging disease-associated single driven exposure to certain lipids interacts with the nucleotide polymorphisms (SNPs) to cellular disease genomic risk for AD, we will integrate publicly available mechanisms. There is a need for systematic strategies GWAS datasets for AD with a novel, transcriptionally that prioritize relevant genes of interest by accounting derived signature of lipotoxicity in neurons, the primarily for environmental risk, especially given scenarios where implicated neuronal cell type in AD. More specifically, we genetic risk factors are often only revealed by an envi- will expose iPSC derived neurons to a library of 61 bio- ronmental trigger. An important environmental trigger logically relevant but structurally diverse FFAs and per- for a whole array of complex disease including, but not form transcriptomics for each of them. The resulting, limited to, T2D, coronary artery disease and AD is the unbiased signature of lipotoxicity will then be overlaid overabundance of dietary lipids, predominately in the with genes ranked by their proximity to SNPs resulting form of triglycerides (TAGs). This leads to the accumula- from GWAS for AD. We expect the integration of these tion of free fatty acids (FFAs) in various tissues, inducing two orthogonal lines of evidence to reveal disease rel- a detrimental cellular state known as lipotoxicity. To evant genes at the intersection of environmental and date, there is no comprehensive understanding of the genomic risk for AD that constitute prime candidates for contribution across the full spectrum of structurally further validation studies to investigate their potential heterogenous FFAs to disease pathogenesis. AD is one as novel drug targets. of the most prevalent complex neurological disorders
Mentors
Univ.-Prof. Dr. med. Harald Prüß Prof. Dr. med. Dr. rer. nat. Anna Greka Univ.-Prof. Dr. med. Clinical Mentor Clinical Mentor Stephan Ripke, PhD Clinical Mentor Charité – Universitätsmedizin Berlin Broad Institute of MIT & Harvard Department of Neurology Medical School (Harvard) Charité – Universitätsmedizin Berlin and Experimental Neurology Department of Psychiatry and [email protected] Psychotherapy [email protected] [email protected] 240 Junior Digital Clinician Scientist Alumni Junior Digital Clinician Scientist Alumni 241
Dr. med. Tizian Rosenstock Dr. med. Marie Schafstedde
In Program From – to Fields of Research In Program From – to Director 07.2019–09.2021 › Deep neural networks 07.2019–06.2021 Univ.-Prof. Dr. med. Titus Kühne and › Navigated transcranial magnetic Univ.-Prof. Dr. med. Felix Berger Contact Contact stimuation [email protected] [email protected] Fields of Research › Brain tumor surgery › Image based numerical modelling Clinic Clinic › Machine learning Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin › Digital health Department of Neurosurgery Institute of Computer-assisted Cardiovascular Medicine and Director Charité – Universitätsmedizin Berlin Univ.-Prof. Dr. med. Peter Vajkoczy Department of Pediatric Cardiology and Congenital Heart Disease
Development of Neural Networks for Brain Tumor Patient Hybrid Modelling: Combining Machine Learning with Physiology Imaging Analysis Based Models in Cardiovascular Medicine
The gold standard for treatment of intrinsic brain tumors appropriate. In our initial analysis, we built on deep neu- With increasing affordability of computational power as techniques and to improve clinical feasibility of patient- is a complete resection since the extent of resection ral networks to predict the patients’ postoperative motor well as improvements in medical imaging technology, specific in-silico modelling, thereby facilitating clinical (EOR) is positively correlated with (progression free) status based solely on their preoperative T1 with contrast image-based numerical modelling of hemodynamics is translation. As a proof of concept, this project develops survival. However, the goal of complete tumor removal agent scans. To improve our model performance, we gaining increased attention within the medical commu- an ML-based non-invasive diagnosis method for patients should always be balanced with preservation of function, decided to completely revise and adapt the preprocess- nity. Apart from improving our understanding of the with aortic stenosis, one of the most common acquired because eloquent brain tumors imply the risk of a new ing of the data and to integrate different modalities in cardiovascular system through in-silico studies, such cardiovascular diseases. functional deficits which not only lead to reduced quality our model as well. After training the model, its perfor- methods hold the potential to substantially improve of life, but also to reduced survival. We recently validated mance is further improved by expert validation (super- treatment decision and outcome prediction capabilities. our risk stratification model based on regression tree vised learning) and by integrating external data In col- Using patient-specific 3-dimensional image data com- analysis that enables to estimate the risk of postoper- laboration with other neurosurgical centers. We plan to bined with computational fluid dynamics (CFD) solver, ative motor deficit based on navigated transcranial mag- develop a freely available web-based decision support the ability to non-invasively predict treatment-critical netic stimulation [nTMS] and diffusion tensor imaging tool that can be accessed by any neurosurgeon. In a hemodynamic parameters has been demonstrated. How- (DTI) data. A tumorous motor cortex infiltration and a web-based template, the treating neurosurgeon can ever, such methods are time consuming, cost-intensive distance ≤8mm to the corticospinal tract were risk factors enter all relevant patient characteristics and upload the and require substantial user interaction. As an alternative for the development of a new postoperative motor deficit. available MRI and nTMS data. The probability of periop- to CFD, we propose a novel machine-learning (ML) based In these cases, the risk was even higher if we could erative risk for a new motor deficit is provided, as well method that is user friendly and produces results almost demonstrate impaired cortical excitability, which is as an estimate of the patient's EOR, tumor histology, and instantly. The challenge herein lies in providing a suffi- determined by the motor resting threshold. The aim of survival rate. Relevant risk factors such as tumor motor cient amount of training data for ML-based methods. this project is to combine different modalities such as cortex infiltration or corticospinal tract involvement are Such an amount is not found even in large multicenter structural MRI scans (with diffusion tensor imaging), reported in a standardized manner. studies. To overcome this data gap, available patient-spe- nTMS data and patient characteristics using deep neural cific data is augmented using a statistical shape model networks to further increase the accuracy of motor out- (SSM). With this hybrid approach, we aim to overcome come prediction and identify new correlations where the aforementioned limitations of traditional numerical
Mentors Mentors
Univ.-Prof. Dr. med. Peter Vajkoczy PD Dr. med. Dr. med. Thomas Picht Prof. Dr. Christoph Lippert Prof. Dr. med. Prof. Dr. med. Prof. Dr.-Ing. Prof. Dr. Christoph Lüth Clinical Mentor Scientific Mentor Digital Mentor Katharina Schmitt Alexander Meyer Leonid Goubergrits Scientific Mentor Clinical Mentor Scientific Mentor Digital Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Hasso Plattner Institute German Research Center Department of Neurosurgery Department of Neurosurgery Digital Health - Machine Learning DHZB – Department of Charité – Charité – for Artificial Intelligence Congenital Heart Disease – Universitätsmedizin Berlin Universitätsmedizin Berlin Cyber-Physical Systems [email protected] [email protected] [email protected] Pediatric Cardiology Institute for Imaging Science Institute of Computer- [email protected] and Computational Modelling assisted Cardiovascular [email protected] in Cardiovascular Medicine Medicine [email protected] [email protected] 242 Digital Clinician Scientists Alumni Digital Clinician Scientists 243
Dr. med. Martin Atta Mensah
In Program From – to Fields of Research 08.2020–07.2023 › Computer Vision › Next Generation Phenotyping Contact › High Throughput Sequencing [email protected] › Rare Diseases Clinic Charité – Universitätsmedizin Berlin Institute of Medical and Human Genetics Director Digital Univ.-Prof. Dr. med. Stefan Mundlos Clinician Scientists Computer-Aided Phenotyping of Patient Images in Clinical Genetics
Patients with genetic syndromes often show character- data. This should enable faster and more efficient filter- istic facial features and pathognomonic malformations, ing and prioritization of the huge amounts of data that which can also be recognized on image data. Due to the are generated, for example, during the exome analysis rarity of specific disease entities and the multitude of of a patient. The time spent waiting for a diagnosis is different syndromes, it requires special expertise and supposed to be shortened and the rate of correctly diag- great experience to assign the particular phenotypes to nosed cases increased. the correct diagnoses. This process of phenotyping is accordingly lengthy and expensive. It is usually per- formed at specialized centers, which also have modern DNA sequencing technology to confirm suspected diag- noses by means of molecular genetics. Recently, com- puter-based diagnostic decision support systems have been developed that can analyze patient portrait images and return a list of suspected diagnoses using machine learning techniques. In my research, I am evaluating the diagnostic value of these systems, try to make them applicable to other image types (photographs and radio- graphs of the hands and feet), and integrate them into pipelines for interpreting high-throughput sequencing
Mentors
Univ.-Prof. Dr. med. Denise Horn Univ.-Prof. Dr. med. Stefan Mundlos Prof. Dr. rer. medic. Dominik Seelow Clinical Mentor Scientific Mentor Digital Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Institute of Medical and Human Genetics Institute of Medical and Human Genetics Institute of Medical and Human Genetics [email protected] [email protected] [email protected] 244 Digital Clinician Scientists Digital Clinician Scientists 245
Dr. med. Katarina Braune Dr. med. Keno Bressem
In Program From – to Fields of Research In Program From – to Fields of Research 08.2020–07.2023 › Digital Health 08.2020–07.2023 › Deep Learning in computer vision and › Patient-Led Innovation natural language processing focussed Contact Contact › Open-Source on radiology [email protected] [email protected] › Automated Insulin Delivery Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Pediatric Department of Radiology Endocrinology and Diabetology Director Director Univ.-Prof. Dr. med. Bernd Hamm Prof. Dr. med. Klemens Raile
Open-Source Artificial Pancreas Systems – Translating Experienced-Based Improving the Generalizability of Radiological Deep Learning Evidence from Patients to Academia and Industry Models Through a Prospective Study Infrastructure
Despite advances in care, pharmaceuticals and techno- of real-world data from which has yet to be fully analyzed, Translating deep learning models into clinical practice logical developments, type 1 diabetes remains a chal- leaving the rich vein of expertise, knowledge, and expe- is a fundamental challenge and is expected to grow in lenging chronic condition that impacts life expectancy rience that exists within patient communities largely importance. Deep learning models often suffer from low and diminishes quality of life. Technological approaches untapped by key stakeholders in healthcare and science. generalizability when applied to new data, which means aim to diminish the decision-making complexity in As Digital Clinician Scientist fellow and co-founder of that the accuracy of the models used is much lower than self-management and alleviate the cognitive and emo- the OPEN project (www.open-diabetes.eu), I am part of the accuracy achieved during development under con- tional burden on people with diabetes, simultaneously an international and intersectoral consortium striving trolled conditions. To prevent this, deep learning models improving glycemic levels and variability. Automated to establish an experienced-based evidence base for should be clinically tested before they are used. To accel- Insulin Delivery (AID) systems combine glucose sensors open-source AID and identify challenges and possible erate this process, I am developing an infrastructure at and insulin pumps with control algorithms to automat- solutions to enable its wider diffusion. The majority of Charité Universitätsmedizin Berlin to facilitate the pro- ically adjust insulin delivery. Despite significant research the team lives with diabetes and is using open-source spective evaluation of deep learning models. Together and commercial interest, a limited number of AID systems AID, which makes OPEN a truly patient-led research proj- with my team, we aim to integrate deep learning algo- are currently licensed for use, and their functionality is ect. Our research addresses the following questions: rithms into the radiological productive system (the Pic- limited by regulatory authorities. AID systems are, there- Does open-source AID improve clinical outcomes and ture Archiving and Communication System – PACS). This fore, not universally available, accessible, affordable, or the quality of life of the users? How can healthcare pro- will allow us to immediately test and continuously individually suitable. Given these limitations, a patient fessionals best support ethical use of open-source AID? improve developed algorithms until they are highly reli- community, united under the hashtag #WeAreNotWaiting, What experiences do users have with this technology? able and can be used in clinical practice. has created open-source AID systems to better utilize How can we further improve and automate predictions existing devices and data. Not approved by regulatory and therapeutic adaptations of AID for certain indica- bodies, but with code and documentation freely acces- tions? Are there barriers to further dissemination (e.g. sible online, the use of open-source AID continues to age, gender, socio-economic status)? And finally – what increase globally, with an estimated ten thousand indi- can industry, research and other stakeholders learn from viduals using them. There are around 25 million hours the #WeAreNotWaiting movement?
