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Structure of the Group Group Leader Dr. Dominik N. Müller Associated Scientists and Clinician-Scientists Dr. Wolf-Hagen Schunck Dr. Anette Fiebeler Dr. Ralf Dechend Dr. Robert Fischer Dr. Duska Dragun Dr. Joon-Keun Park Participating Scientists Dr. Wolfgang Derer Dr. Norbert Henke Dr. Fatimunnisa Qadri Dr. Maren Wellner Graduate Students Sandra Feldt Heda Kvakan Carolin Stocker Technicians May-Britt Köhler Jutta Meisel Gabi N’diaye Petra Quaß Mathilde Schmidt Manager of Sponsored Programs Susanne Wissler * part of the period reported Renal tumor necrosis factor (TNF)-α expression is greatly suppressed in hypertensive kidneys of Tie-1- ∆N mice. Glomeruli and blood vessel cross sections are shown. with the analyses of the role tubular and macrophage-specific NF-κB suppression in hypertension-induced target organ damage. We will next investigate the potential of regulatory T-cells as a putative target organ protection therapy. Therefore, we will treat mice with hypertension-induced target organ damage, pressure overload and ischemia/ reperfusion damage with regulatory T cells. We hypothesize that regulatory T-cells might limit inflammatory and immunological vascular, renal and cardiac damage. Sudden death is “nature’s way” of slowing us down Together with Ralf Dechend and Robert Fischer (Cardiology), we investigated whether p38 mitogen-activated protein kinase inhibition (p38i) ameliorates Ang IIinduced target-organ damage and improves sudden death. We used double transgenic rats harboring both human renin and angiotensinogen genes (dTGR). Systolic blood pressure of untreated dTGR was >200 mm Hg, but partially reduced after p38i treatment. Cardiac hypertrophy index was unchanged in untreated and p38i-treated dTGR. The β- myosin heavy chain expression of p38i-treated hearts was significantly lower in p38i compared to dTGR, indicating a delayed switch to the fetal isoform. P38i treatment significantly reduced cardiac fibrosis, connective tissue growth factor, tumor necrosis factor-α (TNF-α), interleukin-6, and macrophage infiltration At week 8, mortality of untreated dTGR was 100%, but was reduced to 10% in the p38i group. Cardiac magnetic field mapping showed prolongation of depolarization and repolarization in untreated dTGR with a partial reduction by p38i. Programmed electrical stimulation elicited ventricular tachycardias in 81% of untreated dTGR, but only in 48% p38i-treated dTGR. In conclusion, p38i prevented dTGR from slowing down, improved survival, target organ damage, and arrhythmogenic potential in Ang II-induced target organ damage. Cytochrome P450 (CYP) enyzmes and target organ damage Dominik Müller and Wolf-Hagen Schunck have a long-lasting collaborative partnership for research on the role of cytochrome P450 (CYP)-dependent eicosanoids in the regulation of cardiovascular function. We studied the role of CYP enzymes and arachidonic acid (AA) metabolites in targetorgan damage. We identified CYP2C23 as the major AA epoxygenase in the rat kidney. We also found that the PPARalpha agonist fenofibrate induced CYP2C23 activity. We recently found that several CYP isoforms and other enzymes involved in arachidonic acid metabolism show sex-specific expression. Therefore, we now will investigate the hypothesis that CYP-dependent eicosanoids act as mediators in prohypertrophic and anti-hypertrophic pathways and may thus contribute to gender differences in the development of cardiac hypertrophy and heart failure. Selected Publications Shagdarsuren, E, Wellner, M, Braesen, J-H, Park, J-K, Fiebeler, A, Henke, N, Dechend, R, Gratze P, Luft, FC, Müller, DN. (2005) Complement activation in angiotensin II-induced organ damage. Circ Res. 97, 716-724. Burckle, CA, Danser, AHJ, Müller, DN, Garrelds, IM, Gasc, JM, Popova, E, Plehm, R, Peters, J, Bader, M, Nguyen, G. (2006) Elevated blood pressure and heart rate in human renin receptor transgenic rats. Hypertension. 47, 552-556. Henke, N, Schmidt-Ullrich, R, Dechend, R, Park, JK, Qadri, F, Wellner, M, Obst, M, Gross, V, Dietz, R, Luft, FC, Scheidereit ,C, Muller, DN. (2007) Vascular Endothelial Cell-Specific NF-κB Suppression Attenuates Hypertension-Induced Renal Damage. Circ Res. 101, 227-229. Park, JK, Fischer, R, Dechend, R, Shagdarsuren, E, Gapeljuk, A, Wellner, M, Meiners, S, Gratze, P, Al-Saadi, N, Feldt, S, Fiebeler, A, Madwed, JB, Schirdewan, A, Haller, H, Luft, FC, Müller, DN. (2007) p38 mitogen-activated protein kinase inhibition ameliorates angiotensin II-induced target organ damage. Hypertension. 49, 481-489. Muller, DN, Schmidt, C, Barbosa-Sicard, E, Wellner, M, Gross, V, Hercule, H, Markovic, M, Honeck, H, Luft, FC, Schunck, WH. (2007) Mouse Cyp4a isoforms: enzymatic properties, genderand strain-specific expression, and role in renal 20-hydroxyeicosatetraenoic acid formation. Biochem J. 403, 109-118. 24 Cardiovascular and Metabolic Disease Research
Differentiation and Regeneration of Kidney Epithelia Kai M. Schmidt-Ott (Emmy Noether Research Group) In the embryo, kidney epithelia develop from non-epithelial progenitors in the intermediate mesoderm in a process called mesenchyme-to-epithelium conversion. Our laboratory investigates the molecular events underlying this process. The mechanisms involved are intriguing for several reasons. First, kidney embryonic development constitutes one of the rare examples in which virtually unorganized mesenchymal cell aggregates differentiate into highly specialized epithelial tubules (Figure 1A). The sequence of events can be closely monitored in organ cultures or in vivo. Second, perturbation of epithelial differentiation in the developing kidney can lead to quantitative or qualitative defects in kidney development resulting in congenital renal diseases. Third, adult kidney epithelia preserve the ability to reactivate earlier developmental stages in certain disease states, including tumors, kidney fibrosis, and acute tubular injury. Herein, aspects of epithelial differentiation are transiently or permanently reversed. Our research takes a sequential approach to these aspects. We begin by elucidating molecular signals that facilitate survival, expansion, and differentiation of embryonic epithelial progenitors in an organ culture system. Next, we utilize genetic mouse models to transfer these findings to the in vivo situation and address the genetic basis of congenital diseases. Finally, we investigate the role of these molecular pathways in adult renal disease. Thereby, we aim to translate our discoveries into novel strategies to improve the diagnosis and treatment of kidney disease. Survival, proliferation and early differentiation of renal epithelial progenitors We recently used a microarray-based screen of gene expression in differentiating renal epithelial progenitors and discovered activation of targets of the