SURGICAL STUDIES ON METABOLISM OF GI HORMONES

本提案中的研究旨在提供新的信息， 关于肠道代谢的改变 激素反映在肠道功能的变化上。 为了达到这个目的， 具体目标有三个。 第一个具体目标是研究 免疫系统和胃泌素的相互作用在溃疡形成中的作用 和致癌作用。 这一目标有三个假设：a）免疫 系统对胃分泌产生抑制影响，B）在 在某些情况下，高胃泌素血症导致保护作用， 防止溃疡形成，和c）高胃泌素血症可能促进 结肠癌的发生。 为了探索这些假设，我们计划三个 研究的一般途径：a）研究免疫系统的作用， 胃分泌，B）研究可能的机制，防止 高胃泌素血症期间的溃疡形成，和c）研究 高胃泌素血症对化学诱导的结肠癌发生的影响。 的 第二个具体目标是确定胃肠道（GI）的作用 激素对胰腺外分泌和内分泌的影响，胰腺 炎症和再生的胰腺在实验 胰腺炎 有两个假设在这个目的：a）胰腺， 内分泌和外分泌通常是次最大的， 胆囊收缩素、胰泌素和其他胃肠道激素被释放并相互作用 在次最大水平，和B）胰腺的分泌状态，如 CCK和其他胃肠激素的影响，影响预后 急性胰腺炎 为了评估这些假设，我们计划三个 研究过程：a）确定内源性CCK和 胰泌素（及其相关肽）在体内和体外对胰腺 外分泌和内分泌，B）研究胃肠激素的作用 在实验性胰腺炎和c）研究胃肠道激素的作用， 胰腺炎的胰腺恢复 第三个具体目标是 确定胃肠激素在肠道适应性增生中的作用。 与此相关的假设是，激素调节在 在回肠空肠后的粘膜适应中起重要作用， 移位术（IJT）和小肠切除术（SBR）。 为了验证这一 假设，我们计划五组实验，旨在：a） 确定IJT和SBR对基础和刺激血浆的影响， 神经降压素（NT）和CCK的水平，B）决定IJT的作用， SBR对NT和CCK的粘膜水平的影响， IJT和SBR后NT和CCK mRNA水平，d）确定空间 原位法研究NT和CC mRNA及肽在肠粘膜中的分布 杂交和免疫细胞化学，和e）确定是否增加 在稳定状态下，NT和CCK的mRNA水平与 转录率。 这项补助金与健康的关系在于 确定新信息的可能性，首先，机制 刺激胃酸分泌（对消化性疾病很重要） 溃疡病）以及诱导和刺激癌症生长 第二，对胰腺的生理学有了新的认识， 分泌，激素刺激在胰腺炎中的作用和因素 影响胰腺炎后的再生，第三，了解 胃肠道激素在以下肠粘膜增生中的作用 研究和换位（了解粘膜的机制 增生可以提供关于最终的 肠道癌的发展）。

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).