ENDOTHELIAL CELL PROTEIN C RECEPTOR

蛋白C途径的组分在以下方面起着关键作用： 防止血栓形成，在体内，活化蛋白c（APC）出现 以显示抗炎活性。我们最近发现， 克隆并启动了对一种新的内皮细胞调节的研究， 细胞蛋白C受体（EPCR），结合蛋白C或APC，但不 其他几种相关的维生素K依赖蛋白质。的结构 蛋白质揭示了与CD 1/MHC 1类蛋白质超家族的相似性 和CCD 41，一种鼠中心体细胞周期依赖性蛋白。这 该提案旨在阐明EPCR的功能。这些目标是 1）表达和分离EPCR; 2）建立结构-功能 EPCR和APC之间的关系; 3）确定EPCR是否与APC结合 改变底物特异性（如血栓调节蛋白对凝血酶的作用），和 增强因子Va失活，这一假设得到了 EPCR的性质、细胞特异性和对细胞因子的敏感性; 4） 研究APC-EPCR复合物在内皮细胞和异源细胞上的命运， 5）确定EPCR-APC复合物是否具有抗炎性， 6）确定EPCR是否作为异源二聚体存在于细胞表面; 7)研究该基因的调控元件，以建立该机制 在培养物和体内下调EPCR;和8）评估 通过反义和抗体抑制方法可能的EPCR功能 在体内和细胞培养中。这些研究将提供以下信息： EPCR的结构、功能和生理作用， 确定了蛋白C抗凝剂途径的成员。

The components of the protein C pathway play a critical role in preventing thrombosis, and, in vivo, activated protein c (APC) appears to exhibit anti-inflammatory activity. We have recently identified, cloned and initiated studies on the regulation of a novel endothelial cell protein C receptor (EPCR) that binds protein C or APC, but not several other related vitamin K dependent proteins. The structure of the protein reveals similarity to the CD1/MHC class 1 superfamily of proteins and to CCD41, a murine centrosome, cell cycle dependent protein. This proposal is designed to elucidate the functions of EPCR. The goals are to I) express and isolate EPCR; 2) establish structure-function relationships between EPCR and APC; 3) determine if EPCR binding to APC changes substrate specificity (as thrombomodulin does with thrombin), and augments factor Va inactivation, a hypothesis supported by the properties, cell specificity and sensitivity of EPCR to cytokines; 4) study the fate of APC-EPCR complexes on endothelium and heterologous cells; 5) determine if the EPCR-APC complex has anti-inflammatory activity; 6) determine if EPCR exists as a heterodimer on cell surfaces; 7) study the regulatory elements of the gene to establish the mechanisms of down regulation of EPCR in culture and in vivo; and 8) evaluate possible EPCR functions by antisense and antibody inhibition approaches in vivo and in cell culture. These studies will provide information on the structure, function and physiological role of EPCR, the most recently identified member of the protein C anticoagulant pathway.