The Role of GDF-15 in Organ Injury

描述（由申请人提供）：本提案旨在为 Leonidas Koniaris医学博士的科学发展，助理教授 罗切斯特大学医学院外科。候选人A 胃肠道和创伤外科医生，具有四年以上的基础科学 细胞因子和生长的功能和信号传导的研究培训 因素，寻求资金的指导研究计划，以检查的作用， 新型分泌因子GDF-15在休克和器官损伤中的作用休克和器官 损伤是导致 几乎所有严重疾病状态的发病率和死亡率。我们 和其他人已经克隆了新的转化生长因子-B（TGF-B）超家族 成员GDF-15及其人同源物GDF-14。GDF-15表达是有效的， 在小鼠肝、胆管、肾和肺损伤和休克模型中诱导。 同样，GDF-14在急性和慢性人类肝脏疾病中高度表达。 来自GDF-15缺失小鼠的巨噬细胞过度表达炎性细胞因子， 非刺激状态和佛波醇治疗后的趋化因子 酯。其他人报道GDF-14可以通过TGF-β受体发出信号， 发挥TGF-β样抗增殖作用。综合这些数据， GDF-14/15是休克和器官损伤的早期信号或介质， GDF-14/15可能通过调节细胞因子来抑制炎症反应 GDF 14/15可调节实质细胞的生长， 组织损伤后增殖。本建议旨在确定 通过描述其表达模式，通过评估GDF-15的功能， GDF-15敲除小鼠对器官损伤和休克的反应，并通过检查 重组GDF-15体外对巨噬细胞和实质细胞作用 在过表达小鼠体内。候选人将由 外科主席，James V. Silzmann，医学博士，免疫学教授I Nickolas Crispe博士，世卫组织将在以下领域提供专门知识和培训： 分别采用小鼠手术、休克和巨噬细胞方法。的 完成这一指导研究培训将进一步候选人？的目标 将实验室衍生的科学发现应用于外科手术治疗 作为一名独立的研究者。

DESCRIPTION (provided by applicant): 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.