Intestinal Inflammation: Signaling proteins and the rate of PMN transmigration

描述（由申请人提供）：中性粒细胞（PMN）是急性炎症反应期间肠粘膜的第一反应者。除了在清除入侵微生物中发挥关键作用外，浸润性PMN还介导粘膜损伤和修复。这些不同的职能部分取决于有效的征聘和移徙以及“已使用” PMN的死亡和清除。虽然人们对PMN的趋化性、杀微生物性和组织功能的调节机制了解甚多，但在体内调节PMN向肠道募集的机制方面仍有相当大的空白。此外，PMN在维持粘膜稳态中的作用尚不清楚。在过去的二十年中，许多膜蛋白已经被确定在调节PMN的迁移和其他关键功能中发挥关键作用。其中一种被称为CD47的蛋白质在PMN和身体的大多数其他细胞中大量表达。根据表达它的细胞类型，CD47参与了一系列不同的功能。在PMN中，我们和其他人已经证明CD47在迁移和吞噬的调节中起重要作用，但是它如何在组织（肠）反应的背景下介导功能仍然不清楚。在本提案中，我们将扩展体内实验结果，突出内在和

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.