The Role of GDF-15 in Organ Injury

描述(由申请人提供)：本提案旨在为 医学博士，医学博士，科学发展观 罗切斯特大学医学院的外科医生。候选人，一个 胃肠和创伤外科医生，有四年以上的基础科学知识 细胞因子的功能和信号与生长的研究培训 因素，为一项有指导的研究计划寻求资金，以审查 新的分泌因子GDF-15在休克和器官损伤中的作用休克与器官 损伤是常见的细胞因子依赖的病理生理过程，导致 几乎所有严重疾病州的发病率和死亡率。我们 还有一些人克隆了新的转化生长因子-B(TGF-B)超家族 成员gdf-15及其人类同源基因gdf-L 4.gdf-15的高效表达 诱导小鼠肝、胆管、肾、肺损伤及休克模型。 同样，GDF-14在急性和慢性人类肝病中高度表达。 GDF-15基因缺失小鼠巨噬细胞高表达炎性细胞因子和 未刺激状态和佛波醇治疗后的趋化因子 埃斯特。另有报道称，GDF-14可以通过转化生长因子-β受体和 发挥转化生长因子-β样抗增殖作用。总而言之，这些数据表明 GDF-14/15是休克和器官损伤的早期信号或介体， GDF-14/15可能通过调节细胞因子来限制炎症反应 巨噬细胞产生GDF14/15可能调节实质细胞 组织损伤后的增殖。这项提案旨在确定 GDF-15的功能，通过描述其表达模式，通过评估 GDF-15基因缺失小鼠对器官损伤和休克的反应 重组GDF-15体外对巨噬细胞和实质细胞的影响 在体内过表达的小鼠体内。候选人将由 外科主席、医学博士、免疫学I教授詹姆斯·V·西尔兹曼。 Nickolas Crispe博士，他将在以下领域提供专业知识和培训 小鼠外科手术和休克及巨噬细胞方法学。这个 本次辅导性研究培训的完成是否会进一步推动候选人S的目标？ 将基础科学发现应用于外科手术的治疗 疾病作为一个独立的调查者。

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.