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.
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