SURGICAL STUDIES ON METABOLISM OF GI HORMONES

这项建议的研究目的是提供新的信息 关于肠道新陈代谢改变的中心假说 荷尔蒙反映在肠道功能的变化上。为了实现这一目标， 有三个具体目标。第一个具体目标是研究 免疫系统与胃泌素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 系统对胃分泌有抑制作用，b)在 在某些情况下，高胃泌素血症会导致一种保护作用， 防止溃疡形成，以及c)高胃泌素血症可促进 结肠癌的发生。为了探索这些假设，我们计划了三个 研究的一般途径：a)研究免疫系统在 胃分泌物，b)研究可能的机制，以防止 高胃泌素血症时溃疡的发生，以及c)研究补肾活血方对胃溃疡的影响。 高胃泌素血症对化学诱导的结肠癌变的影响。这个 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 实验性胰腺的炎症和再生 胰腺炎。在这个目标中有两个假设：a)胰腺 内分泌和外分泌的分泌量通常是次最大的，因为 缩胆囊素、促胰液素和其他胃肠道激素释放并相互作用 在次最大水平，以及b)胰腺的分泌状态，如 受CCK等胃肠激素的影响，影响预后 急性胰腺炎。为了评估这些假设，我们计划了三个 研究课程：a)确定内源性CCK和 胰腺促胰液素(及相关多肽)的体内外研究 外分泌和内分泌分泌，b)研究胃肠激素的作用 C)研究胃肠激素在实验性胰腺炎中的作用。 胰腺从胰腺炎中恢复。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。 与这一主题相关的假设是荷尔蒙调节起作用 在回肠空肠黏膜适应中的重要作用 移位术(IJT)和小肠切除术(SBR)。为了测试这一点 假设，我们计划五组实验，旨在：a) 测定IJT和SBR对基础血浆和刺激血浆的影响 神经降压素(NT)和CCK，b)的水平决定了IJT和 SBR对粘膜NT和CCK水平的影响，c)检测稳态粘膜 IJT和SBR后NT和CCK mRNA水平决定空间 肠粘膜NT和CC基因及多肽的原位分布 杂交和免疫细胞化学，以及e)确定是否增加 在稳态中，NT和CCK的mRNA水平与血管内皮细胞的变化有关 转录速度。这项资助与健康的关系在于 确定关于第一个机制的新信息的可能性 刺激胃酸分泌(在消化性疾病中很重要 溃疡疾病)以及癌症的诱导和刺激生长 第二，对胰腺生理学的新认识 分泌物、激素刺激在胰腺炎中的作用及其影响因素 影响胰腺炎后的再生，第三，了解 胃肠激素在随后的肠粘膜增生中的作用 研究和转位(了解粘膜的机制 增生可能提供有关终极的重要信息 肠癌的发展)。

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).