Genetic defects in purine metabolism in humans result in serious metabolic disorders, often with tissue specific phenotypes. A particularly striking example of this is adenosine deaminase (ADA) deficiency, which results in impaired lymphoid development and a severe combined immunodeficiency (SCID). Hepatic dysfunction is also a recognized complication of ADA deficiency in humans. Efforts to understand the metabolic basis for the hepatic and lymphoid phenotypes that accompany ADA deficiency have been aided tremendously by the availability of genetically engineered mice that retain critical features of the enzyme deficiency in humans. Progress has been made in the last several years toward understanding the metabolic consequences of ADA deficiency, and the proposed research has the following specific aims: 1) to determine the metabolic basis for the hepatocellular impairment associated with ADA deficiency; 2) to identify metabolic and signaling pathways that are involved in the immune phenotype associated with ADA deficiency; 3) to genetically engineer mice that are born without ADA and to determine metabolic and physiological consequences; and 4) to identify additional tissue-specific regulatory elements associated with the murine ADA gene.
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