SURGICAL STUDIES ON METABOLISM OF GI HORMONES

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The aim of studies in this proposal is to provide new information regarding the central hypothesis that alterations in metabolism of gut hormones are reflected in changes of gut function. To achieve this end, there are three specific aims. The first specific aim is to study the role of interactions of the immune system and gastrin on ulcerogenesis and carcinogenesis. This aim has three hypotheses: a) that the immune system exerts an inhibitory influence over gastric secretion, b) that in some instances, hypergastrinemia results in a protective action that guards against ulcerogenesis, and c) that hypergastrinemia may facilitate carcinogenesis of the colon. To explore these hypotheses, we plan three general avenues of study: a) to study the role of the immune system in gastric secretion, b) to study possible mechanisms that protect against ulcerogenesis during hypergastrinemia, and c) to study the influence of hypergastrinemia on chemically-induced carcinogenesis of the colon. The second specific aim is to determine the role of gastrointestinal (GI) hormones on pancreatic exocrine and endocrine secretion, pancreatic inflammation, and regeneration of the pancreas in experimental pancreatitis. There are two hypotheses in this aim: a) that pancreatic endocrine and exocrine secretions are normally submaximal because cholecystokinin, secretin and other GI hormones are released and interact at submaximal levels, and b) the secretory status of the pancreas, as influenced by CCK and other GI hormones, influences the prognosis of acute pancreatitis. In order to evaluate these hypotheses, we plan three courses of study: a) to determine the interactions of endogenous CCK and secretin (and related peptide) in vivo and in vitro on pancreatic exocrine and endocrine secretions, b) to study the role of GI hormones in experimental pancreatitis and c) to study the role of GI hormones in pancreatic recovery from pancreatitis. The third specific aim is to determine the role of GI hormones in adaptive hyperplasia of the gut. The hypothesis related to this theme is that hormonal regulation plays a significant role in the mucosal adaptation that follows ileojejunal transposition (IJT) and small bowel resection (SBR). To test this hypothesis, we plan five groups of experiments that are designed to: a) determine the effects of both IJT and SBR on basal and stimulated plasmal levels of neurotensin (NT) and CCK, b) determine the effects of IJT and SBR on mucosal levels of NT and CCK, c) examine steady-state mucosal levels on NT and CCK mRNA after IJT and SBR, d) determine the spatial distribution on NT and CC mRNA and peptide in gut mucosal by in situ hybridization and immunocytochemistry, and e) determine whether increases in steady-state mRNA levels of NT and CCK are associated with changes in rates of transcription. The relation to health of this grant lies in the potential of determining new information regarding firstly, mechanisms of stimulation of acid secretion from the stomach (important in peptic ulcer disease) and in the induction and stimulation of growth of cancer of the gut, secondly, new understanding of the physiology of pancreatic secretion, the role of hormonal stimulation in pancreatitis and factors influencing regeneration after pancreatitis, and thirdly, understanding the role of GI hormones in the hyperplasia of gut mucosa that follows research and transposition (understanding mechanisms of mucosal hyperplasia may provide important information regarding ultimate development of gut cancer).