The hemostatic process is precisely regulated to insure the rapid and appropriate mobilization of hemostasis after vascular trauma. On the other hand, inappropriate activation of otherwise normal hemostasis plays an important role in the pathogenesis of atherosclerotic vascular disease and arterial and venous thrombosis. Because hemostasis involves an interplay between platelets and endothelial cells, the focus of this Program Project is the regulation of platelet and endothelial cell function. The Program Project consists of five projects and two core units. Bennett will use molecular genetic, biochemical, and biophysical techniques to correlate the structure and function of the platelet fibrinogen receptor, GPIIb-IIIa. Ponoz will continue studies of the molecular biology of GPIIb-IIIa, focusing on the regulation of GPIIb gene expression. Studies to identify Iigand binding and subunit interaction sites using cultured cells and transgenic animals wilt be performed in collaboration with Bennett. Abrams will use in vitro and in vivo models to study the agonist-initiated signaling pathways that lead to platelet actin assembly and shape change. Brass will continue studies of the molecular basis for platelet activation, focusing on Eph kinases. Preliminary experiments indicate that Eph kinases, a family of cell surface receptor tyrosine kinases, promote platelet adhesion via signaling complexes containing Src family members and the cell adhesion molecule L1. Schreiber will generate platelet-specific and macrophage-specific FcgammaRIIA transgenic mice to study the role of platelet vs macrophage FcgammaRIIA in immune clearance and immune complex endocytosis in vivo. The role for the signaling molecule Cbl, likely important in platelet FcgammaRIIA immune clearance, will also be studied, as will the regulation of expression of platelet FcgammaRIIA. The five projects are supported by core facilities for the production of monoclonal antibodies and for the overall administration of the Program.
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