Mentors Mentors
Prof. Dr. med. Klemens Raile Dr. Bryan Cleal, PhD Prof. Dr. Korey Hood Dr. med. Sebastian Wyschkon Prof. Dr. med. Dr. rer. medic. MHBA. Mr. Klaus Moritz Clinical Mentor Scientific Mentor Digital Mentor Clinical Mentor Stefan Markus Niehues Digital Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Steno Diabetes Center (Copenhagen) Stanford University Charité – Universitätsmedizin Berlin Phönix PACS GmbH Department of Pediatric Endocrinology Department of Radiology Charité – Universitätsmedizin Berlin [email protected] [email protected] [email protected] and Diabetology Department of Radiology [email protected] [email protected] [email protected] 246 Digital Clinician Scientists Digital Clinician Scientists 247
Dr. med. Sophy Denker Dr. med. Julius Emmrich
In Program From – to Fields of Research In Program From – to 01.2021–12.2023 › Hematology & Oncology 09.2019–08.2022 › Multi-Omics Contact Contact › Lymphoma Biology [email protected] [email protected] › Machine Learning Clinic › Novel study design Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Hematology, Department of Neurology Oncology and Cancer Immunology and Experimental Neurology Director Director Univ.-Prof. Dr. med. Lars Bullinger Univ.-Prof. Dr. med. Matthias Endres
Anticipation, Rediction and Optimization of the Therapeutic Mechanisms of Neuronal Dysfunction and Death Outcome of Lymphoma Patients Using Digital Model Analysis in Sepsis-Associated Cognitive Impairment
In order to improve the long-term survival of high-risk There is compelling evidence that survivors of critical and there is no available treatment. Microglial phago- lymphoma patients by personalized medicine, the devel- illness that enter medical care with no evidence of cog- cytosis (i.e. engulfment and degradation of a target) is opment of new prediction parameters through a multi- nitive impairment are often discharged with severe de a crucial process to maintain brain homeostasis during modal evaluation approach is necessary. This interdis- novo neurocognitive decline that is long- lasting and injury as it prevents tissue damage resulting from leakage ciplinary project in close cooperation with Prof. Dr. likely permanent. More than one in three patients have of toxic intracellular components from dying cells. Thus, Roland Eils at the BIH Center for Digital Health combines profound cognitive impairments for at least one year it has previously been assumed that microglial phago- clinical data, basic tumor biology research, and current after release from an intensive care unit (ICU) and as cytosis of neurons is entirely beneficial and always pre- bioinformatics analysis methods and is thus unique to medical care is improving and the number of ICU admis- ceded by a cell’s commitment to cell death. However, this point and represents an innovative and conceptual sions is increasing worldwide, the number of survivors based on our recent observations indicating that microg- new orientation of tumor precision medicine. of critical illness is growing. Sepsis, a potentially lia can engulf and thereby eliminate functional neurons life-threatening systemic inflammation, is a leading cause and/or synapses during neuroinflammation, it is con- of ICU admission and commonly precipitates severe long- ceivable that neuronal and/or synaptic loss following term cognitive impairment. Recent studies aiming to sepsis is executed by microglial phagocytosis. The aim elucidate the neuronal correlate of cognitive demise of this project is to investigate if phagocytosis of neurons have found neuroinflammation (i.e. activation of microg- and/or synapses is beneficial or detrimental for cognitive lia, the immune cells of the central nervous system), and outcome following sepsis and this project will determine neuronal death to be responsible for diffuse cerebral whether anti-phagocytic treatment may be a therapeutic damage and eventually brain atrophy. However, the option for preventing cognitive deficits in sepsis underlying pathophysiology remains poorly understood survivors.
Mentors Mentors
Univ.-Prof. Dr. med. Lars Bullinger Univ.-Prof. Dr. med. Clemens Schmitt Univ.-Prof. Dr. Roland Eils Univ.-Prof. Dr. med. Matthias Endres Prof. Dr. med. Christian Drosten Prof. Dr. Odej Kao Clinical Mentor Scientific Mentor Digital Mentor Clinical Mentor Scientific Mentor Digital Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin BIH – Digital Health Center Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Technical University Berlin Medical Department, Division of Medical Department, Division of [email protected] Department of Neurology Institute of Virology Department of Telecommunication Hematology, Oncology and Tumor Hematology, Oncology and Tumor and Experimental Neurology Systems Complex and Distributed [email protected] Immunology Immunology IT Systems [email protected] [email protected] [email protected] [email protected] 248 Digital Clinician Scientists Digital Clinician Scientists 249
Dr. med. Brigitta Globke Dr. med. Maria Heinrich (geb. Olbert)
In Program From – to Fields of Research In Program From – to Fields of Research 08.2020–07.2023 › Photoplethysmographic visualization 07.2019–01.2024 › Postoperative Neurocognitive of tissue perfusion Disorders Contact Contact › Kidney transplantation [email protected] [email protected] › Liver transplantation Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Surgery Department of Anesthesiology and Operative Intensive Care Medicine Director Univ.-Prof. Dr. med. Johann Pratschke Director Univ.-Prof. Dr. med. Claudia Spies
Intraoperative AR Guided Photoplethysmographic Visualization Multiomics Analysis of Postoperative Neurocognitive Disorders of Tissue Perfusion in Older Patients
The optimal perfusion of kidney grafts is vital for the Postoperative delirium (POD) and postoperative neuro- months after surgery. Genomic, transcriptomic, as well long-term outcome after kidney transplantation. Perfu- cognitive disorder (NCD) are common and severe com- as miRNA profiling data were generated using microarray sion can be influenced by the placement of the organ in plications after surgery and are associated with increased analysis. In addition, proteomic data on selected param- the retroperitoneal space. Using photoplethysmographic morbidity, mortality and loss of autonomy. Both POD eters are available. These data will be analyzed under visualization tools, minimal changes in colour, that can- and NCD can be regarded as complex diseases, as their consideration of the clinical database in a multi-omics not be detected by the human eye, should be made visible development is multifactorial, and only hypotheses are approach. A particular benefit of a multi-omics approach and give an idea about the quality of organ perfusion. currently available regarding their etiology. It is believed, is the possibility of integral (longitudinal) analysis, since In a second step this technology should be made avail- that no single hypothesis can adequately explain the data beyond the gene level can also be considered. able to the surgeon in the operating room via an aug- causal relationships of POD and NCD, and that only path- Another crucial advantage of this project is that omics mented reality tool, so an optimal placement of the graft way interactions can describe the complex phenomena. data from the patient collective of interest are available, can be achieved in less time and with more security A systematic approach combining genomic, transcrip- that regulatory elements can be taken into account by concerning optimal perfusion. tomic, proteomic and environmental data using pathway means of miRNA profiling, and that the clinical database analyses in a patient population has not yet been of the study provides comprehensive information on described. Therefore, the aim of this project is to describe environmental factors. In addition, repeated sampling biological pathways involved in the development of POD enables the consideration of temporal factors related and NCD using multi-omics analysis in a hypothesis-gen- to primary endpoints. All DNA, RNA and plasma samples erating approach. This project is part of the multicenter were stored in a biobank, so that further investigations prospective observational study BioCog – »Biomarker (e.g. methylation patterns, de novo sequencing) are pos- Development for Postoperative Cognitive Impairment in sible. Finally, biological pathways of POD and NCD are the Elderly« (Clinicaltrials.gov ID: NCT02265263). 1032 to be established. These should provide new hypotheses patients ≥ 65 years of age undergoing elective surgery for follow-up studies on the prevention and treatment were included. Primary endpoints are the occurrence of of POD and NCD. POD and NCD. Blood samples were obtained from patients preoperatively, on the first postoperative day, and three
Mentors Mentors
Prof. Dr. med. Robert Öllinger Univ.-Prof. Dr. med. Benjamin Kossack, MSc Univ.-Prof. Dr. med. Claudia Spies Univ.-Prof. Dr. med. Stefan Mundlos Univ.-Prof. Dr. Roland Eils Clinical Mentor Igor Maximilian Sauer Digital Mentor Clinical Mentor Scientific Mentor Digital Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Fraunhofer Heinrich Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Surgery Charité – Universitätsmedizin Berlin Hertz Institute Berlin Department of Anesthesiology and Institute of Medical and Human BIH – Digital Health Center Department of Surgery Operative Intensive Care Medicine Genetics [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] 250 Digital Clinician Scientists Digital Clinician Scientists 251
Dr. med. Marcus Kelm Dr. med. Samuel Knauss
In Program From – to Fields of Research In Program From – to Fields of Research 07.2019–09.2022 › Digital Medicine and Data Science 09.2019–08.2022 › Digital health › Congenital Heart Disease › Global Health Contact Contact › Cardiovascular Imaging › Health economics [email protected] [email protected] Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Pediatric Cardiology and Department of Neurology Congenital Heart Disease and Experimental Neurology Director Director Univ.-Prof. Dr. med. Felix Berger Univ.-Prof. Dr. med. Matthias Endres
Decision Support System for Structural Heart Disease mTOMADY – Building Digital Technology to Provide Access to Quality, Affordable Essential Healthcare
Surgical and catheter-based treatment procedures in tional parameters (arterial blood pressures and myocar- Out-of-pocket payments (OPP) remain the predominant Wallet (MHW), for skilled healthcare during pregnancy acquired and congenital structural heart disease usually dial function) and to provide realistic boundary condi- mode of healthcare financing in many low and middle-in- and delivery. The MHW is a closed loop system enabling focus on normalization of hemodynamics (short term tions for longer-term biomedical models and virtual come countries (LMICs). However, the costs for skilled expectant mothers to save, send, receive and pay money outcome), as well as longer-term goals, including the treatment. Non-invasive and imaging-based biomarkers, care frequently exceed the savings or assets which can exclusively for healthcare. We hypothesize that the MHW restoration of normal arterial/myocardial function, exer- including internal myocardial power, circulatory effi- be accessed at one time by a low-income household, will improve access to skilled care during pregnancy and cise tolerance and absence of re-hospitalization. ciency, and aortic distensibility are, furthermore, eval- leading to medical impoverishment. Today, more than childbirth by reducing financial obstacles. To test this Advances in digital health and biophysical computational uated to gain new insights into disease pathophysiology 70% of worldwide mobile phone subscriptions come from hypothesis, we designed a cluster randomized controlled modeling allow performing virtual interventions that can and individual disease response. LMICs with more than 74 subscriptions per 100 people trial, called the Mobile MOney for maTernal HEalthcare predict short term hemodynamic outcome. However, it in Sub-Sahara Africa (SSA) in 2016. In the footsteps of Related Spending (4MOTHERS) trial for implementation has remained difficult to predict how these immediate this revolution have followed mobile payment systems, of the MHW in public health facilities in Antananarivo, changes translate into mid/long term clinical outcomes. colloquially known as Mobile Money (MM), which com- the capital of Madagascar. In particular, we will adopt a Machine learning that makes use of clinical routine mea- monly utilize low-tech systems to enable financial trans- multidisciplinary, mixed-methods approach to assess surements, sensor data and non-invasive imaging data actions without the need for a bank account. Making use three components of the MHW intervention: i) its impact, have the potential to overcome this knowledge gap and of this technological development, MM-based hospital by measuring usage of public health facilities and health predict important parameters of long term function, pro- insurance or savings mechanisms, which enable low-in- outcomes; ii) its performance, by measuring adoption, viding a Decision Support System that includes: (1) Virtual come households to set aside funds exclusively for usage and user satisfaction; and iii) its economic cost, treatment procedures, which will be performed and val- healthcare, have been introduced successfully in several by measuring incremental costs of the intervention per idated against results from the actual clinical outcome SSA countries. However, a substantial knowledge gap pregnancy and model the cost-effectiveness of the inter- in order to provide reliable and scalable solutions for remains on the impact, performance, and economic costs vention. We expect the results of our study to guide future treatment optimization. (2) Computational bio- of MM-based healthcare financing mechanisms. By build- future initiatives and health policy decisions related to physical models, in order to simulate immediate hemo- ing on existing mobile money infrastructure, we have financial risk protection and universal healthcare cov- dynamic outcome (pressure gradients, flow profiles). (3) developed and implemented a mobile-phone-based erage through digital technology in Madagascar and other Machine learning techniques, to predict long term func- digital savings and payment platform, the Mobile Health low and middle-income countries.
