FEEDBACK REGULATIION OF PANCREATIC ENZYME SECRETION

点击翻译按钮获取中文摘要

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.