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核心组成部分。虽然许多研究都集中在细胞表面水平上确定PMN迁移调节的事件，但在炎症反应中调节PMN迁移的事件序列尚不完全清楚。也许更不为人所知的是控制PMN迁移的途径是如何导致病理性炎症的。事实上，各种人类疾病，在其活跃期和症状期，都以大量中性粒细胞（PMN）通过组织和粘膜表面迁移为特征。我们小组最近研究了PMN在粘膜表面迁移的机制，证明了一种称为CD47的膜蛋白在调节PMN迁移速率方面的重要作用。如本提案所述，我们有证据表明CD47与一种称为信号调节蛋白（SIRPa）的细胞受体结合可调节PMN的迁移速率。此外，我们有数据表明，几种SIRPa蛋白存在于PMN的不同亚细胞区室中。本提案的总体目标是定义这些PMN SIRP蛋白及其在调节PMN迁移中的作用。为了实现这一目标，我们将确定SIRPa上参与PMN迁移调节的区域，表征PMN中表达的SIRP蛋白，并定义它们在化学引诱剂刺激下的细胞分布。来自拟议研究的信息将为sirp在PMN迁移调节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方法提供新的思路。

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.