We propose a detailed study of the vitamin K dependend clotting factors. This study will encompass the Gla modification of the vitamin K substrates and their interactions with their activators, co-factors, substrates, and platelets. This project should lead to new and novel data about normal coagulation and the pathological abnormalities that lead to thrombosis and hemorrhage. In keeping with this broad thematic approach, we propose 4 interrelated projects led by principal investigators who have worked closely together for more than a decade. Project 1 addresses the vitamin K cycle, particularly the relationship of the carboxylase and the vitamin K dependent propeptides, and will attempt the isolation of the vitamin K epoxide reductase. Project 2 will investigate factor X's structure and function. The interactions of factor IX with platelets and endothelial cell surfaces, and how interactions of factor IX and other clotting factors with platelets regulate platelet procoagulant activity. Project 3 focuses on signal transduction events initiated by two major platelet collagen receptors, Alpha-2 Beta-1 and glycoprotein (GP)VI. The hypothesis that two small G-proteins, Rap1 and R-Ras, mediate cross-talk between these two collagen receptors will be tested and strategies to map collagen receptor-mediated signaling pathways, especially related to these small G-proteins, are outlined. Project 4 will develop three-dimensional structural models of complexes of vitamin K-dependent proteins and their inhibitors. This study will utilize the algorithms developed by the PI and his colleagues as well as recent advances in our knowledge of the partial x-ray crystal structures of several isolated components. These studies will make predictions that can be tested by the work proposed in Project 2.
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