The hemostatic process is precisely regulated to insure the rapid and appropriate mobilization of hemostasis after vascular trauma. Conversely, inappropriate activation of otherwise normal hemostasis plays an important role in the pathogenesis of atherosclerotic vascular disease and arterial and venous thrombosis. Essential features of hemostatic regulation are control of the interplay between circulating platelets and the interplay between circulating platelets and the endothelial lining of blood vessels. Because of the interests and expertise of the participants in this Program, its projects are focused on the regulation of platelet function. The Program Project consists of five projects and one core unit. Project 1 will use molecular genetic, biochemical, and biophysical techniques to correlate the structure and function of the major platelet integrin ?IIb??. On the basis of discoveries made the last funding period, studies will focus on the transmembrane domain interactions that appear to regulate the function of this integrin. Project 2 will continue studies of the biology of megakaryocyte development, focused on the observation that the platelet specific chemokine platelet factor 4 is a negative paracrine regulator of megakaryocyte development in vivo. Project 3 will continue studies of intracellular signaling pathways that contribute to actin dynamics in platelets and other cells. Proposed studies will focus on two critical aspects of platelet actin dynamics, phospholipid signaling and post-translational actin modification. Project 4 will identify and characterize molecules on the platelet surface that participate in contactdependent signaling at the junctions between activated platelets. The hypothesis to be tested is that although these molecules promote thrombus growth and stability, but they also function to place limits thrombus growth to avoid vascular occlusion. Project 5 will continue to study the molecular mechanisms underlying platelet Fc? receptor biology. Studies will examine platelet signaling responses to immune complex/Fc?RIIA interactions, focusing on the tyrosine kinase syk and the cbl family of adaptors/E3 ubiquitin ligases, and will make use of unique transgenic and knockout mouse lines. The five projects are supported by a single core unit that provides for common program needs including the continuing supply of essential monoclonal antibodies and for program administration.
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