The Role of GDF-15 in Organ Injury

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This proposal seeks funding for the scientific development of Leonidas Koniaris, M.D., an Assistant Professor of Surgery at the University of Rochester School of Medicine. The candidate, a gastrointestinal and trauma surgeon with over four years of basic science research training in the function and signaling of cytokines and growth factors, seeks funding for a mentored research program to examine the role of a novel secreted factor, GDF-15, in shock and organ injury. Shock and organ injury are common cytokine-dependent pathophysiologic processes that lead to the morbidity and mortality seen in virtually all serious disease states. We and others have cloned the new Transforming Growth Factor-B (TGF-B) superfamily members GDF-15, and its human homologue GDF-l 4. GDF- 15 expression is potently induced in mouse models of liver, bile duct, kidney and lung injury and shock. Likewise, GDF-14 is highly expressed in acute and chronic human liver disease. Macrophages from GDF-15 null mice hyper-express inflammatory cytokines and chemokines both in the unstimuiated state and after treatment with phorbol ester. Others report that GDF-14 can signal through the TGF-B receptor and exert TGF-B-like anti-proliferative effects. Taken together these data suggest that GDF- 14/15 is an early signal or mediator of shock and organ injury, that GDF- 14/15 may limit the inflammatory response by regulating cytokine production by macrophages, and that GDF 14/15 may regulate parenchymal cell proliferation after tissue injury. This proposal seeks to determine the function of GDF- 15 by describing its expression pattern, by evaluating the response of GDF-15 null mice to organ injury and shock, and by examining the effect of recombinant GDF-15 in vitro on macrophages and parenchymal cells and in vivo in over-expressing mice. The candidate will be sponsored by the Chairman of Surgery, James V. Silzmann, M.D., and Professor of Immunology I. Nickolas Crispe, Ph.D., who will provide expertise and training in the areas of murine surgery and shock and macrophage methodology respectively. The completion of this mentored research training will further the candidate?s goal of applying bench-derived scientific discovery to the treatment of surgical disease as an independent investigator.
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