The objectives of this project are to investigate the molecular mechanisms through which the conditionally essential nutrient glutamine and the peptide growth factor IGF I (insulin-like growth factor 1) stimulate anabolic responses in cells and tissues. Previous work has demonstrated a nutritional requirement for the amino acid glutamine that develops in humans and experimental animals with catabolic disease states arising from such diverse etiologies as traumatic injury, infection, major operation, cancer chemotherapy, the short bowel syndrome, and malnutrition. Plasma concentrations of IGF I often are decreased in the same catabolic disease states that are characterized by a deficiency of glutamine, and recent studies have demonstrated anabolic tissue responses when IGF I is administered under these conditions. In preliminary studies, we have observed an additive or synergistic anabolic interaction when glutamine and IGF I are given in combination to experimental animals. The specific objectives of this project are to investigate the anabolic effects of glutamine and IGF I, their molecular mechanisms of action, and the underlying basis and significance of interactions between glutamine and IGF I. The experimental approach will involve studies on elements of the anabolic responses to glutamine and IGF I in laboratory rats following fasting, feeding with a low protein diet, or partial intestinal resection to create a model of the short bowel syndrome. Signalling events and regulatory molecules involved in the responses to IGF I and glutamine will be investigated with methods that use specific antibodies to assess tyrosine kinase activity, phosphatidylinositol 3-kinase activity, and the levels of signalling intermediates in animal tissues. Northern blotting and related methods will be used to study the expression of transcription activators and other regulatory molecules. Selected mRNA sequences that are modulated in response to glutamine and/or IGF I will be investigated using the recently developed method for differential-display of cDNA fragments following PCR amplification. These studies will increase our understanding of the fundamental mechanisms through which glutamine and IGF I produce anabolic effects in mammalian tissues. This information is essential for developing a rational approach to the use of glutamine- supplemented nutrition and IGF I, alone or in combination, in a broad spectrum of clinical disorders characterized by tissue catabolism and malnutrition.
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