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