Mentors Mentors
Univ.-Prof. Dr. med. Felix Berger Univ.-Prof. Dr.-Ing. Anja Hennemuth Univ.-Prof. Dr. med. Titus Kühne Univ.-Prof. Dr. med. Matthias Endres Prof. Dr. med. Christian Drosten Prof. Dr. Odej Kao Clinical Mentor Scientific Mentor Digital Mentor Clinical Mentor Scientific Mentor Digital Mentor Charité – Universitätsmedizin Berlin Charité – Institute of computer- Charité – Institute of computer- Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Technical University Berlin Department of Pediatric Cardiology assisted cardiovascular medicine assisted cardiovascular medicine Department of Neurology Institute of Virology Department of Telecommunication and Congenital Heart Disease and Experimental Neurology Systems Complex and Distributed [email protected] [email protected] [email protected] IT Systems [email protected] [email protected] [email protected] 252 Digital Clinician Scientists Digital Clinician Scientists 253
Dr. med. Mirja Mittermaier (geb. Ramke) Dr. med. Marcel Naik
In Program From – to Fields of Research In Program From – to Fields of research 08.2020–07.2023 › Deep Learning 08.2019–07.2022 › Nephrology › Viral Pathogenesis › Transplantation Contact Contact › Explainable Deep Learning › Immunology [email protected] [email protected] › Human Lung Tissue › Telemedicine Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Infectious Diseases and Department of Nephrology and Respiratory Medicine Internal Intensive Care Medicine Director Director Univ.-Prof. Dr. med. Norbert Suttorp Univ.-Prof. Dr. med. Kai-Uwe Eckardt
Explainable Deep Learning to Investigate Viral Pathogenesis T-Box: A Model for Predicting Kidney Transplantation Failure in the Human Lung
Understanding viral pathogenesis is a key field of inves- tasks in medical imaging. However, neural networks act Marcel Naik started his academic career during his med- cleared from missings or corrupt data. After that step of tigation in emerging respiratory viruses. It is crucial to like a black box and do not provide any information about ical school and did his thesis under supervision of Prof. data preprocessing a training dataset will be defined to gain a deep understanding of the molecular and cellular what led to the classification decisions. Yet, understand- Dr. Klemens Budde investigating immunosuppressive train an algorithm predicting patients with permanent interplay between viruses and their host to enable inno- ing the algorithms decisions would help to gain profund effects in immune cells for individualization of immu- renal graft failure or death. Collaborating with the vative adjunctive therapies beyond pathogen-directed information and to ensure reproducibility. Although both nosuppressive therapy in renal-transplanted patients. DATEXIS group at Beuth university for applied science clinical approaches. To understand the pathogenesis of technologies show major contributions independently, He was introduced into relational databases and statis- text data from examination and pathology reports will a viral infection, it is pivotal to identify the i.) cell tropism they have not yet been combined to investigate virus tical analysis. He developed interest in the problems of be incorporated into the prediction model. Diogo Telmo (which cells are infected by the virus), along with ii.) other pathogenesis. Thus, we aim to develop deep learning a clinical routine database with missing values and sub- Neves, a data scientist from the medical informatics cell types present in the lung tissue and involved in the algorithms and apply explainable deep learning to ana- optimal normalization. In his BIH funded project, he department at Charité and former DFKI researcher, is immune response. Over the past decade, the field of lyze »omics-data« along with spatially resolved high-res- pursues to establish a prediction model for clinical use programming and fusing all branches together. As of systems virology has evolved and technologies such as olution microscopy images to enhance our understanding in the nephrology department at Charité to determine 04/2021 a baseline prediction model incorporating demo- microarrays and single cell sequencing provide detailed of viral pathogenesis in the human lung. patients at high risk for renal transplant failure or death. graphic data is established using KNN- and Random information e.g. about gene expression signatures. Despite advances in treatment graft loss occurs in 5% Forest algorithm. To incorporate the individual patient’s Although those methods provide insights into global of patients annually, so that 50% are back on dialysis timeline into the prediction model a time dependent responses, they lack the ability to provide spatial context. after 10 years. Unfortunately, early detection of patients long short-term memory network will be set up. Further- The other way round, imaging techniques, such as immu- at high risk is lacking. Patient data from the clinical trans- more, data from newly established home monitoring of nohistochemistry, are giving spatial context by detecting plant database »TBase« is retrieved including all patients vital sign will be included for detecting early signals. All cell types and viruses in infected tissue but are limited above 18 years who had undergone only kidney trans- models will be validated using another cohort from by the number of labels per sample. In recent years, plantation at Charité, Campus Mitte, after 2000. Data Charité Virchow Hospital. The prediction model’s risk advanced microscopy imaging techniques significantly consists of demographic data of recipient, transplant assessment will be integrated into individual patient improved our understanding of viral pathogenesis. In and donor, examination reports from microbiology, record to show the risk to doctors. Ultimately he wants parallel, deep learning models in image classification pathology and clinical notes, laboratory values and hos- to show the individual risk to the individual patient. showed ground-breaking success on general images and pitalizations at Charité. All data needs to be refined and have successfully contributed to solve classification
Mentors Mentors
Univ.-Prof. Dr. med. Norbert Suttorp Univ.-Prof. Dr. med. Andreas C. Hocke Dr. Dagmar Kainmüller Univ.-Prof. Dr. med. Klemens Budde Univ.-Prof. Dr. med. Duška Dragun † Prof. Dr.-Ing. Alexander Löser Clinical Mentor Scientific Mentor Digital Mentor Clinical Mentor Scientific Mentor Digital Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Max Delbrück Center for Molecular Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Beuth University Berlin Department of Infectious Diseases Department of Infectiology and Medicine Department of Nephrology and Department of Nephrology and [email protected] and Respiratory Medicine Pneumology Biomedical Image Analysis – Internal Intensive Care Medicine Internal Intensive Care Medicine Theoretical Advances in Machine [email protected] [email protected] [email protected] Learning and Combinatorial Optimization [email protected] 254 Digital Clinician Scientists Digital Clinician Scientists 255
Dr. med. Jawed Nawabi Dr. med. Akira-Sebastian Poncette
In Program From – to Fields of Research In Program From – to Fields of Research 09.2020–08.2023 › Stroke Imaging 09.2020–08.2023 › Patient Monitoring › Computed Tomography › Clinical Alarm Management Contact Contact › Quantitative Imaging › Intensive Care Medicine [email protected] [email protected] › Outcome Prediction › Implementation Science Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Radiology Department of Anesthesiology and Intensive Care Medicine Director Univ.-Prof. Dr. med. Bernd Hamm Director Univ.-Prof. Dr. med. Claudia Spies
Radiomics Based Machine Learning Prediction of Clinical INALO – Intelligent Alarm Optimizer for Intensive Care Units Outcome on Intracerebral Hemorrhage
Intracerebral hemorrhage (ICH) is the most severe form paved the way for a fully automated radiomics analysis Patient safety has improved significantly in recent of stroke and remains a major cause of morbidity and and therefore hold a clear clinical impact. The application decades due to the monitoring of vital signs in intensive mortality worldwide. Early detection of high-risk patients of ML algorithms for the prediction of clinical outcome care units (ITS). However, between 72 and 99% of these remains a key goal in directing the management and after ICH are still lacking and have not included PHE alarms are described as false positives or »non-action- treatment course. Cerebral injury secondary to ICH is a features. The applicant’s previous results demonstrate able«. They can trigger »alarm fatigue«, a desensitization known factor to potentiate the risk of a poor outcome. that radiomic features provide a high discriminatory of staff to critical alarms that can even lead to patient Rapid advances in our understanding of the underlying power in predicting neoplastic ICH on CT, with signifi- harm and even death. The goal of this project is to mechanisms have fueled an interest in identifying novel cantly higher power than human prediction. Quantitative develop a user-centered platform that will enable therapies targeting secondary injury. However, standard- features of PHE in ICH may distill multiple-but-subtle research and implementation of alarm optimization ized biomarkers for imaging quantification could so far variations such as in thrombin accumulation, influx of approaches for patient monitoring in the ICU by means not be established. Emerging data suggest perihemato- inflammatory mediators, and erythrocyte lysis with sig- of patient-specific data and machine learning approaches. mal edema (PHE) as a promising biomarker as the tem- nificant prognostic value. Following this idea, the clinical In doing so, the perspective is to achieve a reduction of poral course of PHE correlates with the manifestation research project aims at understanding the high-end unnecessary alarms. Digital documentation generates of secondary injury but results remain inconsistent. quantitative imaging characteristics of perihematomal several gigabytes of health data every day. This data can Edema formation comprises multiple coordinated and edema (PHE) which may serve as a predictor of poor already be used as a basis for artificial intelligence (AI) complex mechanisms that are known to be disease-spe- prognosis and examine the efficacy in predicting patient algorithms that support patient care in the ITS. The devel- cific. In line with this, the applicant’s previously published outcomes after ICH. opment of an alarm optimizer could promote a better work highlights the promising prognostic value of early understanding of the alarm situation, as well as reduce edema formation in different forms of ICH. The assump- the workload of ICU staff and improve patient care by tion therefore seems reasonable that perihematomal reducing unnecessary alarms. edema holds additional imaging characteristics that are not visible to the human eye, yet of great prognostic value. Progressive machine learning (ML) algorithms have
Mentors Mentors
Univ.-Prof. Dr. med. Bernd Hamm PD Dr. med. Tobias Penzkofer Dr. med. Helge Kniep Univ.-Prof. Dr. med. Claudia Spies Univ.-Prof. Dr. Roland Eils Prof. Dr. med. Dr. rer. nat. Clinical Mentor Scientific Mentor Digital Mentor Clinical Mentor Scientific Mentor Felix Balzer Digital Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin University Medical Center Charité – Universitätsmedizin Berlin BIH – Digital Health Center Department of Radiology Berlin Department of Radiology) Hamburg-Eppendorf Department of Anesthesiology and Charité – Universitätsmedizin Berlin [email protected] Operative Department of Anesthesiology and [email protected] [email protected] [email protected] Intensive Care Medicine Operative Intensive Care Medicine [email protected] [email protected] 256 Digital Clinician Scientists Digital Clinician Scientists 257
Dr. med. Rolf Otto Reiter Dr. med. Julian Rogasch
In Program From – to Fields of Research In Program From – to Fields of Research 01.2021–12.2023 › Quantitative MRI 08.2020–07.2023 › Quantitative image parameters › MR Elastography › Non-small cell lung cancer Contact Contact › Deep Learning › Machine learning [email protected] [email protected] › Inflammation › Image biomarkers Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Radiology (including Department of Nuclear Medicine Pediatric Radiology) Director Director Prof. Dr. med. Winfried Brenner Univ.-Prof. Dr. med. Bernd Hamm and Univ.-Prof. Dr. med. Ulrich Bick
