The proposal is designed to provide the principal investigator, Dr. Zongdong Li with the necessary scientific experience to allow for a successful transition to an independent investigator. Dr. Li has been involved with research since he was an undergraduate student in China. He is currently working with Dr. Karpatkin on platelet research in the Hematology Division of the NYU Medical School. The Hematology Division has an outstanding research record. There is a wide range of research interests in the division. In addition to many seminar programs sponsored by the different departments in the NYU medical community, the Hematology Division sponsors weekly lecture series from a wide range of scientists with national reputations, and has an active journal club. During the proposed period of time, under the mentorship of Dr. Karpatkin, Dr. Li will devote 95% of his effort to research and will gain knowledge and techniques, which are necessary for becoming an independent investigator in platelet research. The research plan presented in this application builds on the observation that Dr. Li has made in Dr. Karpatkin's lab during the past year on the role of HIV molecular mimicry in HIV-1 related thrombocytopenia (HIV-1 ITP). HIV-1 ITP occurs in 15-60% of patients with AIDS, particularly in homosexuals and drug abusers. It is seen in about 10% of patients during the early stage of HIV infection. During the early stage of infection, HIV-1 ITP is strongly associated with a high affinity IgG1 polyclonal antibody against the platelet integrin subunit GPIIIa 49-66. This antibody induces thrombocytopenia in mice and correlates inversely with platelet count in HIV-1 ITP patients. The antibody has been shown to have the unique property of inducing platelet fragmentation by reactive oxygen species (ROS) in a complement-independent manner by the activation of a platelet NADPH oxidase. This proposal will explore: a. the mechanism of the generation of this antibody; b. the mechanism of platelet fragmentation induced by this antibody. This proposal will gain valuable knowledge about the mechanism of this disease, which could lead to new treatment for HIV-1 related thrombocytopenia. It will also provide a new insight into the mechanism of this novel and unique discovery of antibody-induced fragmentation of platelets via direct activation of platelet NADP Oxidase

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DA020816-02
Application #
7087061
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Khalsa, Jagjitsingh H
Project Start
2005-07-01
Project End
2010-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
2
Fiscal Year
2006
Total Cost
$163,571
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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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
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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
Zhang, Wei; Nardi, Michael A; Borkowsky, William et al. (2009) Role of molecular mimicry of hepatitis C virus protein with platelet GPIIIa in hepatitis C-related immunologic thrombocytopenia. Blood 113:4086-93
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
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