ALCOHOL AND ALTERED REGULATION OF PANCREATIC SECRETION

酒精和胰腺分泌调节的改变

• 批准号: 2047525
• 负责人: DAVID Clement WHITCOMB
• 金额: $ 19.07万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2047525
• 关键词: alcoholism /alcohol abuse; alcohols; autoradiography; disease /disorder model; exocrine glands; gene expression; gene induction /repression; immunocytochemistry; in situ hybridization; laboratory rat; messenger RNA; neuroendocrine system; pancreas; pathologic process; polymerase chain reaction

DESCRIPTION: Alcohol-related acute and chronic pancreatitis is a major health care problem in the U.S. Much effort has been directed at determining the effects of alcohol on the acinar cell, but other factors may be even more important. Earliest changes in patients who ingest alcohol and eventually develop pancreatitis is a functional hyperstimulation of the pancreas which involves over-expression and over-secretion of pancreatic proteins and digestive enzymes that is seen with chronic alcohol use. The mechanism responsible for this phenomena has never been explained. The hypothesis of this proposed project is that it represents a disruption in the neurohormonal control mechanisms regulating the pancreas. This hypothesis is based on a number of recent findings indicating that, under physiologic conditions, the pancreas is primarily under neural control, and that functional hyperstimulation is neurally mediated. The investigators' aims are to clarify the mechanism of alcohol-induced disruption of neurohormonal regulation of pancreatic secretion and to understand the adaptive changes that accompany chronic alcohol ingestion which may predispose patents to acute and chronic pancreatitis. The specific aims are: (1) to test the hypothesis that alcohol causes pathophysiological differences in functional response of the pancreas to physiologic stimuli and regulatory peptides by disrupting key points that regulate pancreatic secretion; (2) to test the hypothesis that alcohol causes differences in mRNA expression patterns through inhibiting specific genes and/or causing adaptive overexpression of other genes in the key regulatory control tissues of the duodenum, brain, and pancreas; and (3) to test the hypothesis that alcohol- induced changes are mediated through a subset of cells in key control sites. Within this application, specific experiments are outlined to clarify the mechanism through which alcohol disrupts neurally mediated pancreatic exocrine secretion. Different rat models will be used for studies of alcohol ingestion (Lieber-DeCarli diet model) and for measurement of pancreatic secretion (Green conscious rat model). Alcohol-induced changes in the mechanism controlling pancreatic secretion will be determined at a functional level using four different routes of pancreatic stimulation, at a molecular level using quantitative polymerase chain reaction (PCR) and differential display (DD), and at a cellular level using quantitative receptor autoradiography, immunohistochemistry, and in situ hybridization. The investigators expect that this approach will allow identification of significant regulatory mechanism that impact on pancreatic secretion. It is hoped that this new information will be useful in developing new procedures for the management of patients developing alcohol related pancreatitis.

描述：与酒精有关的急性和慢性胰腺炎是主要的 美国的医疗保健问题已针对 确定酒精对腺泡细胞的影响，但其他因素 可能更重要。摄入的患者最早变化 酒精并最终发育胰腺炎是一种功能性的 胰腺过度刺激，涉及过表达和 胰腺蛋白质和消化酶的分泌过度分泌 使用慢性酒精。负责这种现象的机制 从未解释过。这个拟议项目的假设是 它代表神经激素控制机制的破坏 调节胰腺。该假设是基于许多最近的 调查结果表明，在生理条件下，胰腺是 主要在神经控制下，功能性过度刺激是 神经介导。 研究人员的目的是阐明酒精引起的机制 胰腺分泌的神经激素调节的破坏和 了解慢性酒精摄入伴随的自适应变化 这可能使专利易于急性和慢性胰腺炎。这 具体目的是：（1）测试酒精引起的假设 胰腺功能反应的病理生理差异 通过破坏关键点的生理刺激和调节肽 调节胰腺分泌物； （2）检验以下假设 酒精通过 抑制特定基因和/或引起自适应过表达 十二指肠的关键调节控制组织中的其他基因， 大脑和胰腺； （3）检验酒精诱导的假设 变化是通过关键控制位点中细胞的子集介导的。 在此应用程序中，概述了特定的实验以阐明 酒精破坏神经介导的胰腺的机制 外分泌分泌。不同的大鼠模型将用于研究 饮酒（Lieber-Decarli饮食模型）和用于测量 胰腺分泌（绿色意识大鼠模型）。酒精引起的 控制胰腺分泌的机制的变化将是 使用四个不同的途径在功能级别上确定 胰腺刺激，在分子水平上使用定量 聚合酶链反应（PCR）和差异显示（DD），在 使用定量受体放射摄影的细胞水平， 免疫组织化学和原位杂交。调查人员 预计这种方法将允许识别重要的 影响胰腺分泌的监管机制。希望 这些新信息对于制定新程序很有用 用于治疗患者与酒精相关的胰腺炎的患者。