HUMAN ARGINASE AND ARGINASE DEFICIENCY

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This proposal focuses on the study and exploitation of the mouse knockout model for human arginase I (AI) deficiency and hyperargininemia, a condition which causes neurological and intellectual deterioration and which results in mental retardation. The model will be used to elucidate the function, regulation and evolution of the two arginase genes in man (AI and AII) and to elucidate the pathology and pathophysiology of AI deficiency. The long term goal is to devise strategies to replace arginase in these patients or otherwise mitigate the impact of the hyperargininemia. These will include gene therapy and induction of AII or "autoenzyme replacement therapy". The biochemistry, molecular biology, pathology of the AI-deficient hyperarginemic mouse after protecting it from hyperammonemia will be studied. Approaches used include: plasma and tissue amino acid measurement; enzyme assay; immunoprecipitation; immunohistochemistry; in situ hybridization; animal behavioral testing; and tissue culture. Studies will test two distinct hypotheses for the neurological damage in hyperargininemia, excess nitric oxide (NO) production and increased synthesis of the neurotransmitters, glutamate and/or gamma aminobutyric acid (GABA). The AI and AII knockout animals will e used to explore the role of the two arginases in inflammatory cells, prostate function and kidney biochemistry. Expression of one or the other arginase transgenes in different tissues will play a prominent role in these studies. This project exploits unique models, at a propitious time, in an ideal environment and with ideal collaborators, to study the effects of a metabolic disease that causes mental retardation, and its treatment by gene manipulation. Results from these studies should provide relevant to a larger number of disorders of this type.