The hemostatic process is precisely regulated to insure the rapid and appropriate mobilization of hemostasis after vascular trauma. Conversely, inappropriate activation of otherwise normal hemostasis plays an important role in the pathogenesis of atherosclerotic vascular disease and arterial and venous thrombosis. Essential features of hemostatic regulation are control of the interplay between circulating platelets and the interplay between circulating platelets and the endothelial lining of blood vessels. Because of the interests and expertise of the participants in this Program, its projects are focused on the regulation of platelet function. The Program Project consists of five projects and one core unit. Project 1 will use molecular genetic, biochemical, and biophysical techniques to correlate the structure and function of the major platelet integrin ?IIb??. On the basis of discoveries made the last funding period, studies will focus on the transmembrane domain interactions that appear to regulate the function of this integrin. Project 2 will continue studies of the biology of megakaryocyte development, focused on the observation that the platelet specific chemokine platelet factor 4 is a negative paracrine regulator of megakaryocyte development in vivo. Project 3 will continue studies of intracellular signaling pathways that contribute to actin dynamics in platelets and other cells. Proposed studies will focus on two critical aspects of platelet actin dynamics, phospholipid signaling and post-translational actin modification. Project 4 will identify and characterize molecules on the platelet surface that participate in contactdependent signaling at the junctions between activated platelets. The hypothesis to be tested is that although these molecules promote thrombus growth and stability, but they also function to place limits thrombus growth to avoid vascular occlusion. Project 5 will continue to study the molecular mechanisms underlying platelet Fc? receptor biology. Studies will examine platelet signaling responses to immune complex/Fc?RIIA interactions, focusing on the tyrosine kinase syk and the cbl family of adaptors/E3 ubiquitin ligases, and will make use of unique transgenic and knockout mouse lines. The five projects are supported by a single core unit that provides for common program needs including the continuing supply of essential monoclonal antibodies and for program administration.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Link, Rebecca P
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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Tomaiuolo, Maurizio; Stalker, Timothy J; Welsh, John D et al. (2014) A systems approach to hemostasis: 2. Computational analysis of molecular transport in the thrombus microenvironment. Blood 124:1816-23
Welsh, John D; Stalker, Timothy J; Voronov, Roman et al. (2014) A systems approach to hemostasis: 1. The interdependence of thrombus architecture and agonist movements in the gaps between platelets. Blood 124:1808-15
Lian, Lurong; Suzuki, Aae; Hayes, Vincent et al. (2014) Loss of ATE1-mediated arginylation leads to impaired platelet myosin phosphorylation, clot retraction, and in vivo thrombosis formation. Haematologica 99:554-60
Stalker, Timothy J; Welsh, John D; Tomaiuolo, Maurizio et al. (2014) A systems approach to hemostasis: 3. Thrombus consolidation regulates intrathrombus solute transport and local thrombin activity. Blood 124:1824-31
Stalker, Timothy J; Welsh, John D; Brass, Lawrence F (2014) Shaping the platelet response to vascular injury. Curr Opin Hematol 21:410-7
Kowalska, M Anna; Zhao, Guohua; Zhai, Li et al. (2014) Modulation of protein C activation by histones, platelet factor 4, and heparinoids: new insights into activated protein C formation. Arterioscler Thromb Vasc Biol 34:120-6
Min, Sang H; Suzuki, Aae; Stalker, Timothy J et al. (2014) Loss of PIKfyve in platelets causes a lysosomal disease leading to inflammation and thrombosis in mice. Nat Commun 5:4691
Brass, Lawrence F; Tomaiuolo, Maurizio; Stalker, Timothy J (2013) Harnessing the platelet signaling network to produce an optimal hemostatic response. Hematol Oncol Clin North Am 27:381-409
Lu, Qiongyu; Dong, Ningzheng; Wang, Qi et al. (2013) Increased levels of plasma soluble Sema4D in patients with heart failure. PLoS One 8:e64265
Stalker, Timothy J; Traxler, Elizabeth A; Wu, Jie et al. (2013) Hierarchical organization in the hemostatic response and its relationship to the platelet-signaling network. Blood 121:1875-85

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