The theme of this Program Project is the regulation of the hemostatic process. This regulation provides for the rapid and appropriate mobilization of hemostasis after vascular trauma, yet maintains the fluidity of the blood under normal circumstances. Furthermore, abnormalities in the regulation of hemostasis play an important role in the pathogenesis of disease processes such atherosclerotic vascular disease and arterial and venous thrombosis. Thus, understanding the basis for these abnormalities can provide rational methods for the treatment of these disease processes. Hemostasis involves an interplay between endothelial cells and circulating platelets. Therefore, the Program Project will continue to focus on the regulation of platelet and endothelial cell function. The Program Project consists of six projects and two core units. Project 1 will use molecular genetic, biochemical, and ultrastructural techniques to define functional domains in the platelet membrane GPIIb-IIIa heterodimer that contains the fibrinogen receptor required for platelet aggregation. Project 2 will study the molecular biology of GPIIb-IIIa, focusing on the organization of the GPIIb and GPIIIa genes and will continue to study the genetic mechanisms responsible for cases of Glanzmann's thrombasthenia. The basis for Project 3 is the observation that the GPIIb-Illa heterodimer can serve as conduit for the transmission of signals in and out of the platelet. Thus, studies in this project will focus on the mechanism and consequences of GPIIb-Illa activation. Project 4 will continue studies of the mechanism of platelet activation, focusing on the platelet thrombin receptor and its interaction with guanine nucleotide binding proteins. The molecular bases for signal termination, down-regulation, and internalization of the thrombin receptor will be examined. Project 5 will study the biology of the platelet Fc- gamma-Rll receptor, a membrane protein that binds the Fc portion of IgG in immune complexes resulting either in platelet activation or increased platelet clearance. Studies will examine regulation of the Fc-gamma-Rll receptor gene and signal transduction mediated by receptor occupation. Project 6 will examine the metabolism and carboxyl terminal processing of the endothelial cell urokinase-type plasminogen activator receptor (uPAR). This receptor regulates the activity of cell-associated urokinase-type plasminogen activator and is involved in processes such as cell migration and tissue repair. The six projects are supported by core facilities providing for cell culture and the production of monoclonal antibodies and for the overall administration of the Program.
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