TCF/Lef transcription factor family. We then examined this pathway more closely in isolated renal epithelial progenitors in organ culture (Figure 1B). We found that activation of these transcription factors is both sufficient and necessary to facilitate survival, proliferation, and early differentiation of these cells. To date, the role of TCF/Lef in the developing kidney in vivo and the functional role of individual target genes controlled by these factors, remain unknown. To address these issues, we will conduct genome wide analyses of targets of TCF/Lef signaling followed by functional characterization in vivo. Mouse models will be established in close collaboration with the group of Thomas Willnow at the MDC. Also, our projects will be closely coordinated and carried out in collaboration with the laboratory of Jonathan Barasch at Columbia University (New York, NY, USA). We believe that a detailed elucidation of the transcriptional network controlled by TCF/Lef will yield fundamental insights into growth, remodeling, and stage progression of the renal epithelial lineage. Establishment and maintenance of mature renal epithelia While TCF/Lef-dependent signaling may account for early developmental programs in renal epithelial progenitors, it may in fact be inhibitory to terminal differentiation of tubular epithelia. Therefore, we are seeking complementary transcriptional regulators that induce the establishment of epithelial polarity and the expression of segment-specific markers. For this purpose, we used expression profiling to identify transcription factors closely co-regulated with markers of epithelial maturity and expressed in a restricted pattern during kidney development in vivo. We are currently testing the role of these factors in establishing and maintaining epithelial polarity and nephron function using cell culture of renal epithelial cells, organ culture of epithelial progenitors, and in vivo genetic models. Reactivation of developmental pathways in renal injury and regeneration Re-expression of embryonic marker molecules is a common feature in disease states and is believed to promote both compensation and regeneration. We recently discovered a Cardiovascular and Metabolic Disease Research 25
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I) Conditional ablation of the Bmp
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Genetics of Tumor Progression and M
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Signaling Mechanisms in Embryonic S
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Surgical Oncology Peter M. Schlag O
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Structure of the Group Group Leader
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Structure bition of differentiation
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such as self-renewal and differenti
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Signal Transduction in Tumor Cells
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Control of DNA Replication Manfred
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Nuclear Signalling and Chromosomal
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Structural and Functional Genomics
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RNA Chemistry Eckart Matthes Hydrox
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Structure and Membrane Interaction
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Tumor Immunology Coordinator: Marti
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Formation of segregated ectopic fol
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Regulatory Mechanisms of Lymphocyte
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Biology and Targeted Therapy of Lym
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A Figure 1. Function of BH3-only pr
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Molecular Immunotherapy Antonio Pez
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Function and Dysfunction of the Ner
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tion of proteins causes human neuro
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- Pathophysiological Mechanisms of
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Stucture of the Group Group Leader
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What are the physiological features
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Visualization of the UniHi interact
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Dagmar Ehrnhöfer* Manuela Jacob* M
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Lack of axonal bifurcation within t
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Molecular Physiology of Somatic Sen
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Mitochondrial Dynamics Christiane A
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Neuronal Stem Cells Gerd Kempermann
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Targeting Ion Channel Function Ines
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RNA Editing and Hyperexcitability D
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Molecular Neurology Frauke Zipp T h
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Academics Akademische Aktivitäten
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Charité-Universitätsmedizin Berli
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Helmholtz Fellows Helmholtz-Stipend
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2007 19. January Neujahrsempfang de
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Speaker Institute Titel of Seminar
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Overview Überblick
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erzielen, brauchen wir neue gemeins
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The Clinical Research Center (CRC)
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y such scientists in conjunction wi
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Zudem bietet das ECRC-Modell eine h
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(Photo: David Ausserhofer/ Copyrigh
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Business School” addressed challe
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Prof. Dr. Gary R. Lewin MDC Berlin-
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Dr. Thomas Müller Prof. Dr. Claus
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Type of Financing/Art der Finanzier
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Collaborative Research Centres (SFB
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MDC MAX-DELBRÜCK-CENTRUM FÜR MOLE
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Campus Map Campusplan Robert-Rössl
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How to find your way to the MDC Der
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