FEEDBACK REGULATION OF PANCREATIC SECRETION

胰腺分泌的反馈调节

• 批准号: 2140108
• 负责人: GARY M GREEN
• 金额: $ 13.04万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-05-01 至 1996-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2140108
• 关键词: cholecystokinin; digestion; endocrine pharmacology; gastrointestinal hormones; growth /development; high performance liquid chromatography; hormone inhibitor; hormone regulation /control mechanism; immunocytochemistry; ion exchange chromatography; laboratory rat; pancreas enzyme; pancreatic islet function; pathogenic diet; protein sequence; radioimmunoassay; secretion; small intestines; swine; synthetic peptide; trypsin inhibitors

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.

胆囊收缩素（CCK）分泌的反馈调节机制 将研究胰腺蛋白酶。 纯化和 肠CCK释放肽的表征， 假设介导CCK的蛋白酶特异性反馈抑制 将尝试释放。 猪近端小动脉酸浸提液 肠粘膜将通过制备型HPLC分级， 通过将它们注入生物测定释放CCK活性的组分 在清醒的大鼠中进行尿道内注射。 释放CCK的组分 活性将通过HPLC进一步纯化，直到适用于氨基酸 测序 肽将是化学合成的， 和合成肽进行生物化学和生理学比较。 将进行生理学研究，以比较 肠CCK释放肽与监测肽， 胰液CCK释放肽。 多克隆和单克隆 抗体将被提高到纯化的或合成的肠道 CCK释放肽用于免疫细胞化学研究， 定位肽在小肠，并开发一个 放射免疫分析法（RIA）。 RIA将用于调查 调节肠道CCK释放肽的分泌 果汁，使用清醒的大鼠与孤立的Thiry-Vella瘘管， 小肠近端 静脉输注胆碱能和 肾上腺素能阻滞剂、生长抑素和肠内输注 氨基酸、脂肪酸、葡萄糖和胆汁酸对分泌的影响 肠CCK释放肽进入Thiry-Vella环， 研究了 胆囊收缩素在胰腺癌诱导和维持中的作用 将研究增长。 适应5%酪蛋白饮食的大鼠将 饲喂70%酪蛋白饲料14天， CCK受体拮抗剂MK-329对胰腺生长的影响 将测定对70%酪蛋白饲喂的响应。 拮抗剂 将在开始喂食70%酪蛋白时开始给药 饮食或7天后开始，以对比MK-329对 胰腺生长的诱导与维持。 类似的研究将 使用胰蛋白酶抑制剂作为饮食营养刺激物。 的 这些研究结果将提供重要的基础生理学 关于CCK分泌的控制及其对 胃肠功能 这些数据将有助于理解和治疗 胃肠道疾病，特别是胰腺和胆囊 疾病