Dr. May's laboratory is involved in three major areas involving antioxidant vitamins and micronutrients: the function of vitamin C in atherosclerosis; study of the role of vitamin C in protection against the oxidant stress of Alzheimer's disease, and study of the antioxidant interactions of selenium and vitamins C and E. Dr. May's research interests invove the antioxidant effects of vitamins C and E in a variety of cell and animal models. His laboratory has long been active in the study of how vitamin C is taken up, maintained in a reduced form, and how it protects cells against oxidant stress. In the last several years, the effort has targeted the early stages of atherosclerosis, especially related to endothelial dysfunction and the ability of the vitamin to enhance release and function of nitric oxide. More recently, efforts have turned to testing whether the vitamin also plays a role in inhibiting the atherosclerotic process in other cells, including macrophages and vascular smooth muscle cells. The central hypothesis in this work is that the vitamin C transporter is crucial for maintaining high intracellular concentrations of this vitamin. Other functions of vitamin C besides those related to antioxidant mechanisms are also explored, including its role in cell proliferation, differentiation, and collagen formation. Alzheimer's disease is associated with oxidant stress, and vitamin C has been implicated in clinical studies in protecting against this stress and in slowing progression of the disease. Studies are underway to assess the role of the vitamin in beta-amyloid secretion and action by cultured neuronal cells, and to asses whether dietary manipulation with vitamin C in normal mice and mice unable to synthesize the vitamin can slow the progression of the behavioral changes seen in animals transgenic for amyloid precursor protein and presenilin 1. Both of these proteins are implicated in many patients with Alzheimer's disease. Selenium is a co-factor for several enzymes with antioxidant function, including glutathione peroxidase and thioredoxin reductase. Dr. May's laboratory showed that the latter enzyme can reduce the oxidized forms of vitamin C back to the reduced form. The ability of this selenoenzyme to recycle vitamin C may provide a missing link between the known ability of vitamin E or selenium to mitigate a deficiency in the other. In cultured cells and in guinea pigs (which can be made deficient in all three factors), studies are underway of the interactions between these factors with regard to cellular metabolism and lipid peroxidation. The approaches used in these studies include HPLC assays of antioxidants, enzyme assays, and assays of lipid peroxidation.