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血管壁中发生的炎症和血管生成事件的调节分子机制。这些目标将通过三位主要研究人员和三位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结合导致炎症细胞因子和趋化因子的产生。我们将描述负责启动这种反应的配体和所涉及的信号通路。我们将分别与Lawrence博士和Zhang博士合作研究尿激酶途径和整合素α β 2在这种反应中的作用。该途径的意义将在巨噬细胞组织特异性LRP敲除小鼠动脉粥样硬化模型中进行评估。Lawrence博士将专注于PAI-1及其在控制血管细胞迁移和血管生成中的作用。血管细胞迁移的机制以及pai - 1、玻璃体连接蛋白、uPA和uPAR在这一过程中的作用将在基因缺乏这些成分的小鼠中进行研究。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。张博士将研究uPA/uPAR系统在调节由整合素α β 2介导的血管壁伤口愈合事件中的作用。uPAR调节alpha4beta2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，LRP可能调节细胞表面uPAR和alphabet2水平的机制将被探索。所有项目都将使用这三个核心来提供行政协助、病理服务和荧光显微镜，以及蛋白质折叠检查和蛋白质-蛋白质相互作用的定量分析。

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.