Quantitative Spatially-Resolved MRI Of Fibrosis and Machine Learning and Quantitative FDG PET-CT Inflammation in Chronic Liver and Bowel Disease Image Parameters for Diagnostics and Prognosis in Patients with Lung Cancer
Purpose: The aim is to determine fibrosis and inflamma- tative image data is performed using a 3D Multi-Channel This project investigates the additional value of machine a decision support system that is ready for clinical use tion in chronic liver and intestinal diseases using quan- Convolutional Neural Network. In this process, the dif- learning (ML) and quantitative image parameters from and that allows individualized assessment of the reli- titative MRI (qMRI) and artificial intelligence. Background: ferent biomarkers can be tested separately and in all FDG-PET/CT in patients with non-small cell lung cancer ability of FDG-PET/CT. This would help physicians to spare Determination of disease activity of fibrosis (scar tissue) possible combinations. Clinical benefit: The number of (NSCLC). In the current clinical application of FDG-PET/ more patients additional (confirmatory) invasive staging. and inflammation is often crucial for therapy, but so far invasive procedures, such as biopsies, endoscopies, and CT, it is usually assessed as an isolated diagnostic tool, The second application that is investigated is the use of can only be determined with invasive procedures, such surgeries, could be reduced. In addition, specific bio- and reporting is mostly confined to visual reading. Con- ML and quantitative image parameters to predict the as biopsies or endoscopies. This is particularly true for markers could be established for stratification of clinical sequently, the reliability and reproducibility of FDG-PET/ patient’s survival after curatively intended treatment. cholestatic liver disease (e.g., primary sclerosing chol- trials and development of new therapies. CT reports is variable, which currently entails frequent Presently, the treatment decision is mainly determined angitis), fatty liver disease, and inflammatory bowel confirmatory invasive diagnostic procedures. Therefore, by the clinical tumor stage although this is not sufficiently disease (Crohn's disease and ulcerative colitis). These substantial advances in the clinical impact of FDG-PET/ differentiated to allow individualized prediction of the diseases share a common diagnostic gap: determining CT in improving patient-relevant outcomes may require patient’s prognosis and the optimal treatment. The cur- the spatial distribution -or heterogeneity- of fibrosis new paradigms. In this project, ML is used both to derive rent project investigates the additional value of textural and inflammation. Methods: Spatially resolved qMRI can the image biomarkers and to integrate image data with features from FDG-PET and CT data to predict the pro- measure this heterogeneity using the following clinical information, pathology reports and lab results gression-free survival and overall survival in patients sequences: Tomoelastography (shear-wave speed in m/s), (so-called integrated diagnostics). Different ML methods with stage I-III NSCLC. These textural features include T1 and T2 mapping (relaxation times in ms), diffusion are investigated, including decision trees as well as deep conventional, mathematically defined features (»radio- imaging (ADC in mm2/s), fat quantification (in %). Image learning (artificial neural networks). The first application mics«) as well as classificators derived with deep acquisition and image processing of multiple quantitative of this methodology is in pretherapeutic thoracic lymph learning. biomarkers simultaneously creates a system-indepen- node staging in patients with NSCLC. Retrospective and dent database and provides the basis to train neural prospective clinical data are used to develop and validate networks. This enables identification of the best param- ML models that provide a differentiated and individual- eters for classification of fibrosis and inflammation in ized estimate of the positive and negative predictive liver and intestine. Automated diagnosis of the quanti- value of FDG-PET/CT. The goal is to equip clinicians with
Mentors Mentors
Prof. Dr. med. Patrick Asbach Univ.-Prof. Dr. rer. nat. Ingolf Sack PD Dr. rer. nat. Jürgen Braun PD Dr. med. Christian Furth Dr. med. Nikolaj Frost PD Dr. med. Tobias Penzkofer Clinical Mentor Scientific Mentor Digital Mentor Clinical Mentor Scientific Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Radiology Department of Radiology Institute of Medical Informatics Department of Nuclear Medicine Department of Infectious Diseases Department of Radiology and Respiratory Medicine [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] 258 Digital Clinician Scientists Digital Clinician Scientists 259
Dr. med. Lara Mirja Steinbrenner Dr. med. Alexander Thieme
In Program From – to Fields of Research In Program From – to 01.2021–12.2023 › epilepsy 07.2019–09.2023 › MRI Contact Contact › EEG [email protected] [email protected] › Epilepsy surgery Clinic Clinic Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology Department of Radiation Oncology and and Experimental Neurology Radiotherapy Director Director Univ.-Prof. Dr. med. Matthias Endres Prof. Dr. med. Dr. h.c. Volker Budach
Using Computational MRI to Automatically Detect Epileptogenic Electronic Patient-Reported Outcomes for Relapse Lesions in Patients Eligible for Epilepsy Surgery Detection in Cancer Patients and Mitigation of the Novel Coronavirus Pandemic
Epilepsy affects about 70 million people worldwide; it is the clinical and neurophysiological focus hypothesis Electronic Patient-Reported Outcomes (ePROs) promote is built based on ePROs to detect patterns with the goal one of the most common neurological disorders in chil- consensus from the multidisciplinary meetings (MDM), patient-centered care by collecting and incorporating of earlier relapse detection with a lower recurrent stage. dren and adults. Up to one third of patients are drug-re- will be collected for each patient. Additionally, we are patient-reported information into clinical settings. At Machine learning methods are used for model creation sistant, with poorly controlled seizures despite adequate comparing this new approach to previously published the heart of this digital health project, an open-source in collaboration with Stanford University. For use case medication. Epilepsy surgery is the most successful methods by applying them to the same data set.The pri- ePRO application (app) was developed with the flexibility 2, the app has been published under the name CovApp treatment option to achieve seizure freedom for patients mary outcome measure is the outlier lesion concordance to be adapted to various clinical situations and a focus and could demonstrate the ability of fast deployment with focal drug-resistant epilepsy, which on average is with the epileptogenic focus defined by MDM consensus. on ease-of-use for the patient. Two different use cases during the onset of the novel coronavirus pandemic and achieved in 65% of patients. The absence of an epilep- Concordance is defined by localisation in the same gyrus are evaluated for this app: 1.) relapse detection for cancer scalability to a larger number of users. CovApp provided togenic lesion on MRI has been shown to decrease the or lobe (depending on specificity of presurgical lesion-hy- patients, 2.) risk evaluation of users potentially infected individualized recommendations based on ePROs regard- probability of seizure freedom by more than 20%. The pothesis). The secondary outcome measure is the overlap with the novel coronavirus (SARS-CoV-2). Regarding use ing laboratory testing, probability of severe covid-19, and detection of an epileptogenic lesion on MRI in so far between the outlier lesion and surgical resection site.In case 1, standard of care for relapse detection in cancer guidance for several million users in Germany and inter- assumed non-lesional pre-surgical candidates remains the long run, we hope, by applying the outlier lesion patients usually involves follow-up visits in fixed inter- nationally. At the hospital, increased efficiency could be an important challenge to improve surgical targeting detection method successfully, to enable more surgeries vals. This leads to unnecessary prolongation of relapse achieved by reducing the time necessary for anamnesis and secondarily postsurgical outcome.In this retrospec- in non-lesional cases and potentially cut down the use detection which can have a deleterious effect on the by providing the function to scan ePROs directly from tive study, we assess a new approach to detect individ- of invasive diagnostics such as intracranial EEG. oncological outcome. ePROs facilitate that patients enter the patient’s smartphone via QR code. Hereby, it con- ualised lesions in patients with epilepsy in a large cohort, symptoms directly into a database that can be evaluated tributed to identify and interrupt infection chains, opti- two-centre study by applying an outlier lesion detection in real-time. Especially, patients with locally advanced mize health care resources and provide crucial informa- machine-learning algorithm. Pre- and if available post- head and neck squamous cell carcinoma (HNSCC) may tion to the general population, especially to high-risk operative MRI scans (T1-weighted (T1 MPR) and profit from earlier relapse detection which is seen in patients. Further development aims to evaluate the T2-weighted FLAIR) of all consecutive patients having 15-50% of the cases. HNSCCs are known to proliferate project's big data for local outbreak detection and case received a recommendation to undergo epilepsy surgery, rapidly and deferred treatment can result in stage pro- number prediction. between 2015 and 2020 at the Epilepsy centers in Berlin gression. Recurrent stage is known to be the most and Bochum, will be analysed. Clinical variables, including important parameter regarding overall survival. A model
Mentors Mentors
Prof. Dr. med. Martin Holtkamp Prof. Dr. med. Jochen Fiebach Univ.-Prof. Dr. rer. nat. PD Dr. med. Dr. med. univ. Dr. med. Sein Schmidt Prof. Dr. Christoph Lippert Clinical Mentor Kerstin Ritter Carmen Stromberger Scientific Mentor Digital Mentor Scientific Mentor Digital Mentor Clinical Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Hasso Plattner Institute Charité – Universitätsmedizin Berlin Department of Neurology and Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology Digital Health - Machine Learning Experimental Neurology Center for Stroke Research Berlin Department of Psychiatry and Department of Radiation Oncology and Experimental Neurology [email protected] Psychotherapy and Radiotherapy [email protected] [email protected] [email protected] [email protected] [email protected] 260 Clincian Scientist »Excellence Track« Alumni Clincian Scientist »Excellence Track« 261
Dr. med. Victor Corman
In Program From – to Fields of Research 09.2020–08.2023 › Acute respiratory infection › Common cold Contact › Picornavirus [email protected] › Coronavirus Clinic Excellent Junior Research Charité – Universitätsmedizin Berlin Group Program Institute for Medical Virology › BMBF Research Group Director Clincian Univ.-Prof. Dr. med. Christian Drosten Scientist »Excellence Virus Evolution and Immune Repertoire Sequencing Track« as a New Approach to Predict the Outcome of ARI
Viral acute respiratory infections (VARI) are the most prevalent infectious diseases in humans. Their onset is non-specific and the immediate clinical courses are highly variable, ranging from recovery to fulminant pneu- monia within a few days. Outcomes are likely determined by the composition and development of the infecting virus population as well as the patientspecific immune response. The focus of this research group will be to analyze the extent to which novel laboratory tools (virus population analysis, B- and Tcell receptor repertoire sequencing, cytokine profiling) can predict the outcome of individuals with VARI, based on patient samples from the first days after disease onset. The group will have access to unique patient cohorts, drawn from the largest clinical virology service in academic medicine in Germany.
