This Program Project brings together six investigators at the University of Pennsylvania and Children's Hospital of Philadelphia who share related interests and provides a unified focus on the 4-dimensional regulation of hemostasis and thrombosis. The overall goal of our Program is to understand how spatially restricted events are integrated into an effective but regulated hemostatic response. This Program consists of five projects, an Imaging Core and an Administrative Core. Each project in the Program takes advantage of recent advances in technology and will utilize state-of-the-art ex vivo and in vivo model systems facilitated by the Scientific Core. This Program will provide a comprehensive description of hemostasis from its initiation at the sites of vascular injury to the formation of stable platelet plugs and thrombi, ad the resultant inflammatory response. The Investigators in the Program have a strong history of productive interaction. Together, the Projects treat hemostasis as a continuum instead of a series of discrete events simply delimited by individual scientific interests. Consequently, the proposed work will contribute to the goals of the program in a synergistic rather than additive way. Project 1 will use novel fluorescent probes designed to image the reactions of coagulation in vivo at the site of the growing thrombus under real-time. Project 2 will analyze an unusual type of platelet-mediated hemostasis at the lympho-venous junction that is stimulated by PDPN-CLEC2 interaction. Project 3 will take a mouse genetics and computation biology approach to determine the influence of the microenvironment and platelet packing density on thrombus growth. Project 4 will test the innovative hypothesis that two inter-convertible conformations of the platelet integrin IIb3 differ in their affinity for fibrinogen and in the mechanical stabilit of the complexes they form with fibrinogen. Project 5 will define the spatially restricted signaling cascades within discrete microdomains that contribute to the synthesis of phosphorylated phosphatidylinositols (phosphoinositides) in platelets. Although the projects address different facets of platelet and coagulation function, taken together within the context of the Program, they will provide an integrated picture of regulated hemostatic function.
Platelet and coagulation factors play a key role in the pathogenesis of atherosclerosis as well as arterial thrombosis leading to acute myocardial infarction, the most common cause of morbidity and mortality in the US. This proposal is aimed to enhance our understanding of mechanisms by which platelets and coagulation factors interact with other components of the blood stream to contribute to inappropriate clot formations.
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