We have discovered a novel mechanism for platelet lysis and clearance in HIV-I-ITP patients, which is complement independent and induced by H202/free radicals. The Ab is directed against an immunodominant platelet GPIIla49-66 epitope and sequestered within serum immune complexes. Other Ab's against GPIIla do not have this effect. A rabbit Ab raised against GPIIla49-66 has the same effect. The mechanism of H202/free radical induction is via an apparent NADPH oxidase pathway in platelets since it is inoperative in NADPH oxidase deficient mice (p47phox(-/-) and gp91phox(-/-)) and dependent upon a functioning platelet 12-1ipoxygenase. I. Analyze the Presence of a Functioning NADPH Oxidase Pathway in Platelets. 2. Analyze the Mechanism of the Requirement of Platelet 12-Lipoxygenase for Ab-induced Platelet fragmentation. 3. Determine whether NADPH oxidase/ROS induced platelet fragmentation is a unique effect of anti- GPIIla49-66 Ab in HIV-I-ITP patients or a general mechanism for other platelet destructive disorders. 4. Determine whether anti-GPIIla49-66 is a result of molecular mimicry with antigen of infectious origin or its products.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL013336-33
Application #
7118014
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Ganguly, Pankaj
Project Start
1992-07-01
Project End
2008-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
33
Fiscal Year
2006
Total Cost
$330,057
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
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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
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Hu, Liang; Roth, Jennifer M; Brooks, Peter et al. (2008) Thrombin up-regulates cathepsin D which enhances angiogenesis, growth, and metastasis. Cancer Res 68:4666-73
Li, Zongdong; Nardi, Michael A; Wu, Jing et al. (2008) Platelet fragmentation requires a specific structural conformation of human monoclonal antibody against beta3 integrin. J Biol Chem 283:3224-30
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
Caunt, Maresa; Hu, Liang; Tang, Thomas et al. (2006) Growth-regulated oncogene is pivotal in thrombin-induced angiogenesis. Cancer Res 66:4125-32
Li, Zongdong; Nardi, Michael A; Karpatkin, Simon (2005) Role of molecular mimicry to HIV-1 peptides in HIV-1-related immunologic thrombocytopenia. Blood 106:572-6
Hu, Liang; Lee, Merlin; Campbell, Wendy et al. (2004) Role of endogenous thrombin in tumor implantation, seeding, and spontaneous metastasis. Blood 104:2746-51

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