Mentors 262 Clincian Scientist »Excellence Track« Clincian Scientist »Excellence Track« 263
Dr. rer nat. Stefan Florian Univ.-Prof. Dr. med. Dr. rer. nat. Ahmed N. Hegazy
In Program From – to Fields of Research In Program From – to Fields of Research 01.2021–12.2023 › Breast cancer – Systems Biology – 07.2018–06.2021 › Mucosal Immunology, Inflammatory RNAseq – Multiplexed bowel diseases, T cell immunology, Contact Contact immunofluorescence Microbiota responses [email protected] [email protected] Excellent Junior Research Excellent Junior Research Clinic Clinic Group Program Group Program Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin › BMBF Research Group › Lichtenberg Professorship of the Institute of Pathology Medizinische Klinik für Volkswagen Foundation Gastroenterologie, Infektiologie and Director Rheumatologie Univ.-Prof. Dr. med. David Horst Director Univ.-Prof. Dr. med. Britta Siegmund
Discovery of Biomarkers Through Multilevel Measurement of Tumor Microbial and Environmental Factors That Control Gut-Resident Heterogeneity in Triple Negative Breast Cancer (TNBC) Memory T Cells in Human Health and Disease
Disentangling the diverse composition of tumors is clones emerge. This integrated dataset will be analyzed The human intestine harbours a vast and diverse bac- approach that combines high throughput culture meth- essential to understanding how they emerge, develop in collaboration with the groups of Adrián Granada (CCCC, terial community that exerts several beneficial effects ods, ex vivo analysis of memory T cells, and in vitro and react to therapy, and thus of utmost importance for Charité-Universitätsmedizin Berlin) and Dr. Katarzyna on the host. For example, the commensal microbiota priming of naïve T cells. Furthermore, gut-resident T cells the development of effective therapies. However, in TNBC, Bozek (CMMC Köln) through iterative combination of his- harvests energy from otherwise indigestible carbohy- will be profiled at the whole population and single cell so far, studies in this direction have been limited to either topathological diagnostic algorithms, machine learning drates, synthesises vitamins, and contributes to the levels using transcriptomics, epigenomics, and metab- a low number of gene loci or a low number of patients. based computer vision, sequence analysis, and dynamic maintenance of the epithelial barrier. Furthermore, it is olomics to decipher their molecular signature. The sig- Moreover, genetic tumor heterogeneity represents only models of cell behavior over time in response to therapy. now clear that the commensal microbiota has a profound nificance and relevance of the identified pathways will a subset of the variability that can be observed within Specifically, we will try to find correlations between the effect on immune responses. Maladaptation of this be tested in mouse models of colitis, human tissue a tumor. Cells with the same genetic information vary in changes in tumor cell composition, expression of groups host-microbe dialogue can promote inflammatory explants, and novel 3D models using primary human their epigenetic profiles, transcriptome, proteome and of markers and prognosis as well as therapy outcome. responses and is implicated in various pathologies tissue. The overall goal is to utilise the acquired knowl- morphology and can adopt different states of differen- We hope to develop new precision medicine based bio- including inflammatory bowel disease (IBD). However, edge to identify targetable cytokine signals and patho- tiation, cell cycle, or circadian rhythm. The goal of this markers based on cellular state defined as a complex the microbial signals and molecular pathways that pro- genic molecular pathways in microbiota-specific CD4+ T project is to generate high-throughput imaging and set of cell properties reaching beyond genomic mutation mote tissue-specific differentiation of gut-resident cell populations for therapeutic development in IBD. -omics data that characterize tumors from TNBC patients profiles and including multiple properties of the pro- immune cells are poorly characterized. Deciphering the before and after therapy at several levels and to provide teome, transcriptome and cell morphology. complex host-microbiota relationship is therefore of a comprehensive, multidimensional representation of great biomedical value.Using cutting-edge technologies, tumor response to therapy over time. We will use mul- a multidisciplinary approach, well-defined patient tiplexed immunofluorescence protocols, combined with cohorts, and mouse models of colitis, I will clarify the DNA and RNA sequencing of selected cell populations interactions between microbial, environmental, and isolated from tissue sections to characterize patient inflammatory factors that promote intestinal inflamma- collectives with TNBC before and after they receive ther- tion. I will assess mucosal and peripheral CD4+ T cell apy in order to better understand which factors best specificity towards intestinal microbiota under steady predict therapeutic outcome and how therapy resistant state and inflammatory conditions using an experimental
Mentors Mentors
Univ.-Prof. Dr. rer. nat. Andreas Radbruch Clinical Mentor Department of Gastroenterology, Infectious Diseases and Rheumatology [email protected] 264 Clincian Scientist »Excellence Track« Clincian Scientist »Excellence Track« 265
Prof. Dr. med. Anton G. Henssen Dr. med. Andreas Horn, MD, PhD
In Program From – to Fields of Research In Program From – to Fields of Research 01.2017–12.2018 › Pediatric Cancer Genomics 09.2020–08.2023 › Deep Brain Stimulation › Personalized Cancer Therapies › Movement Disorders Contact Contact › Pediatric Solid Tumor Biology › Brain Connectivity [email protected] [email protected] Excellent Junior Research Excellent Junior Research Clinic Clinic Group Program Group Program Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin › ERC Starting Grant › DFG Emmy Noether Program Department of Pediatrics, Department of Neurology › DFG Emmy Noether Program Division of Oncology and Hematology and Experimental Neurology Director Director Univ.-Prof. Dr. med. Britta Siegmund Univ.-Prof. Dr. med. Matthias Endres
Understanding the Origin of Complex Structural Variants Toward a Virtual Patient in Deep Brain Stimulation in Pediatric Cancer Genomes
Significant tumor regression can be achieved in many ing DNA recombinases to sequence-specific oncogenic Deep Brain Stimulation – a highly efficacious treatment electrodes in 95 Parkinson patients from two DBS centers cancers by induction chemotherapy. The period of remis- mutations (as published in Nature Genetics and Science option for movement disorders such as Parkinson‘s Dis- (Berlin & Würzburg) were highly predictive of clinical sion varies, and is too often followed by regrowth of Translational Medicine in 2017), which has direct impli- ease – is currently undergoing a paradigm-shift from motor improvement across patients. Moreover, the study aggressive, therapy-resistant lesions. Treatment resis- cations for the understanding of genomic structural stimulating local target regions toward network stimu- defined effective treatment networks for Parkinson‘s tance is believed to be partly driven by the pre-existence variation in pediatric tumors. We aim to determine the lation, i.e. neuronal modulation of distributed brain Disease that may one day be used to guide programming of resistant phenotypes within the clonal population of molecular mechanisms of recombinase-induced genomic networks. Specifically, it was long thought that the pro- and targeting of deep brain stimulation after further the cancer in a single patient. Neuroblastoma is a pro- plasticity and adaptation to targeted therapies using cedure exerts its therapeutic potential by local modu- validation. The technique was introduced for Parkinson‘s totypical example of this phenomenon. Neuroblastomas functional investigation of human tumors and engineered lation of the target region itself. However, accumulating Disease but could even be of stronger use in the case of are the most common tumor in childhood. The majority animal models, with the long-term goal of developing evidence suggests that effects on distributed brain net- Dystonia, where changes in stimulation parameters often of high-risk neuroblastomas are sensitive to induction rational combination therapy for patients with high-risk, works and basal-ganglia-cortical loops are at least lead to a delayed symptom alleviation and guidance from therapy, but quickly recur as chemotherapy-resistant refractory or relapsed pediatric solid tumors. The devel- equally important. Our group published several articles computer models could be even more helpful in clinical disease that is almost uniformly lethal. Neuroblastoma opment and use of functional genomics tools will feature of general network interactions between DBS electrodes practice. Adopting the technique for treatment in Dys- is characterized by a surprising paucity of gene mutations. strongly in our group, and work in our lab will focus on and remote sites using electrophysiology and brain imag- tonia is the current focus of our work. However, recurrent chromosomal and complex genomic investigating the dysregulated organization of cancer ing. However, recently, in cooperation with Harvard Med- rearrangements, including chromothrypsis and double cell genomes with the goal of identifying effective targets ical School, we were able to demonstrate that clinical minutes, are common in high-risk neuroblastomas. It and therapeutic agents for rationally designed combi- DBS improvement may be predicted using MRI-based remains largely unknown what drives neuroblastoma nation therapies. brain connectivity estimates between the site of stim- intratumoral heterogeneity, chemotherapy resistance ulation and distributed cortical areas. In this study, the and disease relapse.We have made new discoveries link- structural and functional connectivity profiles of DBS
Mentors Mentors
Univ.-Prof. Dr. med. Andrea Kühn Clinical Mentor Charité – Universitätsmedizin Berlin Department of Neurology and Experimental Neurology [email protected] 266 Clincian Scientist »Excellence Track« Clincian Scientist »Excellence Track« Alumni 267
Dr. med. univ. Nikolaus Wenger, MSc, PhD
In Program From – to Fields of Research 10.2018-09.2022 › Motor Recovery › Neuroprosthetics Contact › Stroke Research [email protected] Excellent Junior Research Clinic Group Program Charité – Universitätsmedizin Berlin › Freigeist Fellowship der Department of Neurology Volkswagen Foundation and Experimental Neurology Director Clincian Univ.-Prof. Dr. med. Matthias Endres Scientist »Excellence Inducible Neuroplasticity after Stroke Using Neurotransmitter Replacement Strategies Track« Alumni
Translating the behavioral output of the nervous system into movement involves interaction between the brain and the spinal cord. The brainstem provides an essential bridge between these two structures. However, the func- tion of this intermediary system in motor recovery after stroke remains poorly understood. In fact, the brainstem is a major source of monoaminergic neurotransmitters that coordinate movement at the level of the spinal cord (Wenger et al. 2016) and mediate plasticity in the central nervous system (Ng et.al 2015). My hypothesis is that motor cortex stroke alters the activity of monoaminergic brainstem nuclei limiting functional recovery after stroke. Using neural tracing experiments and behavioral analysis, I aim to investigate the therapeutic effect of monoami- nergic neurotransmitter replacement strategies to engage plasticity of neural networks related to motor production. The translational aim of this project is to investigate neuroanatomical rewiring processes that benefit the restoration of function after stroke.
