Support is requested to continue a program aimed at understanding fundamental aspects of hemostasis and thrombosis by defining key mechanisms that regulate thrombus formation in response to wounding or vascular disease. The proposed studies - which utilize reverse genetic, biochemical and structural approaches combined with ex vivo and in vivo videomicroscopy analyses of blood interaction with reactive surfaces under specified hemodynamic conditions - are designed to lead to new approaches for the diagnosis, treatment and prevention of thrombosis. The program will consist of four projects and two core units. Dr. Ruggeri will study the interplay of different constituents responsible for the variable thrombogenicity of extracellular matrices and cell surfaces exposed to flowing blood, and define the mechanisms that regulate the response of platelets to such diverse stimuli. Dr. Ginsberg will define the cellular and extracellular molecular associations and the signaling mechanisms that are responsible for the assembly of extracellular matrices. Dr. Ruf will focus on the modulation of tissue factor procoagulant and signaling activities and the role of these mechanisms in regulating the response to injury and the thrombogenicity of cellular and extracellular vascular surfaces. Dr. Griffin will explore the role of the protein C-dependent pathway in thrombotic and inflammatory processes, and define the bases for the use of recombinant activated protein C species as potential therapeutic agents. Core A will support ex vivo and in vivo models of hemostasis and thrombosis for use by all the projects, and core B will provide administrative support to facilitate the development of the specific aims of the program in a collegial environment. There will be strong interactions and synergy of efforts among all the projects, centered on multifaceted approaches to the study of what constitutes a thrombogenic surface and the mechanisms that initiate and regulate the response of platelets and the coagulation system to different vascular lesions.
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