ENDOTHELIAL CELL PROTEIN C RECEPTOR

蛋白C途径的组成部分在 预防血栓形成，在体内，激活蛋白c(APC)出现 以显示抗炎活性。我们最近发现， 一种新的内皮细胞调控基因的克隆和初步研究 细胞蛋白C受体(EPCR)能结合蛋白C或APC，但不能 其他几种相关的维生素K依赖蛋白。的结构。 蛋白质与CD1/MHC 1类蛋白质超家族相似 以及CCD41，一种小鼠中心体，细胞周期依赖的蛋白质。这 该提案旨在阐明EPCR的功能。我们的目标是 1)表达和分离EPCR；2)建立结构-功能 EPCR与APC的关系；3)决定EPCR是否与APC结合 改变底物特异性(就像血栓调节蛋白对凝血酶所做的那样)，以及 增强因子Va失活，这一假说得到了 EPCR的性质、细胞特异性和对细胞因子的敏感性； APC-EPCR复合体在血管内皮细胞和异种血管上的去向研究 细胞；5)确定EPCR-APC复合体是否具有抗炎作用 活性；6)确定EPCR是否以异源二聚体形式存在于细胞表面； 7)研究基因的调控元件，建立调控机制 EPCR在培养和体内的下调情况；8)评估 反义和抗体抑制途径可能发挥的EPCR作用 在体内和在细胞培养中。这些研究将提供关于 EPCRs的结构、功能和生理作用 确定了蛋白C抗凝途径的成员。

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.