Mentors
Univ.-Prof. Dr. med. Matthias Endres Univ.-Prof. Dr. med. Ulrich Dirnagl Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Department of Neurology Department of Neurology and and Experimental Neurology Experimental Neurology and BIH QUEST Center [email protected] [email protected] 268 Clincian Scientist »Excellence Track« Alumni Clincian Scientist »Excellence Track« Alumni 269
PD Dr. med. Michael Sigal Dr. med. Nicola Wilck
In Program From – to Fields of Research In Program From – to Fields of Research 10.2016–11.2019 › Gastrointestinal Stem Cells 01.2018–12.2020 › Inflammation in Cardiovascular › Epithelial Biology Disease Contact Contact › Gastrointestinal Microbiota › Intestinal Microbiome [email protected] [email protected] › Gastrointestinal Carcinogenesis › Host-Microbiome Interaction Clinic Clinic Excellent Junior Research Excellent Junior Research Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Group Program Group Program Medical Department, Division of Medical Department, Division of Nephrology › DFG Emmy Noether Program › ERC Starting Grant Hepatology and Gastroenterology and Internal Intensive Care Medicine Director Director Univ.-Prof. Dr. med. Bertram Univ.-Prof. Dr. med. Kai-Uwe Eckardt Wiedenmann
Mechanisms of Gastric Stem Cell Control Upon Putative Role for Bacterial Metabolites in Protection Infection and Carcinogenesis from Hypertensive Organ Damage
The gastric epithelium is characterized by rapid self-re- activity. Lineage tracing experiments revealed that infec- Hypertension and subsequent damage to the heart and tective potential in hypertensive double-transgenic rats. newal. Long-lived Lgr5-expressing stem cells that are tion induced a significant increase of the turnover kinet- kidneys contribute to cardiovascular morbidity. Besides Tryptophan metabolite analysis will be performed in localized in the base of the stomach antral glands con- ics of stem cells, resulting in the repopulation of entire hemodynamic stress, an important role for the immune hypertensive patients, potentially enabling future stantly regenerate the epithelium. Lineage tracing exper- glands within five instead of ten to 14 days, finally result- system has been uncovered, linking pro-inflammatory T translation. iments have shown that stomach glands are regenerated ing in severe glandular hyperplasia (Sigal et al., 2015). An effector cells to the development of hypertension. In by Lgr5+ stem cells for a year or more, demonstrating unresolved question is how stem cell number, their divi- particular, interleukin-17A producing TH17 cells promote the longevity of these cells (Barker et al., 2010). In addi- sion rate, and fate determination are controlled under hypertension and organ damage. Although the delete- tion to their physiological relevance, these long-lived physiological conditions as well as upon infection. I plan rious role of inflammation in hypertension has been cells also appear to be critical in the process of carcino- to characterize the gastric stem cell microenvironment, recognized, current treatments insufficiently address genesis (Barker et al., 2009). Accordingly, Lgr5+ cells have the so-called stem cell niche, under physiological con- these mechanisms. This project aims to elucidate the been reported to expand and show increased evidence ditions as well as upon infection to understand how role of tryptophan metabolites of bacterial origin in of DNA damage in patients with gastric cancer (Uehara stem cell number, proliferative activity, and fate deter- hypertensive renal and cardiac damage. It is based on et al., 2013). Chronic infection with the gastric pathogen mination are controlled. I will focus on Wnt signaling, the recognition that gut bacteria affect host organs and H. pylori is the major known risk factor for the develop- study its cellular organization and unravel how alter- the immune system by virtue of their metabolites. Tryp- ment of gastric cancer (Blaser et al., 1995; Parsonnet et ations of Wnt signaling affect stem cell and tissue homeo- tophan is metabolized by intestinal bacteria to indoles. al., 1997). Hypothesizing that H. pylori affects gastric stasis. Further, using an unbiased approach I will inves- We have shown that a probiotic Lactobacillus treatment stem cells, we have previously used mice that express tigate how the myofibroblasts that surround the stem reduces blood pressure and provides beneficial immu- GFP under the Lgr5 promoter to show that although they cells affect stem cell behavior. nomodulation in experimental hypertension, putatively are located at the very base of the gland, H. pylori is via production of indoles. This project aims to expand able to directly colonize and grow on the intercellular on these observations by using cell culture systems, a junctions of stem cells (Sigal et al., 2015). Infection rat model as well as patient material. Candidate indoles induces a two-fold increase in the number of stem cells selected in vitro as well as probiotic treatments will per gland unit and a significantly higher proliferative be tested for their immunomodulatory and organ-pro-
Mentors Mentors
Univ.-Prof. Dr. med. Kai-Uwe Eckardt Prof. Dr. rer. nat. Dominik N. Müller Clinical Mentor Scientific Mentor Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin Medical Department, Division of and Max Delbrück Center for Nephrology and Internal Intensive Molecular Medicine Berlin Care Medicine Experimental and Clinical Research Center [email protected] [email protected] 270 Further Alumni of the Clinician Scientist Program Index 271
Further Alumni of the Index Clinician Scientist Program
Alumnus Dr. med. Omar Dzaye, PhD CC05 – Institute of Pathology (CCM) CC07 – Department of Anesthesiology and Alumni Junior Clinician Scientist Operative Intensive Care Medicine (CVK) 219 Sinn, Bruno (CSP) CCM Alumnus Dr. med. Leif-Christopher Engel 227 von Laffert, Maximilian (CSP) CCM 167 Graw, Jan Adriaan (CSP) CVK Alumni Clinician Scientist 26 Grunow, Julius (JCSP) CVK CC06 – Department of Nuclear Medicine (CVK) 247 Heinrich (geb. Olbert), Maria (DCSP) CVK Alumnus Dr. med. Martin Jonczyk 230 Wollersheim, Tobias (CSP) CVK Alumni Junior Clinician Scientist 255 Rogasch, Julian (DCSP) CVK Alumnus PD Dr. med. Alexander Kowski CC06 – Department of Radiology (CBF) CC08 – Department of Surgery (CBF) Alumni Clinician Scientist 243 Bressem, Keno (DCSP) CBF 65 Hartmann, Lisa (JCSP) CBF Alumnus Dr. med. Matteus Krappitz 254 Reiter, Rolf Otto (DCSP) CBF 45 Strobel, Rahel Maria (JCSP) CBF Alumni Junior Clinician Scientist CC06 – Department of Radiology (CCM) CC08 – Department of Surgery (CCM) Alumna Dr. med. Anne Lesemann 150 Atanasov, Georgi (CSP) CCM Alumni Junior Clinician Scientist 90 Adams, Lisa Christine (CSP) CCM 110 Jahnke, Paul (CSP) CCM CC08 – Department of Surgery (CVK) Alumnus PD Dr. med. Vincent Prinz 38 Pohlan, Julian (JCSP) CCM Alumni Clinician Scientist 99 Dziodzio, Tomasz (CSP) CVK CC06 – Department of Radiology (CVK) Alumna Dr. med. Julia Sbierski-Kind 102 Feist, Mathilde (CSP) CVK Alumni Junior Clinician Scientist 92 Auer, Timo Alexander (CSP) CVK 163 Feldbrügge, Linda (CSP) CVK 158 Collettini, Federico (CSP) CVK 58 Felsenstein, Matthaeus (JCSP) CVK Alumna PD Dr. med. Anja Schirbel 59 Fleckenstein, Florian Nima (JCSP) CVK 246 Globke, Brigitta (DCSP) CVK Alumni Clinician Scientist 68 Kahn, Johannes Frederik (JCSP) CVK 66 Hillebrandt, Karl Herbert (JCSP) CVK Alumnus Prof. Dr. med. Malte Spielmann 200 Penzkofer, Tobias (CSP) CVK 179 Kern, Barbara (CSP) CVK Alumni Clinician Scientist 40 Savic, Lynn Jeanette (JCSP) CVK 184 Krenzien, Felix (CSP) CVK 215 Schreiter (geb. Fröling), Vera (CSP) CVK 36 Moosburner, Simon (JCSP) CVK 205 Raschzok, Nathanael (CSP) CVK CC06 – Institute of Neuroradiology (CCM) 133 Ritschl, Paul (CSP) CVK 213 Schmuck, Rosa Bianca (CSP) CVK 208 Scheel, Michael (CSP) CCM 138 Schulte, Wibke (CSP) CVK CC06 – Institute of Neuroradiology (CVK) 222 Strücker, Benjamin (CSP) CVK
86 Theilig, Dorothea (JCSP) CVK CC08 – Department of Urology (CCM)
CC07 – Department of Anesthesiology and 77 Ralla, Bernhard (JCSP) CCM Operative Intensive Care Medicine (CCM) CC09 – CMSC – Center for Musculoskeletal Surgery (CCM) 188 Lachmann, Gunnar (CSP) CCM 178 Keller, Johannes (CSP) CVK 190 Liotta, Agustin (CSP) CCM 28 Kienzle, Arne (JCSP) CCM 191 Lütz, Alawi (CSP) CCM 73 Palmowski, Yannick (JCSP) CCM 253 Poncette, Akira-Sebastian (DCSP) CCM 62 Graef, Frank (JCSP) CKV 226 von Dincklage, Falk (CSP) CCM 117 Maleitzke, Tazio (CSP) CVK
CC09 – Department of Oral and Maxillofacial Surgery (CVK) 206 Rendenbach, Carsten (CSP) CVK 143 Voß, Jan (CSP) CVK 272 Index Index 273
