The recent epidemic of acquired immunodeficiency syndrome has made it crucially important to elucidate the metabolic factors that influence T lymphocyte senescence in humans, and to determine how they are altered in pathologic states. These are the long-term objectives of the present grant application. With the previous support of the research grant, this laboratory has studied in detail an """"""""experiment of nature"""""""", adenosine deaminase deficiency, which also produces selective attrition of T lymphocytes. The results of our investigations suggest that normal T cells have a tightly regulated """"""""programmed cell death"""""""" mechanisms, which links DNA integrity to adenine nucleotide metabolism via the action of the chromatin-bound enzyme poly(ADP-ribose) synthetase. In adenosine deaminase deficient children, the accumulation of dATP in T cells triggers the suicide pathway and leads to cells lysis. Exposure of lymphocytes to reactive oxygen species causes lymphocyte dysfunction via the same mechanism. The renewal application aims to analyze the individual metabolic components of the programmed cell death pathway in T lymphocytes, emphasizing the factors that control DNA strand break formation and repair, the regulation of poly(ADP-ribose) synthetase, and the coordination of NAD+ and ATP synthesis and catabolism. Additional experiments will determine how these parameters are changed by exposure of the cells to deoxyadenosine and toxic oxygen species, and most importantly, by infection with human immunodeficiency virus (HIV). Related techniques will be used to analyze lymphocytes from patients with acquired immunodeficiency syndrome, as well as cells from a recently discovered group of patients with high titers of autoantibodies to poly(ADP-ribose) synthetase. Based upon the results, strategies will be pursued to modify pharmacologically the programmed cell death pathway in vitro, and eventually in vivo.
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