The objective of this proposal is a comprehensive investigation leading to an understanding of those inherited metabolic diseases which have been called disorders of transport. The underlying approach continues to be the application of biochemical techniques to delinate the basic derangements of cellular function resulting from genetic abnormality phenotypically expressed as aminoaciduria, mellituria, and uricosuria. Various model systems ranging from the intact animals to isolated membranes will be employed. Those aspects to be examined are: 1) the basic molecular abnormality underlying human cystinuria by a multifaceted approach which characterizes cystine and dibasic amino acid transport in isolated intestinal and renal membranes and which examines physiological handling of these amino acids in intact cystinuric animals, the dog and the maned wolf; 2) developmental characteristics of amino acid, sugar, and urate transport, focusing on regulation and control; 3) the underlying defect responsible for the global dysfunction of transport called the Fanconi syndrome by utilizing the affected Basenji dog as a model; 4) the mechanisms of urate transport in isolated renal membranes with regard to the Fanconi syndrome, the Dalmatian dog syndrome, and hyperuricemia in man, and 5) the relation of membrane structure and function by dissembling the renal brushborder, analyzing its components and their contribution to the transport process, and then reconstituting the transport system by incorporating components into artificial proteoliposomes.
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