CC11 – Department of Cardiology (CBF) CC12 – Medical Department, Division of Infectiology CC13 – Medical Department, Division of Nephrology CC14 – Department of Radiation Oncology and Pneumonology (CVK) and Internal Intensive Care Medicine (CVK) and Radiotherapy (CVK) 18 Beyhoff, Niklas (JCSP) CBF 152 Bobbert, Peter (CSP) CBF 187 Kurth, Florian (CSP) CVK 162 Enghard, Philipp (CSP) CVK 257 Thieme, Alexander (DCSP) CVK 57 Dirks, Fabian (JCSP) CBF 67 Holstein, Judith (JCSP) CVK 232 Zschaeck, Sebastian (CSP) CVK 103 Friebel, Julian (CSP) CBF CC13 – Department of Endocrinology and Metabolic 207 Schachtner, Thomas (CSP) CVK 24 Gerhardt, Teresa (JCSP) CBF Disease (CCM) 267 Wilck, Nicola (X-CSP) CVK CC15 – Center for Stroke Research Berlin (CCM) 61 Girke, Georg (JCSP) CBF 176 Jumpertz-von Schwartzenberg, Reiner (CSP) CCM 33 Kufner, Anna (JCSP) CCM CC14 – Department of Hematology, Oncology 175 Jakob, Philipp (CSP) CBF 180 Kienitz, Tina (CSP) CCM and Cancer Immunology (CBF) 231 Wurster, Thomas Heinrich (CSP) CBF 193 Maurer, Lukas (CSP) CCM CC15 – Department of Neurology with 151 Bastian, Lorenz (CSP) CBF Experimental Neurology (CBF) CC11 – Department of Cardiology (CCM) CC13 – Medical Department, Division of Gastro- 17 Baumgartner, Francis (JCSP) CBF 96 Brämswig, Tim Bastian (CSP) CBF enterology, Infectiology and Rheumatology (CBF) 149 Althoff, Till (CSP) CCM 56 Demel, Uta Margareta (JCSP) CBF 69 Khalil, Ahmed (JCSP) CBF 170 Hewing, Bernd (CSP) CCM 107 Haag, Lea-Maxie (CSP) CBF 108 Habringer, Stefan (CSP) CBF 209 Scheitz, Jan Friedrich (CSP) CBF 203 Poller, Wolfram (CSP) CCM 261 Hegazy, Ahmed Nabil (X-CSP) CBF 181 Klinghammer, Konrad (CSP) CBF 256 Steinbrenner, Lara Mirja (DCSP) CBF 129 Prüß, Magdalena Sarah (CSP) CBF 197 Ochsenreither, Sebastian (CSP) CBF 44 Stengl, Helena (JCSP) CBF CC11 – Department of Cardiology (CVK) 131 Rademacher, Judith (CSP) CBF 132 Rieke, Damian Tobias (CSP) CBF 91 Alogna, Alessio (CSP) CVK 82 Schulz, Emanuel (JCSP) CBF 134 Rittig, Susanne (CSP) CBF CC15 – Department of Neurology with 173 Hohendanner, Felix (CSP) CVK 217 Schumann, Michael (CSP) CBF 136 Schmalbrock, Laura Katharina (CSP) CBF Experimental Neurology (CCM) 122 Oeing, Christian (CSP) CVK 84 Staudacher, Jonas J. (JCSP) CBF CC14 – Department of Hematology, Oncology 234 Behr, Nikolaus (JDCSP) CCM 128 Primessnig, Uwe (CSP) CVK 225 Treese, Christoph (CSP) CBF and Cancer Immunology (CCM) 153 Böhmerle, Wolfgang (CSP) CCM 146 Zhang, Kun (CSP) CVK 228 Weidinger, Carl (CSP) CBF 52 Borngräber, Friederike (JCSP) CCM 109 Hilfenhaus, Georg (CSP) CCM 21 de Almeida Marcelino, Ana Luísa (JCSP) CCM CC11 – Institute for Computer-assisted CC13 – Medical Department, Division of Hepatology 37 Neumann, Christopher (JCSP) CCM 245 Emmrich, Julius (DCSP) CCM Cardiovascular Medicine (CVK) and Gastroenterology (CCM) 142 Vecchione, Loredana (CSP) CCM 101 Euskirchen, Philipp (CSP) CCM 249 Kelm, Marcus (DCSP) CVK 20 Blüthner, Elisabeth (JCSP) CCM 22 Feldmann, Lucia Katharina (JCSP) CCM CC14 – Department of Hematology, Oncology 239 Schafstedde, Marie (JDCSP) CVK 113 Kidess-Sigal, Evelyn (CSP) CCM 60 Gerischer, Lea (JCSP) CCM and Cancer Immunology (CVK) 172 Hoffmann, Christian Johannes (CSP) CCM CC12 – Department of Dermatology, CC13 – Medical Department, Division of Hepatology 15 Arends, Christopher Maximilian (JCSP) CVK 263 Horn, Andreas (X-CSP) CCM Venerology and Allergology (CCM) and Gastroenterology (CVK) 50 Arnhold, Viktor (JCSP) CVK 174 Hühnchen, Petra (CSP) CCM 118 Muñoz Roldán, Melba Lucia (CSP) CCM 100 Engelmann, Cornelius (CSP) CVK 51 Bittner (geb. Essig), Aitomi (JCSP) CVK 249 Knauss, Samuel (DCSP) CCM 224 Terhorst-Molawi, Dorothea (CSP) CCM 235 Eschrich, Johannes (JDCSP) CVK 160 Damm, Frederik (CSP) CVK 29 Koschützke, Leif Torben (JCSP) CCM 164 Fischer, Andreas (CSP) CVK 244 Denker, Sophy (DCSP) CVK 32 Kuchling, Joseph (JCSP) CCM CC12 – Department of Rheumatology 124 Peiseler, Moritz (CSP) CVK 165 Frick, Mareike (CSP) CVK 189 Liman, Thomas (CSP) CCM and Clinical Immunology (CCM) 130 Püngel, Tobias (CSP) CVK 64 Halik, Adriane (JCSP) CVK 70 Lofredi, Roxanne (JCSP) CCM 168 Hansmann, Leo Alexander (CSP) CVK 116 Mainka, Tina (CSP) CCM 140 Siegert, Elise (CSP) CCM 266 Sigal, Michael (X-CSP) CVK 46 Wizenty, Jonas (JCSP) CVK 27 Käbisch, Eva (JCSP) CVK 194 Mergenthaler, Philipp (CSP) CCM CC12 – Medical Department, Division of 177 Kase, Julia (CSP) CVK 71 Mossakowski, Agata (JCSP) CCM Infectiology and Pneumonology (CCM) CC13 – Medical Department, Division of 196 Nörenberg, Daniel (CSP) CVK 119 Nave, Alexander Heinrich (CSP) CCM Nephrology (CBF) 74 Penter, Livius (JCSP) CVK 123 Pache, Florence (CSP) CCM 250 Mittermaier (geb. Ramke), Mirja (DCSP) CCM 79 Schmiester, Maren (JCSP) CVK 76 Raffaelli, Bianca (JCSP) CCM 171 Hinze, Christian (CSP) CBF 252 Nawabi, Jawed (DCSP) CCM 80 Schrezenmeier, Jens Florian (JCSP) CVK 39 Rößling, Rosa (JCSP) CCM 75 Pfannkuch, Lennart (JCSP) CCM CC13 – Medical Department, Division of Nephrology 229 Wittenbecher, Friedrich (CSP) CVK 42 Schinke, Christian (JCSP) CCM 141 Tabeling, Christoph (CSP) CCM and Internal Intensive Care Medicine (CCM) 210 Schlemm, Ludwig (CSP) CCM 212 Schmidt, Felix Alexander (CSP) CCM 251 Naik, Marcel (DCSP) CCM 43 Steiner, Leon Amadeus (JCSP) CCM 199 Paliege, Alexander (CSP) CCM 264 Wenger, Nikolaus (X-CSP) CCM 80 Schrezenmeier, Eva (CSP) CCM 236 Wieder, Nicolas (JDCSP) CCM 274 Index Index 275
CC15 – Department of Neurology with CC16 – Department of Ophthalmology (CVK) CC17 – Department of Pediatrics, Experimental Neurology (CVK) Division of Oncology and Hematology (CVK) 156 Brockmann, Tobias (CSP) CVK 94 Bartels, Frederik (CSP) CVK 53 Busch, Catharina (JCSP) CVK 93 Balcerek, Magdalena (CSP) CVK 97 Danyel, Leon Alexander (CSP) CVK 55 Davids, Anja-Maria (JCSP) CBF 98 Dörr, Jan Rafael (CSP) CVK 114 Kroneberg, Daniel (CSP) CVK 192 Maier-Wenzel, Anna-Karina (CSP) CVK 105 Fuchs, Steffen (CSP) CVK 115 Kübler, Dorothee (CSP) CVK 202 Pilger, Daniel (CSP) CVK 262 Henssen, Anton (X-CSP) CVK 220 Skowronek, Cornelia (CSP) CVK 127 Pohlmann, Dominika (CSP) CVK 186 Künkele, Annette (CSP) CVK 221 Streitberger, Kaspar Josche (CSP) CVK 135 Rübsam, Anne (CSP) CVK 34 Launspach, Michael (JCSP) CVK 72 Müller, Thilo (JCSP) CVK CC15 – Department of Neuropathology (CCM) CC17 – Department of Gynecology (CVK) 198 Oevermann, Lena (CSP) CVK 204 Radke, Josefine (CSP) CVK 154 Braicu, Elena Ioana (CSP) CVK 41 Scheiermann, Julia (JCSP) CVK 139 Schweizer, Leonille (CSP) CCM 87 Woopen, Hannah (JCSP) CVK 81 Schulte, Stefanie (JCSP) CVK 88 Zirngibl, Felix (JCSP) CVK CC15 – Department of Neurosurgery (CBF) CC17 – Department of Neonatalogy (CVK) CC17 – Department of Pediatrics, Division of 159 Czabanka, Marcus (CSP) CBF 23 Friedrich, Vivien Leonie (JCSP) CVK Pulmology and Immunology (CVK) 218 Sharkovska, Yuliya (CSP) CVK CC15 – Department of Neurosurgery (CCM) 95 Bélard, Sabine (CSP) CVK CC17 – Department of Obstetrics (CCM) 25 Goetzke, Carl Christoph (JCSP) CVK 148 Acker, Güliz (CSP) CCM 106 Gräber, Simon (CSP) CVK 238 Rosenstock, Tizian (JDCSP) CCM 49 Altmann, Judith (JCSP) CCM 145 Xu, Ran (CSP) CCM 166 Golic, Michaela (CSP) CVK CC17 – Institute of Experimental Pediatric 83 Seidel, Vera (JCSP) CVK Endocrinology (CVK) CC15 – Department of Psychiatry and Psychotherapy (CBF) CC17 – Department of Pediatrics, Division of 185 Kühnen, Peter (CSP) CVK Cardiology (CVK) 54 Cho, An-Bin (JCSP) CBF CC17 – Institute of Medical Genetics and Human 169 Hellmann-Regen, Julian (CSP) CBF 30 Krech, Jana (JCSP) CVK Genetics (CVK) 111 Kaczmarczyk, Michael (CSP) CBF 126 Piber, Dominique (CSP) CBF CC17 – Department of Pediatrics, Division of 241 Atta Mensah, Martin (DCSP) CVK 201 Ta, Thi Minh Tam (CSP) CBF Endocrinology and Diabetology (CVK) 161 Ehmke, Nadja (CSP) CVK 63 Hägerling, Rene (JCSP) CVK 47 Zierhut, Marco (JCSP) CBF 242 Braune, Katarina (DCSP) CVK 155 Brandl, Eva Janina (CSP) HK 183 Krawitz, Peter (CSP) CVK 104 Friedel, Eva (CSP) CCM CC17 – Department of Pediatrics, Division of German Heart Center Berlin 112 Kaminski, Jakob (CSP) CCM Gastroenterology, Nephrology 182 Köhler, Stephan (CSP) CCM and Metabolic Disease (CVK) 120 Nazari-Shafti, Mir Timo (CSP) CVK 35 Michely, Jochen (JCSP) CCM 16 Azabdaftari, Aline (JCSP) CVK 211 Schmack, Katharina (CSP) CCM German Heart Center Berlin, Department of Cardiothoracic and Vascular Surgery (CVK) 216 Schreiter, Stefanie (CSP) CCM CC17 – Department of Pediatrics, Division of 85 Stuke, Heiner (JCSP) CCM Neurology (CVK) 195 Meyer, Alexander (CSP) CVK 144 Weilnhammer, Veith-Andreas (CSP) CCM 31 Kreye, Jakob (JCSP) CVK German Heart Center Berlin, Department of CC16 – Department of Ophthalmology (CBF) 121 Nikolaus, Marc Joachim (CSP) CVK Congenital Heart Disease-Pediatric Cardiology (CVK) 201 Picker-Minh, Sylvie (CSP) CVK 156 Brockmann, Claudia (CSP) CBF 214 Schneider, Joanna Barbara (CSP) CVK 125 Pfitzer, Constanze (CSP) CVK 78 Rosenthal, Lisa-Maria (JCSP) CVK 276 BIH Biomedical Innovation Academy Team BIH Biomedical Innovation Academy Team 277
BIH Biomedical Innovation Academy Team
Directorate Acting Heads of BIH Biomedical Innovation Academy (BIA)
Prof. Dr. Duška Dragun † Alke Freese Dr. Nathalie Huber Dr. Iwan Meij Former Director of BIH Biomedical Personal Advisor to the Directorate of Head (interim) of BIA Head (interim) of BIA Innovation Academy BIH Biomedical Innovation Academy Head of BIA Strategic Career Head of BIA Personnel- and Development & Talent Management Finance Management Head of Clinician Scientist Office Head of BIH Application and Reporting Portal Coordination of Program Activities Evaluations and Data Management
