This Program Project, under the direction of Robert W. Coleman, Molecular Basis for Platelet Function in Hemostasis, will exist within the Sol Sherry Thrombosis Research Center of Temple University School of Medicine. The Center is a formally established research institute within the School of Medicine dedicated to advancing our understanding of the etiology/pathogenesis, diagnosis and treatment of arterial and venous thrombosis and hemorrhagic diseases. To fulfill this goal, investigators in this project will examine the mechanisms of activation of platelets in hemostasis and thrombogenesis. Each project in the present proposal has the potential to indicate or provide the foundation for development of an appropriate inhibitory drug or therapeutic approach to prevent platelet activation, aggregation, and coagulant activity. and second messengers in particular, cyclic nucleotides and platelet coagulant activities. Project 1, Active Site Amino Acids of cAMP Phosphodiesterase 3A (R.W. Colman), concentrates on the delineation on the critical amino acids in active sites of the major cAMP phosphodiesterase in platelet. The amino acids critical for catalysis and metal binding of type 3A PDE will be identified by affinity labeling and site-directed mutagenesis. Project 2, Platelet Factor XI (P.N. Walsh), will structurally characterize platelet factor XI and study the mechanism of agonist exposure of actor XI in platelets. The mode of activation, cellular localization, and functional characteristics of platelet factor XI will be investigated. Project 3, Signal Transduction Defects in Human Platelets (A.K. Rao), will seek new insights into platelet signal transduction mechanisms by the biochemical and molecular biological dissection of the defects of a selected group of patients with qualitative defects focusing on abnormalities in PLC-b1a and Gaq. Project 4, Platelet ADP Receptors (S.P. Kunapuli), will elucidate the role of 3 ADP receptor subtypes in platelet fibrinogen receptor activation. Core A, Administration (R.W. Colman), will provide fiscal oversight and clerical support for all projects. Core B, Cell Culture (S.P. Kunapuli), will facilitate and support all of the projects and thus efficiently expedite the research. Core C, Flow Cytometry (J.K. deRiel), will provide fluorescent-activated cell analysis and confocal services to all projects. All of these investigators have a history of collaborative research with more than one of the other project leaders and will consult and share intellectual and physical resources with the other project leaders. The knowledge gained from these studies will provide therapeutic approaches to enhancing hemostasis and preventing thrombosis.
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