Intestinal Inflammation: Signaling proteins and the rate of PMN transmigration

描述（由申请人提供）：胃肠道粘膜中的中性粒细胞（PMN）迁移是宿主防御和病理生理过程（如炎症性肠病（IBD））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PMN迁移的细胞粘附水平，事件，以调节的速率，PMN迁移通过肠粘膜炎症反应过程中了解甚少。我们小组的研究已经证明了上皮细胞和PMN表达的膜蛋白的重要贡献，这些膜蛋白在连接后启动对PMN迁移动力学具有深远影响的信号。该建议将集中在一个受体-配体对称为CD 47-SIRPalpha和蛋白酶激活受体（PAR），这是差异表达在肠粘膜和白细胞和调节PMN的迁移率，通过不同的影响PMN和上皮细胞的一类蛋白质。我们已经观察到，暴露于肠道衍生的微生物产物的迁移PMN有深远的影响，可能与部分CD 47介导的信号转导和部分PMN刺激的上皮通透性通过PAR的改变。我们的总体目标是了解CD 47，SIRP和PARs如何在结构和功能的基础上调节肠道中PMN的迁移。为了实现这一目标，我们将采用体外方法与急性结肠炎小鼠模型进行研究，以确定肠上皮和PMN表达的CD 47的贡献以及与TLR对PMN跨上皮迁移速率的潜在串扰，确定SIRP α中介导配体结合/蛋白质相互作用的结构元件，并研究PMN的作用。通过PAR的上皮信号调节PMN穿过肠上皮的迁移速率。了解调节中性粒细胞跨上皮迁移速率的基本机制可能为粘膜的病理生理学提供线索！疾病如IBD，并有助于开发新的治疗策略，旨在减少与这些病症相关的渗透性增强和粘膜损伤。

DESCRIPTION (provided by applicant): Neutrophil (PMN) migration in the gastrointestinal mucosa is a central component of both host defense and pathophysiologic processes such as inflammatory bowel disease (IBD). While many studies have focused on defining events involved in the regulation of PMN migration at the level of cell adhesion, events that serve to regulate the rate with which PMN migrate through intestinal mucosa during the inflammatory response are poorly understood. Studies from our group have demonstrated important contributions from epithelial and PMN expressed membrane proteins which, upon ligation, initiate signals that have profound effects on the kinetics on PMN transmigration. This proposal will focus on a receptor-ligand pair termed CD47-SIRPalpha and a class of proteins termed protease activated receptors (PARs) that are differentially expressed in the intestinal mucosa and on leukocytes and modulate the rate of PMN transmigration through distinct effects on PMN and epithelial cells. We have observed that exposure of migrating PMN to gut-derived microbial products have profound effects on transmigration that may be linked in part to CD47 mediated signaling and in part to PMN stimulated alterations in epithelial permeability through PARs. Our overall goal is to understand the mechanisms of how CD47, SIRP and PARs regulate PMN transmigration in the gut on a structural and functional basis. To achieve this goal we will perform studies employing in vitro methods in concert with murine models of acute colitis to define the contribution(s) of intestinal epithelial and PMN expressed CD47 and potential crosstalk with TLRs on the rate of PMN transepithelial migration, determine structural elements in SIRPalpha that mediate ligand binding/ protein interactions and investigate the role of PMN-epithelial signaling through PARs in regulating the rate of PMN migration across intestinal epithelium. Understanding basic mechanisms regulating the rate of PMN migration across epithelia may provide clues to the pathophysiology of mucosa! diseases such as IBD and aid in the development of new therapeutic strategies aimed at diminishing enhanced permeability and mucosal injury associated with these conditions.