Hemostatic and thrombotic disorders are among the most common disease processes encountered in clinical medicine. Abnormalities in the activation of platelets and blood coagulation are critical events in the pathogenesis of these disorders. The objective of this SCOR Program is to further understanding of these events at the laboratory and clinical levels, with the goal of providing a rational basis for novel therapies. The SCOR Program is composed of five projects that examine the formation and stabilization of hemostatic plugs under normal and pathologic conditions. Project 1 examines the structural features of the GPllb-lla molecule involved in its activation by platelet agonists. The contribution of the cytoplasmic and transmembrane domains of GPiib and GPiia in GPiib- iiia activation will be studied, sites in the extracellular domain of GPiib-llla involved in ligand binding will be identified, and the role of GPiib cleavage in GPiib-illa function will be evaluated. Project 2 examines the role of pleckstrin and pleckstrin homology (PH) domains in intraplatelet signal transduction. Pleckstrin is the most prominent platelet substrate for protein kinase C. The structural features of pleckstrin involved its interaction with GTP binding proteins will be identified, as will functions that are independent of GTP binding proteins. Project 3 will compare the interaction of thromboxane A2 (TxA2) and 8-epi PGF2a with the native TxA2 receptor and a recently described carboxyl terminal splice variant of this receptor. The project will address differences in the affinities of these ligands for the receptors and differences in the consequences of ligand binding, such as receptor desensitization and the initiation of various signal transduction pathways. The goal of Project 4 is to define the molecular basis of heparin- associated thrombocytopenia (HAT). HAT, the most common cause of drug- induced thrombocytopenia, is unique because the interaction of anti-heparin antibodies with platelets results in platelet activation and thrombosis. The HAT antigen appears to consist of a heparin/platelet factor 4 (PF-4) complex. The molecular nature of this antigen will be studied, the ability of antigen/antibody complexes to bind to the platelet FcgammaRiiA receptor will be tested, and the molecular nature of the autoantibodies in HAT will be determined. The long term objective of Project 5 is to use gene therapy to correct the genetic defects responsible for hemophilia B. Various approaches to the stable expression of Factor IX (FIX) in hematopoietic cells using retroviral and adeno-associated viral vectors will be examined. FIX expression will then be assessed in long term human bone marrow cultures, in mice who have received transduced cells from syngeneic animals, and in a hemophilia B dog model. These projects will be supported by an Administrative Core to provide for the administrative and secretarial requirements of the SCOR Program.
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| Grosser, Tilo; Fries, Susanne; Lawson, John A et al. (2013) Drug resistance and pseudoresistance: an unintended consequence of enteric coating aspirin. Circulation 127:377-85 |
| Ricciotti, Emanuela; FitzGerald, Garret A (2011) Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol 31:986-1000 |
| Skarke, Carsten; FitzGerald, Garret A (2010) Training translators for smart drug discovery. Sci Transl Med 2:26cm12 |
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| Reilly, Dermot F; Curtis, Anne M; Cheng, Yan et al. (2008) Peripheral circadian clock rhythmicity is retained in the absence of adrenergic signaling. Arterioscler Thromb Vasc Biol 28:121-6 |
| Siegel, Don L (2008) Translational applications of antibody phage display. Immunol Res 42:118-31 |
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