This is a proposal for continuation of a Program Project Grant to study fundamental and clinical aspects of coagulation, including cellular and clotting factor interactions, fibrin formation, thrombus prevention and thrombolytic therapy.
Specific aims of basic studies are to determine the role of the amino-terminus of the fibrin Beta chain in mediating platelet and endothelial call spreading, adhesion and platelet activation and to determine the role of fibrin crosslinking on platelet and endothelial cell spreading to determine conformational structures of the alpha chain residues of fibrinogen that interact with rickettsial organisms and to determine whether such changes occur ax vivo in umbilical cored vessels an underlie the vascular thrombosis that occurs in animals with rickettsial infection, and to study the macromolecular interactions of human factor VIII thrombin, vonWillabrand factor, and factor IXa and phospholipid, Clinical studies will develop new approaches which optimize clinical thrombolysis, emphasizing the potential of lym- plasminogen administration in randomized clinical trials of patients with acute myocardial infraction and peripheral arterial occlusion, assess the potential of a non-invasive tests for thrombolysis, specifically magnetic resonance imaging and a modified D-dimer assay that accounts for degradation of soluble fibrin, and maximize the application of thrombolytic therapy to appropriate patients, especially women, by educational progress in university and community hospital. The five research projects will be supported by two core facilities devoted to administration (Core A) and tissues culture (Core B). The program emphasizes a balance between the expertise of fundamental and clinical scientists working independently and in concert with each other, and in the bidirectional flow of ideas and data between the laboratory bench and the hospital bed.
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