This is a competing continuation study of the medical consequences of HIV infection in drug abusers and homosexuals co-infected with HIV-1. Thrombocytopenia is a frequent occurrence in HIV-1 infected intravenous drug abusers (HIV-1-IIP). We have discovered a unique Ab in these patients which is capable of inducing platelet fragmentation and destruction in the absence of complement via the elaboration of H2O2 and other reactive oxygen species (ROS). This Ab is directed against a specific epitope of the platelet B3 integrin, GPIIIa49-66 and induces its effect through activation of platelet NADPH oxidase and platelet 12-lipoxygenase. The oxidative fragmentation of platelets requires Ca++ and Protein Kinase C activation, indicating a role for intracellular signaling. The physiologic requirement for this mechanism is yet to be determined. Cross-talk between platelet ROS and endothelial cells or other cells after platelet GPIIIa49-66 perturbation is a distinct possibility. Since patients with HIV-1-ITP respond to glucocorticoids as do classic autoimmune thrombocytopenic patients (whose platelets undergo Ab-opsonized phagocytosis by macrophages), we looked for the effect of glucocorticoids (Dexamethasone) on this new mechanism of Ab-induced platelet oxidation/fragmentation. Dexamethasone inhibits this effect as well. We therefore, propose to study the mechanisms of this disorder by: 1. Elucidating the signaling pathways involved in Ab-induced platelet oxidation/fragmentation. 2. Elucidating the mechanism of dexamethasone-induced inhibition of Ab-induced platelet oxidation/fragmentation. 3. Exploring the effect of anti-GPIIIa49-66 Ab on megakaryocyte production. 4. Exploring the possible pathophysiologic role of platelet cross-talk with other cells (endothelial, fibroblast, neutrophil, and macrophage) by a cell peptide reacting with platelet GPIIIa49-66 to release ROS capable of activating these cells.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA004315-21
Application #
7281723
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Khalsa, Jagjitsingh H
Project Start
1986-09-30
Project End
2010-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
21
Fiscal Year
2007
Total Cost
$400,606
Indirect Cost
Name
New York University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Wang, Jianhui; Zhang, Wei; Yi, Zanhua et al. (2012) Identification of a thrombin cleavage site and a short form of ADAMTS-18. Biochem Biophys Res Commun 419:692-7
Pan, Ruimin; Wang, Jianhui; Nardi, Michael A et al. (2011) The inhibition effect of anti-GPIIIa49-66 antibody on megakaryocyte differentiation. Thromb Haemost 106:484-90
Wang, Jianhui; Yi, Zanhua; Wang, Shiyang et al. (2011) The effect of decitabine on megakaryocyte maturation and platelet release. Thromb Haemost 106:337-43
Dang, Suying; Hong, Tao; Wisniewski, Thomas et al. (2011) Dissolution of pre-existing platelet thrombus by synergistic administration of low concentrations of bifunctional antibodies against ?3 integrin. PLoS One 6:e27012
Wang, J; Zhang, W; Nardi, M A et al. (2011) HIV-1 Tat-induced platelet activation and release of CD154 contribute to HIV-1-associated autoimmune thrombocytopenia. J Thromb Haemost 9:562-73
Zhang, Wei; Li, Yong-Sheng; Nardi, Michael A et al. (2010) Dissolution of arterial platelet thrombi in vivo with a bifunctional platelet GPIIIa49-66 ligand which specifically targets the platelet thrombus. Blood 116:2336-44
Zhang, Wei; Dang, Suying; Wang, Jianhui et al. (2010) Specific cross-reaction of anti-dsDNA antibody with platelet integrin GPIIIa49-66. Autoimmunity 43:682-9
Li, Zongdong; Nardi, Michael A; Li, Yong-Sheng et al. (2009) C-terminal ADAMTS-18 fragment induces oxidative platelet fragmentation, dissolves platelet aggregates, and protects against carotid artery occlusion and cerebral stroke. Blood 113:6051-60
Hu, Liang; Ibrahim, Sherif; Liu, Cynthia et al. (2009) Thrombin induces tumor cell cycle activation and spontaneous growth by down-regulation of p27Kip1, in association with the up-regulation of Skp2 and MiR-222. Cancer Res 69:3374-81
Nardi, Michael A; Gor, Yelena; Feinmark, Steven J et al. (2007) Platelet particle formation by anti GPIIIa49-66 Ab, Ca2+ ionophore A23187, and phorbol myristate acetate is induced by reactive oxygen species and inhibited by dexamethasone blockade of platelet phospholipase A2, 12-lipoxygenase, and NADPH oxidase. Blood 110:1989-96

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