We propose a broadly based, multidisciplinary research program focusing on metabolism and cellular interactions of coagulation proteins. Three particular areas will be investigated: i) the interaction of specific coagulation proteins (fibrinogen, von Willebrand Factor, fibronectin, thrombospondin) with platelets, emphasizing mechanisms of platelet activation; ii) mechanisms of thrombus formation on polymeric ex vivo and minimally traumatized in vivo surfaces; and iii) control of and mechanisms of synthesis and secretion of coagulation proteins by hepatocytes, monocytes/macrophages, and parenchymal cells. Specific experiments include: i) high voltage electron microscopic localization of protein- or antibody-coated gold beads in whole mounts of spreading platelets with concomitant identification of cytoskeletal elements; ii) a comprehensive description of platelet glycosyltransferases; iii) immunologic quantitation and localization of thrombospondin, a major glycoprotein which is secreted by activated platelets, and is also synthesized and secreted by endothelial cells and fibroblasts in culture; iv) a detailed analysis of how surface properties of ex vivo polymeric shunts influence cells to express procoagulant and fibrinolytic activities; v) exploration of the mechanisms of formation of transient platelet thrombi in the constricted coronary artery; vi) investigations of Alpha 2-macroglobulin synthesis, secretion, physiologic function, and catabolism in culture, with an emphasis on thiol ester formation and role of transamidation reactions; vii) investigations of immune-mediated production of procoagulant molecules by monocytes/macrophages; and viii) investigations of the level of Gamma-carboxylation of Vitamin K-dependent factors in normal and anticoagulated animals.
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