Despite decades of basic and clinical research, thrombosis, a consequence of perturbed hemostasis, remains the major cause of morbidity and mortality in the United States. The topic of this Program Project, currently in its twenty-fifth year, is the regulation of the hemostatic process. Regulated hemostasis insures that following vascular trauma, hemorrhage is rapidly quenched, but at the same time, the fluidity of the blood is maintained. It is clear that both hemostasis and thrombosis are dynamic processes, characterized by the sequential accumulation and removal of newly activated platelets and fibrin at sites of vascular damage. The overall goal of this Program Project is to discover ways in which the dynamic nature of hemostasis and thrombosis can be interrupted for therapeutic benefit. Because of the interests and expertise of the participants in the Program, its projects are focused primarily on platelets. The projects will address the remarkably rapid activation of quiescent platelets, the dynamic nature of platelet plugs, and the use of platelets for targeted drug delivery. The Program Project consists of four projects and one core unit, all based at the University of Pennsylvania. The goals of Project 1 entitled "Controlling allbps Function by Altering Its Energy Landscape," are to gain a thermodynamic understanding of allbps regulation and to use this understanding to develop novel allosteric modulators that attenuate allbpS function. Project 2, entitled "Platelet-Targeted Pro-Urokinase for Thrombolysis," will continue the development of PLT/uPA-T, focusing on its use in the treatment of deep venous thrombosis. PLT/uPA-T is designed to target nascent thrombi while sparing stable mature clots by tethering thrombin-activatab;e urokinase to platelets using single-chain variable region fragments (scFv) of anti-allbps monoclonal antibodies. Project 3, new to the Program Project, is entitled "Phosphatidylinositol Transfer Proteins &Platelet Biology" and addresses the role of Class I phosphatidylinositol transfer proteins in the synthesis of phosphoinositides by platelets. This is a novel topic not previously studied in the context of hemostasis and thrombosis. Project 4, entitled "Subcellular Mechanisms of Platelet Activation," will extend an ongoing project, merging new hypotheses about the platelet signaling network with new models of platelet activation in vivo. Studies will examine the structure of platelet thrombi by testing ideas about the development and contribution of a hierarchical thrombus structure, will consider how the platelet signaling network affects thrombus structure, and will study contact-dependent events arising from molecules present in the junctions between aggregating platelets. The four projects are supported by a single core unit that provides for the common administrative needs of the program.
Heart attack and stroke remain among the leading causes of morbidity and mortality in the United States. The formation of platelet thrombi at sites of vascular damage, such as that caused by atherosclerosis, is the usual precipitating event for both of these processes. The goal of this Program Project has been, and remains, to understand how platelet function is regulated in order to devise more efficacious and safer ways to attenuate platelet accumulation sites at vascular damage, preventing subsequent tissue ischemia.
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