This Program Project will exist within the Sol Sherry Thrombosis Research Center which is dedicated to advancing our understanding of the etiology, pathogenesis, diagnosis and treatment of arterial and venous thrombosis and hemorrhagic diseases. The research activities of the Program are divided into projects that are unified in the examination of the interactions between various plasma proteins with platelet endothelial cell and leukocyte receptors involved int he physiological and pathological processes of hemostasis and thrombogenesis and the regulation of the enzymatic activity of various serine proteases. Project 1 (P.N. Walsh, Platelet Receptor-Mediated Factor-X Activation) focuses on the mechanisms of membrane assembly of the F-X activating complex and aims to accomplish a complete structural and functional characterization of the protein- receptor interactions involved in the assembly of the F-X activating complex on the platelet surface. Project 2 (R.W. Colman, Antiadhesive and Anticoagulant Activity of Kininogens) will probe the interactions of plasma high molecular weight kininogen (HK) with blood cells including platelets, neutrophils and monocytes as well as endothelial cells. The domains with HK that interact with various cellular and protein ligands will be characterized. Project 3 (S.C. bock, Serpin Structure and the Development of Neutrophil-Resistant Serpins) will focus on the structure-activity relationships with a naturally occurring anticoagulant serpin, antithrombin III, and will aim to develop recombinant serpins which are targeted tot he vessel wall to block the actions of thrombin and elastase locally. Core A (P.N. Walsh, Administrative Core) will provide fiscal oversight and clerical support. Core B (J.D. Lambris, Protein chemistry and Molecular Modeling Core Laboratory) will provide both technical support and advice on molecular modeling and rational synthetic peptide design and synthesis. All the investigators have plans for collaborative research with each of the other project leaders and will consult with and share intellectual and physical resources with the other project leaders. The information gained from these studies will make possible the rational development of therapeutic interventions designed to treat hemorrhagic syndromes or to inhibit or prevent thrombogenesis in blood vessels.
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