Abstract

Little is known of the adhesive interactions between platelets, leukocytes, and endothelial cells, interactions that are involved in the processes of inflammation, atherogenesis, and thrombosis. The PI has identified specific interactions between the platelet gpIb-IX-V complex and members of the selectin and leukocyte integrin families. Each of these interactions is mediated by the gpIb-alpha. The hypothesis that drives this application is that the interaction of gpIb on resting platelets with P-selectin on activated platelets is involved in growth of thrombi and in promoting platelet aggregation by acting synergistically with subthreshold concentrations of platelet agonists. Leukocytes interact with the surfaces of adherent platelets by attachment, rolling, firm adhesion and migration through the surface. L selectin and Mac-1 have been identified as leukocyte receptors for these events, but the platelet counter-receptors have not yet been identified. Preliminary data from the PI indicates that the gpIb complex is a likely candidate counter-receptor for both rolling and firm adhesion. The experiments proposed in this application will test these hypotheses in model systems and in vivo and will characterize in detail the interactions between gpIb and P-selectin, L-selectin, and Mac-1.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL064796-04
Application #
6638637
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Ganguly, Pankaj
Project Start
2000-05-01
Project End
2005-04-30
Budget Start
2003-06-16
Budget End
2004-04-30
Support Year
4
Fiscal Year
2003
Total Cost
$373,750
Indirect Cost

  Institution

Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030

  Publications

Del Conde, I; Bharwani, L D; Dietzen, D J et al. (2007) Microvesicle-associated tissue factor and Trousseau's syndrome. J Thromb Haemost 5:70-4
Chen, Junmei; Lopez, Jose A (2005) Interactions of platelets with subendothelium and endothelium. Microcirculation 12:235-46
Tao, Zhenyin; Wang, Yongtao; Choi, Huiwei et al. (2005) Cleavage of ultralarge multimers of von Willebrand factor by C-terminal-truncated mutants of ADAMTS-13 under flow. Blood 106:141-3
Wang, Yunmei; Sakuma, Masashi; Chen, Zhiping et al. (2005) Leukocyte engagement of platelet glycoprotein Ibalpha via the integrin Mac-1 is critical for the biological response to vascular injury. Circulation 112:2993-3000
Del Conde, Ian; Cruz, Miguel A; Zhang, Hui et al. (2005) Platelet activation leads to activation and propagation of the complement system. J Exp Med 201:871-9
Peng, Yuandong; Berndt, Michael C; Cruz, Miguel A et al. (2004) The alpha1 helix-beta13 strand spanning Leu214 to Val229 of platelet glycoprotein Ibalpha facilitates the interaction with von Willebrand factor: evidence from characterization of the epitope of monoclonal antibody AP1. Blood 104:3971-8
Ehlers, Raila; Ustinov, Valentin; Chen, Zhiping et al. (2003) Targeting platelet-leukocyte interactions: identification of the integrin Mac-1 binding site for the platelet counter receptor glycoprotein Ibalpha. J Exp Med 198:1077-88
Baglia, Frank A; Shrimpton, Corie N; Lopez, Jose A et al. (2003) The glycoprotein Ib-IX-V complex mediates localization of factor XI to lipid rafts on the platelet membrane. J Biol Chem 278:21744-50
Dong, Jing-fei; Moake, Joel L; Nolasco, Leticia et al. (2002) ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions. Blood 100:4033-9
Baglia, Frank A; Badellino, Karen O; Li, Chester Q et al. (2002) Factor XI binding to the platelet glycoprotein Ib-IX-V complex promotes factor XI activation by thrombin. J Biol Chem 277:1662-8

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