The apparent inactivity of the hemostatic system under normal circumstances and its rapid mobilization during episodes of hemostatic stress indicates that it is tightly regulated. The objective of this Program Project is to study this regulation. Because hemostasis invovles an interplay between endothelial cells and circulating platelets, the Program Project will focus on the regulation of platelet and endothelial cell function. The Program Project consists of seven projects and three core units. Project 1 will use molecular genetic, biochemical, and ultrastructural techniques to define functional domains in the platelet membrane llb/llla heterodimer complex which contains the platelet fibrinogen receptor required for platelet aggregation. Project 2 will focus on the molecular biology of llb/llla, examining the organization of the genes for these proteins and determining the genetic mechanisms responsible for Glanzmann's thrombasthenia. Project 3 will investigate factors involved in the exposure of the fibrinogen receptor on activated platelets with emphasis on the specific role of guanine-nucleotide binding proteins. The nature of the fibrinogen binding site on llb/llla will be examined, as will clinical abnormalities of platelet activation abnormalities. Project 4 will study stimulus-response coupling in platelets through an examination of the role of guanine-nucleotide binding proteins, phosphoinositides, and calcium in this process. Project 5 will examine the molecular mechanisms of icosanoid production. These compounds are mediators of cellular activation in platelets and endothelial cells. Project 6 will examine the role of immune injury of vascular lining cells in abnormal regulation of hemostatsis. The effect of lupus inhibitors on endothelial cell and trophoblast function and the interaction of plasminogen activators and inhibitors with these cells will be studied. Project 7 will study of the structure and function of the platelet Fc(gamma) receptor to understand the mechanisms by which immune complexes activate platelets and shorten platelet survival. To support these projects, core units for cell culture and monoclonal antibody production, for molecular biology technology, and for administration will be established. Abnormalities in the regulation of hemostasis play an important role in the pathogenesis of processes such atherosclerotic vascular disease and arterial and venous thrombosis. Understanding these abnormalities may provide rational methods for the treatment of these dieases.
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