Role of signal regulatory protein in neutrophil function

描述(由申请人提供)：中性粒细胞(PMN)在组织内的迁移是宿主防御和许多病理生理过程的中心组成部分。虽然许多研究集中于在细胞表面水平上定义参与调节PMN迁移的事件，但在炎症反应过程中用于微调PMN迁移的事件序列尚不完全清楚。也许更不被理解的是，控制PMN迁移的途径如何促进病理性炎症。事实上，各种人类疾病，在其活动期和症状期，都以大量中性粒细胞(PMN)在组织和粘膜表面迁移为特征。我们课题组最近对PMN在粘膜表面迁移机制的研究表明，一种名为CD47的膜蛋白在调节PMN迁移速度方面发挥着重要作用。正如这项提议所概述的，我们有证据表明，CD47与一种称为信号调节蛋白(SIRPA)的细胞受体结合调节PMN的迁移速度。此外，我们有数据表明，在PMN的不同亚细胞内存在几种SIRPA蛋白。这项建议的总体目标是确定这些PMN Sirp蛋白及其在调节PMN迁移中的作用(S)。为了实现这一目标，我们将在SIRPA上找出参与PMN迁移调控的区域(S)，鉴定在PMN中表达的Sirp蛋白，并确定它们在趋化刺激过程中的细胞分布。来自拟议研究的信息将为SIRP在调节PMN迁移中的作用提供新的见解，并可能为旨在抑制病理性炎症的治疗提供新的想法。

DESCRIPTION (provided by applicant): Neutrophil (PMN) migration within tissues is a central component of both host defense and many pathophysiologic processes. While many studies have focused on defining events involved in the regulation of PMN migration at the level of the cell surface, the sequence of events that serve to fine-tune PMN migration during the inflammatory response are incompletely understood. Perhaps even less well appreciated is how the pathways controlling PMN migration contribute to pathologic inflammation. Indeed, a variety of human diseases, in their active and symptomatic stages, are characterized by migration of large numbers of neutrophils (PMN) through tissues and across mucosal surfaces. Recent studies from our group investigating the mechanisms of PMN migration across mucosal surfaces demonstrated an important role of a membrane protein termed CD47 in regulating the rate of PMN migration. As outlined in this proposal, we have evidence demonstrating that CD47 binding to a cellular receptor termed signal regulatory protein (SIRPa) regulates the rate of PMN migration. Furthermore, we have data suggesting that several SIRPa proteins are present within different subcellular compartments in PMN. The overall goal of this proposal is define these PMN SIRP proteins and their role(s) in regulating PMN migration. To achieve this goal, we will identify region(s) on SIRPa that are involved in modulation of PMN migration, characterize SIRP proteins that are expressed in PMN and define their cellular distributions during chemoattractant stimulation. Information from the proposed studies will provide new insights into the role of SIRPs in the regulation of PMN migration and may yield new ideas for therapeutics aimed at inhibiting pathologic inflammation.