SIGNALING THROUGH CELL SURFACE RECEPTORS ON ENDOTHELIAL CELLS

其目的是了解内皮细胞的分子基础 对外部事件的反应，包括局部损伤和炎症。 为了实现这一点，我们将继续我们对两组细胞的工作 可启动细胞内信号转导的表面受体 内皮细胞：蛋白酶激活受体(PARs)与Eph 激活剂。蛋白水解酶激活受体是G蛋白的一个亚家族 偶联受体，通过受体的蛋白分解激活， 是由受体N末端的蛋白水解酶激活的。四名成员 到目前为止，这个家庭已经被确认。EphK受体是一种 膜结合酪氨酸激酶大家族，其配体也是 细胞表面蛋白。这两个受体家族都被选中 因为它们与内皮细胞的生长和功能有关。 蛋白水解酶激活的受体，因为它们在中介中的作用 对大量积累的蛋白水解酶的反应 在损伤和炎症部位的浓度。Eph受体是 基于它们在细胞-细胞中起作用的假设进行选择 内皮细胞、白细胞和血小板之间的相互作用，如 以及调节内皮细胞之间的相互作用。这是我们的 认为这些受体家族在表面上的比较 表达和分布，启动的信号通路 通过受体激活，受体和适应之间的串扰 对当地环境包括流动和切变的变化，将 在一定程度上提供对内皮细胞生物学和病理学的见解 超越专注于任何一个人而产生的组织 受体家族。事实上，这是将这三个部分联系在一起的主题 -并将其与本提案中的其他4个提案相关联 计划项目，每个项目都涉及内皮细胞的反应 细胞、平滑肌细胞或血小板对其局部的变化 环境通过细胞表面受体或整合素。

The goal of this to understand the molecular basis for endothelial cell responses to external events, including local injury and inflammation. To accomplish this we will continue our work on two groups of cell surface receptors that can initiate intracellular signaling in endothelial cells: the protease-activated receptors (PARs) and Eph kinases. The protease-activated receptors are a subfamily of G protein coupled receptors that are activated by proteolysis of the receptor that are activated by proteolysis of the receptor N-terminus. Four members of this family have been identified to date. Eph kinase receptors are a large family of membrane-bound tyrosine kinases whose ligands are also cell surface proteins. Both of these receptors families was chosen because of their relevance to endothelial cell growth and function. Protease-activated receptors because of their role in mediating responses to the proteolytic enzymes that accumulate at high concentrations at sites of injury and inflammation. Eph receptors were selected based upon the hypothesis that they play a role in cell-cell interactions between endothelial cells, leukocytes and platelets, as well as mediating interactions between endothelial cells. It is our belief that comparisons among these receptor families in term of surface expression and distribution, the signaling pathways that are initiated by receptor activation, crosstalk between the receptors and adaptations to the local environment including changes in flow and shear, will provide insights into endothelial cell biology and pathology at a level of organization beyond that which comes from concentration on any one receptor family. This is, in fact, the theme that unites the three parts of this proposal-and relates it to the other 4 proposals within this program project, each of which deals with the responses of endothelial cells, smooth muscle cells or platelets to changes in their local environment via cell surface receptors or integrins.