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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08GM063603-05
Application #
6800759
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
2001-09-01
Project End
2006-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
5
Fiscal Year
2004
Total Cost
$121,205
Indirect Cost
Name
University of Miami School of Medicine
Department
Surgery
Type
Schools of Medicine
DUNS #
052780918
City
Miami
State
FL
Country
United States
Zip Code
33146
Jin, Xiaoling; Zimmers, Teresa A; Zhang, Zongxiu et al. (2010) Interleukin-6 is an important in vivo inhibitor of intestinal epithelial cell death in mice. Gut 59:186-96
Jin, Xiaoling; Zhang, Zongxiu; Beer-Stolz, Donna et al. (2007) Interleukin-6 inhibits oxidative injury and necrosis after extreme liver resection. Hepatology 46:802-12
Jin, Xiaoling; Zimmers, Teresa A; Perez, Eduardo A et al. (2006) Paradoxical effects of short- and long-term interleukin-6 exposure on liver injury and repair. Hepatology 43:474-84
Zimmers, Teresa A; Jin, Xiaoling; Hsiao, Edward C et al. (2005) Growth differentiation factor-15/macrophage inhibitory cytokine-1 induction after kidney and lung injury. Shock 23:543-8
Zimmers, Teresa A; McKillop, Iain H; Pierce, Robert H et al. (2003) Massive liver growth in mice induced by systemic interleukin 6 administration. Hepatology 38:326-34