Engineering glutamate metabolism

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DESCRIPTION (provided by applicant): The aim of this work is to produce a transgenic mouse model to study the role of glutamate availability in the regulation of nitrogen partitioning within the body. Glutamate makes up to 10-15% of dietary protein but most ingested glutamate is metabolized by the enterocytes of the small intestine. However, glutamate plays a major role in nitrogen metabolism within the body and, in skeletal muscle, is the direct precursor of glutamine which is utilized by a number of tissues (intestinal mucosa, liver, kidneys and immune cells) particularly in catabolic states. Supplemental glutamine is increasingly being given to a variety of patients, most notably those with impaired digestive function and/or muscle wasting. Since glutamine is synthesized from amino acids derived from muscle protein breakdown the rationale for glutamine supplementation is that it will decrease endogenous glutamine synthesis and thereby maintain muscle mass. In addition to glutamine, skeletal muscle also shows net production of alanine and ammonia but little is known about the regulation of this process. There is evidence that intracellular glutamate is limiting for glutamine synthesis in catabolic states and this work will test the hypothesis that glutamate availability is a prime determinant in the partitioning of nitrogen into glutamine, alanine and ammonia. A transgenic mouse model expressing glutamate dehydrogenase in skeletal muscle will be developed which will enable us to manipulate intramuscular glutamate levels through dietary means. We hypothesize that changing intramuscular glutamate content will change the ratio of glutamine, alanine and ammonia synthesized and released by this tissue in response to dietary amino acids and catabolic stress. The long term goals of the work are to formulate optimal delivery of amino acids and protein to enhance protein accretion and limit protein wasting in the treatment, and prevention, of disease.