Intestinal adaptation is the process of modulated cell proliferation and differentiation, resulting in growth of intestinal mucosa, to preserve or enhance digestive and absorptive capabilities during different physiological and pathophysiological circumstances. This proposal will test the hypothesis that intestinal adaptation is regulated by interactions among peptide hormones and growth factors produced locally in intestine, or in other tissues, in response to nutrients or other stimuli. Epidermal growth factor (EGF), products of intestinal proglucagon (enteroglucagon, glucagon-like peptides I and II (GLP-I and II), insulin-like growth factor I (IGF-I) and growth hormone GH will be the focus of study. Synthesis and/or serum levels of these peptides in will be assessed in intestine, liver, pancreas, submaxillary gland and kidney of three different models of adaptation. The time course, magnitude and cellular sites of regulated peptide synthesis or secretion will be tested for correlations with adaptive growth of small intestine. Models will include hyperplastic adaptation to small bowel resection, adaptation to mucosal injury by arabinofuranosyl-cytosine (ara-C) and adaptation to fasting and refeeding. Direct testing of putative trophic peptides alone or in combination, at doses observed during adaptation, will then establish their actions and interactions in regulating mucosal growth or the synthesis and secretion of other trophic peptides. Enteral nutrients are important for adaptive growth of the mucosa of the small intestine but the precise mechanisms by which they act are nor defined. Single nutrients will be given to rats after proximal small bowel resection via an intragastric cannula and the remainder of nutrient requirements will be given parenterally. The effects of specific intragastric nutrients on local production of specific trophic peptides and mucosal growth will be defined. Replacement of individual nutrients by the trophic peptide(s) they stimulate will then establish the extent to which the peptides mediate nutrient effects on adaptation. These studies will provide definitive information relevant to the optimal nutrient regime for recovery from small bowel surgery in humans and to the therapeutic benefits of trophic peptides for stimulating adaptive growth of small bowel. Completion of this proposed combination of (i) a molecular approach to study trophic peptide synthesis by Northern hybridization and at a cellular level by in situ hybridization histochemistry (ii) and endocrinologic approach using radioimmunoassay, immunocytochemistry and biological testing and (iii) a physiologic approach to study mucosal growth in different models, will have implications for future studies of the roles of the peptides studied herein, as well as other hormones and growth factors, in situations of normal and abnormal intestinal function.
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