Information Signaling Pathways in the Vasculature

这个竞争性项目更新申请的统一主题是定义调节血管壁中发生的炎症和血管生成事件的分子机制。这些目标将通过三名主要调查员和三名核心主任的共同努力来实现。Strickland博士将专注于一种新的信号通路，其中配体与LRP的结合导致炎症细胞因子和趋化因子的产生。负责启动这一反应的配体和信号通路将被描绘。将分别与Lawrence博士和Zhang博士合作研究尿激酶途径和整合素β 2在这种反应中的作用。将使用动脉粥样硬化的小鼠模型在巨噬细胞组织特异性LRP敲除中评价该途径的意义。Lawrence博士将专注于派-1及其在控制血管细胞迁移和血管生成中的作用。定义血管细胞迁移的机制和PAI-1，玻连蛋白，uPA和uPAR在这一过程中的作用将在这些组件的遗传缺陷的小鼠中进行检查。LDL受体家族成员（LRP和VLDL受体）在血管生成和血管细胞迁移中的作用也将与Strickland博士合作进行研究（项目1）。此外，uPAR与整合素在血管细胞迁移和血管生成过程中的重要性将与张博士合作进行研究。Zhang博士将研究uPA/uPAR系统在调节血管壁中由整合素β 2介导的伤口愈合事件中的作用。uPAR调节α 4 β 2功能的分子机制及其在体内伤口愈合中的作用将在与Lawrence博士的合作研究中进行探索。与Strickland博士合作，将探索LRP调节uPAR和β 2细胞表面水平的机制。这三个核心将用于所有项目，以提供行政援助、病理学服务和荧光显微镜检查，以及蛋白质折叠和蛋白质-蛋白质相互作用的定量研究。

The unifying theme of this competitive program project renewal application is to define the molecular mechanisms regulating inflammatory and angiogenic events that occur in the vessel wall. These objectives will be achieved through the combined effort of three principal investigators and three core directors. Dr. Strickland will focus on a novel signaling pathway in which ligand association with LRP leads to production of inflammatory cytokines and chemokines. The ligands responsible for initiating this response and the signaling pathways involved will be delineated. The role of components of the urokinase pathway and the integrin alphambeta2 in this response will be investigated in collaboration with Dr. Lawrence and Dr. Zhang, respectively. The significance of this pathway will be evaluated in macrophage tissue-specific LRP knockouts using a mouse model of atherosclerosis. Dr. Lawrence will focus on PAI-1 and its role in the control of vascular cell migration and angiogenesis. Mechanisms defining vascular cell migration and the role of PAI-I, vitronectin, uPA, and uPAR in this process will be examined in mice that are genetically deficient in these components. The role of LDL receptor family members (LRP and the VLDL receptor) in angiogenesis and vascular cell migration will also be examined in collaboration with Dr. Strickland (Project 1). Additionally, the importance of uPAR's association with integrins during vascular cell migration and angiogenesis will be examined in collaboration with Dr. Zhang. Dr. Zhang will investigate the role of the uPA/uPAR system in modulating wound healing events in the vessel wall that are mediated by the integrin, alphambeta2. The molecular mechanisms by which uPAR modulates alpha4beta2 function and their roles in wound healing in vivo will be explored in collaborative studies with Dr. Lawrence. In collaboration with Dr. Strickland, the mechanism by which LRP may regulate cell surface levels of uPAR and alphambeta2 will be explored. The three cores will be used by all projects to provide administrative assistance, pathology services and fluorescence microscopy, and examination of protein folding and quantification of protein-protein interactions.