FEEDBACK REGULATION OF PANCREATIC SECRETION

胆囊收缩素（CCK）分泌反馈调节的机制

The mechanism of feedback regulation of cholecystokinin (CCK) secretion by pancreatic proteases will be studied. The purification and characterization of an intestinal CCK-releasing peptide that is hypothesized to mediate protease-specific feedback inhibition of CCK release will be attempted. Acid extracts of porcine proximal small intestinal mucosa will be fractionated by preparative HPLC and the fractions bioassayed for CCK-releasing activity by infusing them intraduodenally in conscious rats. Fractions possessing CCK-releasing activity will be further purified by HPLC until suitable for amino acid sequencing. The peptide will be chemically synthesized and the natural and synthetic peptide will be compared biochemically and physiologically. Physiological studies will be conducted to compare the actions of intestinal CCK-releasing peptide with that of monitor peptide, the CCK-releasing peptide of pancreatic juice. Polyclonal and monoclonal antibodies will be raised to the purified or synthetic intestinal CCK-releasing peptide to be used in immunocytochemical studies to localize the peptide in the small intestine, and to develop a radioimmunoassay (RIA). The RIA will be used to investigate the regulation of the secretion of the CCK-releasing peptide in intestinal juice, using conscious rats with isolated Thiry-Vella fistulas of proximal small intestine. The effect of i.v. infusion of cholinergic and adrenergic blockers, somatostatin, and of intraintestinal infusion of amino acids, fatty acids, glucose and bile acids on secretion of the intestinal CCK-releasing peptide into the Thiry-Vella loop will be studied. The role of CCK in induction and maintenance of pancreatic growth will be studied. Rats adapted to 5% casein diets will be presented with 70% casein diets for 14 days and the effect of administration of the CCK receptor antagonist MK-329 on pancreatic growth in response to 70% casein feeding will be determined. The antagonist will be administered beginning at the onset of feeding the 70% casein diet or beginning 7 days later, to contrast the effect of MK-329 on induction vs maintenance of pancreatic growth. Similar studies will be done using trypsin inhibitor as the dietary trophic stimulus. The results of these studies will provide important basic physiological information about the control of CCK secretion and its influence in gastrointestinal function. These data will help to understand and treat gastrointestinal diseases, particularly pancreatic and gallbladder diseases.