Information Signaling Pathways in the Vasculature

描述（由申请人提供）： 脉管系统内和血脑屏障处的炎症途径调节血管壁对损伤的反应。这项竞争性项目更新的统一主题是脂蛋白受体（LRP 1、LRP 1B和VLDLR）以及白细胞和内皮受体整合素Mac-1和VE钙粘蛋白以受其配体tPA、PA 1 -1和纤维蛋白（原）影响的合作方式调节炎症反应。总体目标是确定LRP、Mac-1、tPA、派-1和纤维蛋白通过调节炎性细胞迁移协同调节动脉粥样硬化形成期间的炎性反应的分子途径，并确定这些分子调节血脑屏障（BBB）完整性的机制。这些目标将通过四名主要调查员和三个核心设施的共同努力来实现。Strickland博士（项目1）将专注于研究脂蛋白受体在血管壁炎症中的作用。与Zhang博士（项目3）和Medved博士（项目4）合作，他将测试脂蛋白受体，特别是LRP，通过调节整合素的功能特性及其与纤维蛋白（原）相互作用的能力来调节炎症过程，从而影响巨噬细胞迁移的假设。使用巨噬细胞特异性LRP敲除小鼠，他将测试LRP参与刺激促炎细胞因子产生的新信号通路的假设。Lawrence博士（项目2）将研究组织型纤溶酶原激活剂与LRP的相关性如何调节卒中中血脑屏障的完整性，以及整合素Mac-1和纤维蛋白在这种反应中的作用。研究将检验这样的假设，即靶向这些相互作用将导致开发更有效的治疗缺血性卒中的疗法。Zhang博士（项目3）将研究tPA、LRP、派-1、Mac-1和纤维蛋白在巨噬细胞外排中的作用，并检验LRP通过介导整合素分离和再循环来调节该过程的假设。Medved博士（项目4）将研究纤维蛋白（原）在白细胞跨内皮迁移中的作用，沿着Zhang博士将确定纤维蛋白在炎症反应中的作用。这三个核心将用于所有项目，以提供管理辅助（核心A），组织学，显微镜和成像辅助（核心B），以及蛋白质折叠，蛋白质组学和基因表达分析的辅助（核心C）。

DESCRIPTION (provided by applicant): Inflammatory pathways within the vasculature and at the blood brain barrier regulate the response of the vessel wall to injury. The unifying theme of this competitive program project renewal is that lipoprotein receptors (LRP1, LRP1B, and VLDLR) and the leukocyte and endothelial receptors integrin Mac-1 and VEcadherin modulate the inflammatory response in a cooperative fashion that is influenced by their ligands, tPA, PA1-1, and fibrin(ogen). The overall objective is to define molecular pathways by which LRP, Mac-1, tPA, PAI-1, and fibrin cooperate to modulate the inflammatory response during atherogenesis by regulating inflammatory cell migration and function to define mechanisms by which these molecules modulate the integrity of the blood brain barrier (BBB). These objectives will be achieved through the combined efforts of four principal investigators and three core facilities. Dr. Strickland (Project 1) will focus his research on the role of lipoprotein receptors in inflammation in the vessel wall. In collaboration with Dr. Zhang (Project 3) and Dr. Medved (Project 4), he will test the hypothesis that lipoprotein receptors, particularly LRP, regulate inflammatory processes by modulating the functional properties of integrins and their ability to interact with fibrin(ogen), thereby affecting macrophage migration. Using macrophage-specific LRP knockout mice, he will test the hypothesis that LRP participates in a novel signaling pathway that stimulates the production of pro-inflammatory cytokines. Dr. Lawrence (project 2) will investigate how association of tissue-type plasminogen activator with LRP modulates the integrity of the blood brain barrier in stroke, and the role of the integrin Mac-1 and fibrin in this response. Studies will test the hypothesis that targeting these interactions will lead to the development of more effective therapies for the treatment of ischemic stroke. Dr. Zhang (project 3) will investigated in role of tPA, LRP, PAI-1, Mac-1, and fibrin in macrophage efflux and test the hypothesis that LRP modulates this process by mediating integrin detachment and recycling. Dr. Medved (project 4) will investiage the role of fibrin(ogen) in the transendothelial migration of leukocytes, and along with Dr. Zhang will define the role of fibrin the inflammatory response. The three cores will be used by all projects to provide administratvie assistance (Core A), histology, microscopy and imaging assistance (Core B), and assistance in protein folding, proteomics and gene expression analysis (Core C).