MOLECULAR INTERACTIONS IN INFLAMMATION AND COAGULATION

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Inflammation and coagulation are linked processes leading to thrombosis and vascular injury. To address the mechanisms by which these pathways interact, our immediate goal is to analyze structure-function relationships between specific receptors and their ligands with an emphasis on how these interactions may modulate the function of the proteins involved. Project 1 will analyze the molecular basis for the interaction of protein C and activated protein C (APC) with the endothelial cell protein C receptor (EPCR), the influence of this interaction on APC function and enzyme specificity, and the role EPCR plays in inflammation Project 2 will examine the molecular mechanisms responsible for the restricted substrate specificity exhibited by thrombin, APC, and factor Xa, and the molecular mechanisms by which the cofactors modulate the function of these enzymes. Project 3 will analyze structure-.function relationships critical to P- and E-selectin interaction with a target ligand, PSGL-1, and correlate these findings with studies of leukocyte interaction under static and flow conditions. Project 4 complements Project 3 by characterizing the oligosaccharides on PSGL-1 critical for P-selectin interaction and the mechanisms of PSGL- 1 biosynthesis. Our long term objective is to understand how these systems interact. We envision the following potential links among these projects. Adhesion of leukocytes to endothelium mediated by P and E- selectin can increase the local concentration of inflammatory mediators (elastase or cytokines) that can either directly or indirectly inhibit the function of the protein C pathway. For instance, EPCR is down regulated by tumor necrosis factor (TNF). APC exhibits apparent anti- inflammatory activity in vivo. EPCR, which binds APC, is homologous to the CD1/MHC superfamily involved in inflammation. This suggests that EPCR may be involved in inflammation and that EPCR is a candidate to contribute to the anti-inflammatory activity of APC observed in vivo. Leukocyte adhesion to selectins is likely to modulate both EPCR expression and function. The structural information derived from these studies should allow the design of specific inhibitors that would facilitate analysis of the physiological links between cell adhesion and inflammation-mediated vascular damage, and the role of the protein C system in regulating this process.