Dr. Mareike Behmann Dr. Angelika Kusch Dr. Cyril Cheret Dr. Rüdiger Hesse Coordinator Leadership Academy Coordinator Advanced Coordinator Data Management Coordinator Program Evaluations Initiatives Clinician Scientist Program and Meta Researcher and Curriculum and Meta Researcher
Team Assistant
Dr. Beatrice Sobek Dr. Katharina Walentin Nele Mohr Coordinator BIA Clinician Scientist Program Manager BIA Digital Clinician Team Assistant BIA Program Scientist Program and MD Research Stipends 278 Clinician Scientist Board (incl. Deputies) Clinician Scientist Board (incl. Deputies) 279
Clinician Scientist Board (incl. Deputies)
Charité – Universitätsmedizin Berlin Univ.-Prof. Dr. med. Andrea Kühn Berlin Institute of Health at Charité (BIH) Berlin Department of Neurology Univ.-Prof. Dr. med. Britta Siegmund Univ.-Prof. Dr. med. Christopher Baum (ex officio) with Experimental Neurology Interim Director of the BIH Charité Clinician Chairman of the Board of Directors of Berlin Institute Scientist Program Dr. Christine Kurmeyer (ex officio) of Health and Chief Translational Research Medical Department, Division of Gastroenterology, Central Counsellor for Women’s Affairs Officer of Charité – Universitätsmedizin Berlin Infectiology and Rheumatology and Equal Opportunities Karin Höhne (ex officio) Univ.-Prof. Dr. med. Marc Dewey Dr. André Lottmann Equal Opportunity Officer Department of Radiology Head of Office, Stiftung Charité Univ.-Prof. Dr. med. Ulrich Dirnagl Univ.-Prof. Dr. Il-Kang Na Max Delbrück Center for Molecular Medicine in the Department of Neurology and Experimental Department of Hematology, Oncology Helmholtz Association/Experimental and Clinical Neurology and BIH QUEST Center and Tumor Immunology and BIH Research Center (ECRC) Univ.-Prof. Dr.-Ing. Georg Duda Univ.-Prof. Dr. Sebastian Paris Prof. Dr. rer. nat. Dominik N. Müller Julius Wolff Institute for Biomechanics Department of Resorative and Preventive Dentistry Interim Director of BIH Charité and Musculoskeletal Regeneration and BIH Clinician Scientist Program Univ.-Prof. Dr. Friedemann Paul (ex officio) Hypertension-Mediated End-Organ Damage Univ.-Prof. Dr. med. Volkmar Falk Vice Dean of Research (Clinical Affairs) Department of Cardiothoracic and Univ.-Prof. Dr. med. Silke Rickert-Sperling Univ.-Prof. Dr. med. Johann Pratschke Vascular Surgery, German Heart Center Berlin Cardiovascular Genetics Department of Surgery Thomas Gazlig (ex officio) Univ.-Prof. Dr. med. Simone Spuler Univ.-Prof. Dr. med. Axel Radlach Pries (ex officio) Head of Business Division of Research Myology Dean Univ.-Prof. Dr. Dipl. Psych. Isabella Heuser-Collier Univ.-Prof. Dr. rer. nat. Ulrike Stein Univ.-Prof. Dr. Geraldine Rauch Department for Psychiatry and Psychotherapy Translational Oncology of Solid Tumors Institute of Medical Biometrics Univ.-Prof. Dr. med. Antonia Joussen, FEBO and Clinical Epidemiology Representatives of the Clinician Scientists Department of Ophthalmology Univ.-Prof. Dr. med. Claudia Spies Dr. med. Jakob Kaminski Univ.-Prof. Dr. Ulrich Keilholz Department of Anesthesiology and Department for Psychiatry and Psychotherapy Comprehensive Cancer Center Operative Intensive Care Medicine Dr. med. Eva Vanessa Schrezenmeier Univ.-Prof. Dr. med. Ulrich Keller Prof. Dr. E. Jürgen Zöllner Medical Department, Division of Nephrology Department of Hematology, Oncology CEO of Stiftung Charité and Internal Intensive Care Medicine and Tumor Immunology Dr. med. Elise Siegert Univ.-Prof. Dr. rer. nat. Achim Kramer (ex officio) Department of Rheumatology and Clinical Immunology Institute for Medical Immunology Chairman of Charité »Nachwuchskommission« Representative of the Junior Clinician Scientists Univ.-Prof. Dr. med. Martin Kreis (ex officio) Medical Director Dr. med. Leif Koschützke Department of Neurology and Experimental Neurology Dr. rer. hum. biol. Jochen Kruppa Institute of Biometry and Clinical Epidemiology 280 Digital Clinician Scientist Board (incl. Deputies) Photo Credits 281
Digital Clinician Scientist Board Photo Credits (incl. Deputies)
Charité – Universitätsmedizin Berlin Univ.-Prof. Dr. med. Petra Ritter Private, except: 95 Foto Fehling Department of Neurology and Experimental Neurology Charité – Universitätsmedizin Berlin 56, 134, 181 Foto Kirsch Univ.-Prof. Dr. med. Igor M. Sauer 52 Foto Krause Director of the BIH Charité Univ.-Prof. Dr. med. Johannes H. Schulte Page 24, 28, 39, 45, 57, 99, 132, 137, 165, 169, 171, 54 Foto Kühnel GmbH Digital Clinician Scientist Program Department of Pediatric Oncology and Hematology 173, 174, 189, 196, 238, 246, 251 188 Foto-Blumrich Department of Surgery Univ.-Prof. Dr. med. Surjo R. Soekadar 106 Andreas Süß 220 Fotostudio Elke Schöps Univ.-Prof. Dr. rer. nat. Robert Gütig Department of Psychiatry and Neurosciences 25, 114 Birgit Formann 179 Fotostudio Heinz Stanger Deputy Director of the BIH Charité 33 Center for Stroke Research (CSB) 55 Fotostudio Ludwig Univ.-Prof. Dr. med. Claudia Spies Digital Clinician Scientist Program 219, 227, 19 Christoph Weber 34 Fotostudio Monbijou Department of Anesthesiology and Operative Cluster of Excellence NeuroCure – 184 Kerstin Müller 239 Hoffotografen Intensive Care Medicine Mathematical Modeling of Neural Learning 255 Mediencenter 125, 247 iKlicK Fotostudio Berlin Univ.-Prof. Dr. med. Philipp Sterzer 192 Scharf 183 Katharina Wislsperger Prof. Dr. med. Dr. rer. nat. Felix Balzer Department of Psychiatry and Neurosciences 87, 229, 80 Simone Baar 39 L.Eigel Department of Anesthesiology and Operative 118 Stefan Trappe 70 Lea Dietschmann Intensive Care Medicine Berlin Institute of Health at Charité (BIH) 141 LUMENTIS GbR Prof. Dr. rer. nat. Nils Blüthgen Berlin Institute of Health 241 Manuel Tennert Institute for Pathology – Karin Höhne (ex officio) 50 Memorial Sloan Kettering Cancer Center Computational Modelling in Medicine Equal Opportunity Officer 194 David Ausserhofer 244 Michael Gotthardt 9 Stefan Zeitz 200 Peter Johann Kierzkowski Univ.-Prof. Dr. med. Ulrich Dirnagl Prof. Dr. rer. medic. Dominik Seelow 3, 274, 275 Thomas Raflzyk 216 Philipp Leu Department of Neurology and Experimental Bioinformatics and Translational Genetics 264 PicturePeople Neurology and BIH QUEST Center Prof. Dr. med. Sylvia Thun Other 15 Raphael Hablesreiter for Transforming Biomedical Research Core Unit eHealth and Interoperability 30 AG Katharina Schmitt 66 Simon Mossburner Univ.-Prof. Dr. med. Angelika Eggert 121 Amelia Rösel 261 The Kennedy Institute Of Rheumatology Department of Pediatric Oncology and Hematology Max Delbrück Center for Molecular Medicine 170 Andreas Löchte 124, 178 UKE Unternehmenskommunikation in the Helmholtz Association/ 205 University Health Network, Toronto Univ.-Prof. Dr. med. Bernd Hamm 259 Andreas Thiel Experimental and Clinical Research Center (ECRC) 47 Ute Oedekoven Institute of Radiology 256 Anette Koroll Fotos Dr. Sofia Forslund 206 Anja Meyer/UKE Univ.-Prof. Dr. med. Andreas C. Hocke Host-Microbiome Factors in Cardiovascular Disease 31 Anna Kreye Department of Infectiology and Pneumology and 248 Antje Lindner Advanced Medical BioImaging Core Facility Dr. Dagmar Kainmüller 243 Apropos_Foto Biomedical Image Analysis – Theoretical Advances in Dr. rer. hum. biol. Jochen Kruppa 35 Benno Zöllner Machine Learning and Combinatorial Optimization Institute of Biometry and Clinical Epidemiology 218 Berlin Medical School Univ.-Prof. Dr. med. Silke Rickert-Sperling 203 Birgit Fromann Dr. Christine Kurmeyer (ex officio) Cardiovascular Genetics 242 Chris Marxen Central Women’s and Equal Opportunity Officer 120 Christian Maier PD Dr. med. Tobias Penzkofer Humboldt-Universität zu Berlin 100 Cornelius Engelmann Department of Radiology 64 d&d Fotostudio/Herford Univ.-Prof. Dr. rer. nat. Ulf Leser 78, 195 Deutsches Herzzentrum Berlin Univ.-Prof. Dr. med. Johann Pratschke Institute for Computer Science – 177 Dietmar Spolert Department of Surgery Knowledge Management in Bioinformatics 127 Dirk Scharf Univ.-Prof. Dr. rer. nat. Geraldine Rauch 62 Dominik Lammerding Institute of Biometry and Clinical Epidemiology Representative of the Digital Clinician Scientists 22 Dr. Renata Ch. Feldmann Dr. med. Alexander H. Thieme, MSc 29 Eyesland Berlin Department of Radiation Oncology and Radiotherapy 8 Falko Alexander/Fotostudio Helle Kammer 83 Foto Borchard/Angelika Löffler 282 Imprint Imprint 283
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Responsible Dr. Nathalie Huber Head (interim) of BIH Biomedical Innovation Academy (BIA) Head of BIA Strategic Career Development & Talent Management Head of Clinician Scientist Office Dr. Iwan Christiaan Meij Head (interim) of BIH Biomedical Innovation Academy (BIA) Head of BIA Personnel- and Finance Management Head of BIH Application and Reporting Portal
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