Role of signal regulatory protein in neutrophil function

描述（由申请人提供）：组织内的中性粒细胞（PMN）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定义事件参与的调节中性粒细胞迁移的细胞表面的水平，事件的顺序，以微调中性粒细胞迁移的炎症反应过程中不完全理解。也许更不被理解的是控制PMN迁移的途径如何导致病理性炎症。事实上，多种人类疾病在其活动和症状阶段的特征在于大量中性粒细胞（PMN）通过组织和穿过粘膜表面的迁移。我们小组最近的研究表明，一种称为CD47的膜蛋白在调节PMN迁移速率中起着重要作用。如本提案所述，我们有证据表明，CD47与称为信号调节蛋白（SIRPa）的细胞受体结合可调节PMN迁移速率。此外，我们有数据表明，几个SIRPa蛋白存在于PMN的不同亚细胞区室。该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，我们将鉴定SIRP α上参与调节PMN迁移的区域，表征在PMN中表达的SIRP蛋白，并确定其在化学引诱物刺激期间的细胞分布。从拟议的研究信息将提供新的见解SIRPs在调节PMN迁移的作用，并可能产生新的想法，旨在抑制病理性炎症的治疗。

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.