FEEDBACK REGULATIION OF PANCREATIC ENZYME SECRETION

说明：缩胆囊素在高血压的调节中起着重要作用。 然而，餐后胰腺分泌和胆囊壁收缩 人们对其分泌的调节机制知之甚少。在.期间 在这笔赠款的前几个周期，调查员探索了机制 负责腔内酶对CCK释放的反馈调节 并鉴定出一种对胰酶敏感的CCK释放肽因子，它是 分泌到近端的肠道。现在已经对其进行了纯化和测序 以证明其与安定结合抑制剂的同一性。目标 当前提案的核心是这样一个假设，即DBI是 CCK释放肽对胰腺的反馈调节作用 这种激素的分泌和餐后分泌；DBI的分泌 是受神经激素控制的，由肠神经介导释放 涉及5-羟色胺肠嗜铬细胞、P物质感觉的回路 神经元和胆碱能分泌运动神经元；DBI直接作用于 CCK释放细胞。组件目标侧重于演示DBI是 在胆胰液的分流过程中释放到管腔内 营养刺激，它的分泌与CCK平行。它是 推测十二指肠内DBI的免疫中和应取消 在此条件下，CCK和胰腺分泌。结构-功能 计划利用体内大鼠模型和STC-1进行研究 CCK释放细胞，以确定生物活性的关键区域。 另一个目标是证明营养刺激的释放 DBI的发生通过先前提出的神经回路发生。最后， CCK和DBI在肠道和苯二氮类药物中的定位 可能介导这一活动的受体将使用 免疫组织化学和受体放射自显影。苯二氮卓类 负责CCK释放的结合位点的特征是 生物学和约束性研究。通过这些研究，调查人员 希望加深他们对CCK调节机制的了解 分泌物。

DESCRIPTION: Cholecystokinin plays a major role in the mediation of pancreatic secretion and gallbladder contraction after a meal, however little is known about the mechanisms regulating its secretion. During previous cycles of this grant, the investigator explored mechanisms responsible for feedback modulation of CCK release by intraluminal proteases and identified a trypsin-sensitive CCK-releasing peptide factor which is secreted into the proximal bowel. This has now been purified and sequenced to demonstrate its identity with the diazepam-binding inhibitor. The aims of the current proposal revolve around the hypothesis that DBI is the CCK-releasing peptide responsible for feedback regulation of pancreatic secretion and post-prandial secretion of this hormone; that secretion of DBI is under neurohormonal control with release mediated by enteric neural circuitry involving serotonin enterochromaffin cells, substance P sensory neurons, and cholinergic secretomotor neurons; and that DBI acts directly on CCK-releasing cells. Component aims are focused to demonstrate that DBI is released into the lumen during diversion of bile-pancreatic juice and nutrient stimulation, and that its secretion parallels that of CCK. It is postulated that immunoneutralization of DBI in the duodenum should abolish CCK and pancreatic secretion under these conditions. Structure-function studies are planned utilizing both the in vivo rat model as well as STC-1 CCK-releasing cells to identify key regions for biological activity. Another aim is focused toward demonstrating that nutrient-stimulated release of DBI occurs via the neural circuitry previously suggested. Finally, the localization of CCK and DBI in the intestine and the benzodiazepine receptors that may mediate this activity will be performed using immunohistochemistry and receptor autoradiography. The benzodiazepine binding sites responsible for CCK release will be characterized by both biological and binding studies. Through these studies, the investigators hope to further their understanding of the mechanisms regulating CCK secretion.