Epidemiological studies have shown that antioxidants play a role in the prevention of cardiovascular disease in humans and that dietary antioxidant consumption is inversely associated with the development of coronary artery disease. The precise mechanisms that underlie these observations, however, are not clear. While the beneficial effects of antioxidants have been attributed to the prevention of oxidative modification of low-density lipoprotein (LDL) and the inhibition of atherogenesis, other factors may also be important. Preliminary data presented in this application suggests that platelet function is dependent upon the balance between oxidative stress and antioxidant protection. In the first two years of this proposal, the applicant will study antioxidant biochemistry and free radical chemistry under the direction of Dr. Balz Frei, Ph.D., an established investigator in this field. The applicant will participate in successful research already in progress in Dr. Frei's laboratory and begin to specifically address the first aim of the proposal; namely, the effect of cytosolic antioxidant status on platelet function and the mechanisms responsible for any observed effects. In the latter three years the applicant will begin a period of independent investigation further examining the biochemical and molecular effects of antioxidants on platelet function with the sponsor of this proposal, Dr. Joseph Loscalzo, M.D., Ph.D. During this period, the applicant will: 1) characterize the role of membrane antioxidant status in modulating platelet function and 2) determine the in vivo relevance of these findings by studying an antioxidant-depleted or - supplemented animal model. The work contained in this proposal will provide new insights into the mechanism(s) by which antioxidants provide benefit for patients with vascular disease. The applicant's ultimate goal is to pursue the preliminary data presented in this application and develop an independent research program examining the interaction between cellular redox status, antioxidants, and vascular homeostasis.
