RIP-Mediated Signaling in Intestinal Epithelial Cell Death During Sepsis

Emory University, Atlanta GA

Investigators

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Abstract

? DESCRIPTION (provided by applicant): My objective in writing this proposal is to facilitate the development of a skill set that will ultimately lead to my ability to function successfully as an independent investigator. To that end, the proposal makes use of the substantial research and mentoring experience of two very successful senior investigators, Dr. Coopersmith and Dr. Mocarski. Their combined expertise results in a powerful multidisciplinary collaboration that is uniquely able to foster the continued growth of my scientific knowledge, experimental abilities, and skill at scientific authorship. Sepsis, a syndrome resulting from the body's systemic and maladaptive response to infection, is a serious health concern in the United States, with up to 300,000 people dying from the disease annually. As knowledge of the basic pathophysiology of sepsis has increased, experimental findings have come to indicate that changes within the gut - specifically along the epithelium of the small intestine - may be key factors in driving disease progression and mortality. Receptor interacting protein 1 (RIP1) has recently been identified as a potential master regulator of cell death in the intestinal epithelium. RIP1 signaling is capable f inducing profound intestinal injury and causing substantial gut cell death by both apoptotic and receptor-mediated necrotic or necroptotic mechanisms. Despite its powerful role in maintaining epithelial homeostasis, how changes in its signaling or expression may contribute to gut compromise in sepsis has not been studied. This proposal, under the experienced guidance of Drs. Coopersmith and Mocarski, experts in sepsis and cellular death pathways, respectively, aims to gain insight into RIP1 control over intestinal cell death during sepsis with the ultimate goal of identifying potential points of intervention that may one day benefit critically ill patiens.