At the site of vascular injury, platelet adhesion, activation, and aggregation culminate in thrombus information, the principle event underlying most acute arterial thromboocculsive disorders. Given that thrombosis is the leading cause of death world-wide, understanding the contribution of platelets to the process is of particular importance. Our novel observation of altered platelet thrombus formation in mice deficient in P-selectin serves as the basis of this proposal. Until recently, the primary function of P-selectin on activated platelets and endothelial cells was thought to be promotion of the initial interaction of these cells with leukocytes. However, P-selectin on activated endothelial cells was implicated in recruitment of platelets, and our observations suggest that the protein may also play a role in promoting platelet-platelet interactions. Thus, P-selectin and its ligand may be involved in promoting the interactions of platelets with leukocytes, endothelial cells, and with other platelets. This proposal will determine the role of platelet P-selectin in platelet-platelet interactions in vitro and platelet thrombus formation in vivo. This proposal tests the hypothesis that P-selectin on activated platelets interacts with a specific platelet counterreceptor and that this interaction affects platelet signaling and influences platelet-platelet interactions mediated by alpha Ilb,beta3. Complementary in vitro experiments will be conducted with human and mouse platelets, and mouse models of thrombosis will serve to define in vivo function of P-selectin.
The Specific Aims are to: (1) establish an in vitro assay of platelet adhesion to Pselectin to be used to identify the platelet counter-receptor(s) for P-selectin, (2) determine the role of P-selectin in platelet-platelet interactions in vitro, (3) determine the role of P-selectin in models of thrombosis, and (4) to delineate the contribution of platelet and endothelial P-selectin to thrombosis and the arterial response to injury. This work will identify a novel target for future antithrombotic strategies and challenge the assumption that the beneficial effects of P-selectin antagonists are exclusive to leukocytes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08HL070304-01
Application #
6475424
Study Section
Special Emphasis Panel (ZHL1-CSR-M (M1))
Program Officer
Mondoro, Traci
Project Start
2001-08-01
Project End
2006-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
1
Fiscal Year
2001
Total Cost
$124,539
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Smyth, Susan S (2010) Platelets unplugged: an ATVB special series focused on platelet biology. Arterioscler Thromb Vasc Biol 30:2339-40
Morris, A J; Panchatcharam, M; Cheng, H Y et al. (2009) Regulation of blood and vascular cell function by bioactive lysophospholipids. J Thromb Haemost 7 Suppl 1:38-43
Pamuklar, Zehra; Federico, Lorenzo; Liu, Shuying et al. (2009) Autotaxin/lysopholipase D and lysophosphatidic acid regulate murine hemostasis and thrombosis. J Biol Chem 284:7385-94
Panchatcharam, Manikandan; Miriyala, Sumitra; Yang, Fanmuyi et al. (2008) Lysophosphatidic acid receptors 1 and 2 play roles in regulation of vascular injury responses but not blood pressure. Circ Res 103:662-70
Pamuklar, Zehra; Lee, Jin Sun; Cheng, Hsin-Yuan et al. (2008) Individual heterogeneity in platelet response to lysophosphatidic acid: evidence for a novel inhibitory pathway. Arterioscler Thromb Vasc Biol 28:555-61
Evangelista, Virgilio; Pamuklar, Zehra; Piccoli, Antonio et al. (2007) Src family kinases mediate neutrophil adhesion to adherent platelets. Blood 109:2461-9
Barrick, Cordelia J; Rojas, Mauricio; Schoonhoven, Robert et al. (2007) Cardiac response to pressure overload in 129S1/SvImJ and C57BL/6J mice: temporal- and background-dependent development of concentric left ventricular hypertrophy. Am J Physiol Heart Circ Physiol 292:H2119-30
Matsuo, O; Lijnen, H R; Ueshima, S et al. (2007) A guide to murine fibrinolytic factor structure, function, assays, and genetic alterations. J Thromb Haemost 5:680-9
Dorsch, Michael P; Lee, Jin Sun; Lynch, Donald R et al. (2007) Aspirin resistance in patients with stable coronary artery disease with and without a history of myocardial infarction. Ann Pharmacother 41:737-41
Li, Guohong; Keenan, Alison C; Young, Justin C et al. (2007) Effects of unfractionated heparin and glycoprotein IIb/IIIa antagonists versus bivalirdin on myeloperoxidase release from neutrophils. Arterioscler Thromb Vasc Biol 27:1850-6

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