Intestinal Inflammation: Signaling proteins and the rate of PMN transmigration

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DESCRIPTION (provided by applicant): Neutrophils (PMN) are the first responders to the intestinal mucosa during an acute inflammatory response. In addition to playing a critical role in clearing invading microorganisms, infiltrating PMN mediate both mucosal injury and repair. These diverse functions are dependent, in part, on efficient recruitment and migration in concert with death and clearance of "used" PMN. While much is known about the mechanisms regulating chemotaxis, microbicidal, and tissue functions of PMN, there are considerable gaps in the understanding of mechanisms regulating recruitment of PMN to the intestine in-vivo. Furthermore, the role(s) of PMN in maintenance of mucosal homeostasis is not well understood. Over the past two decades, a number of membrane proteins have been identified that play key roles in regulating migration and other key functions of PMN. One such protein termed CD47 is abundantly expressed in PMN and most other cells of the body. Depending on the type of cell that expresses it, CD47 has been implicated in a diverse set of functions. In PMN, we and others have shown that CD47 plays important roles in regulation of migration and phagocytosis however how it mediates function in the context of tissue (intestine) responses remains poorly defined. In this proposal, we will extend in-vivo experimental results that highlight intrinsic and extrinsic roles for CD47 in regulating the rate of PMN recruitment, tissue injury and clinical responses in models of acute and chronic intestinal inflammation. Furthermore, we will pursue studies directed at elucidating how CD47 regulates death and clearance of PMN. From these proposed studies, we will define the contributions of PMN and epithelial- derived CD47 to the regulation of the rate of PMN recruitment and intestinal mucosal homeostasis. It is hoped that these studies will provide new ideas for the development of agents that can exploit CD47-dependent function to attenuate pathologic inflammation and promote mucosal healing.