Regulation of Stomach Ghrelin

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DESCRIPTION (provided by applicant): Our long-term working hypothesis is that the recently discovered stomach hormone, ghrelin, is a critical signal of nutritional status to the growth hormone (GH) neuroendocrine axis serving to integrate energy balance and the growth process. The primary goal of this research is to define physiological and molecular mechanisms underlying the regulation of stomach ghrelin production, secretion and action. Preliminary Findings demonstrate that stomach ghrelin expression and secretion are regulated by dietary and gastrointestinal and pancreatic hormonal manipulations, and that there is a stomach ghrelin-pituitary GH axis. Our Specific Aims are: Aim 1. To test the hypotheses that stomach ghrelin plays a role in the regulation of pituitary GH secretion; that a bi-directional feedback loop exists 3etween pituitary GH and stomach ghrelin secretion; that the stimulatory action of ghrelin on GH secretion is modulated by dietary intake; and that vagal capsaicin sensitive fibers participate in ghrelin secretion and ghrelin-activated GH secretion. Aim 2. To test the hypothesis that stomach ghrelin homeostasis is regulated by cholecystokinin (CCK), glucagon and insulin-like growth factor-1 (IGF-I). Aim 3. To characterize the regulatory elements of the rat and human ghrelin genes and to test the hypotheses that regulatory elements are responsive to GH, glucagon and nutrients. Based upon Preliminary Findings we expect to demonstrate that endogenous stomach ghrelin participates in the regulation of GH secretion, that GH exerts a feedback action on stomach ghrelin secretion and that this ghrelin-GH axis is modulated by dietary intake; that ghrelin homeostasis is regulated by CCK, glucagon and IGF-I; and, that the promoter activity (ie, ghrelin production) of the ghrelin gene is regulated by GH, glucagon and nutrients. Nutritional status is critical in predicting survival in a variety of catabolic diseases and Lrauma. This research is significant because our studies will elucidate physiological and molecular mechanisms behind regulation of GH secretion by ghrelin and will open up new therapeutic strategies for treatment of diseases in which weight loss or gain plays a critical role. This is a compelling reason to define nutritional regulation of ghrelin production and secretion and its role in regulation of GH secretion.