BILE ACID METABOLISM IN HEALTH AND DISEASE

健康和疾病中的胆汁酸代谢

• 批准号: 3227014
• 负责人: ALAN F HOFMANN
• 金额: $ 32.65万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-04-01 至 1993-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3227014
• 关键词: active transport; aminoacid; bile circulation; biliary tract disorder chemotherapy; biliary tract disorder diagnosis; biliary tract imaging /visualization; biliary tract pharmacology; biotransformation; chenodeoxycholate; cholelithiasis; cooperative study; dogs; drug design /synthesis /production; gallbladder; gastrointestinal absorption /transport; glucose; glucuronides; guinea pigs; hamsters; human subject; image processing; laboratory rat; liver circulation disorder; liver disorder chemotherapy; liver metabolism; membrane permeability; passive transport; phospholipids; radiotracer

An integrated multidisciplinary research program is proposed whose aim is to develop general principles of hepatic and intestinal transport of bile acids (BA), bile acid biotransformation during hepatic and intestinal transport as well as principles and mechanisms of bile acid dependent bile flow and biliary lipid secretion. To this end, natural and novel BA will be purchased or synthesized and their physiological properties defined. Biotransformation during hepatic transport and enterohepatic cycling in mammals including man will be quantified using chromatographic and spectroscopic methods. The effect of these bile acids on bile flow and biliary lipid secretion will be measured using biliary fistula animals (including man) as well as the isolated perfused liver. Experiments will be continued to validate (or refute) the presence of cholehepatic cycling as a mechanism of hypercholeresis; the experimental approach will involve pharmocological, physiological, and imaging approaches. In collaborative studies, attempts will be made to identify the canalicular carrier for bile acid glucuronides using photo-affinity labelling techniques and canalicular membrane preparations. Studies will be carried out to test whether active ductular reabsorption of solutes filtered into canalicular bile (such as glucose and amino acids) influences bile flow. Aspects of passive and active intestinal transport of BA in mammals including man will be investigated by a novel intestinal perfusion technique. Attempts will be made to isolate the protein involved in active transport by the terminal ileum. Multicompartmental modelling of the metabolism and enterohepatic circulation of BA in man will be continued in collaborative studies. Biliary bile acid and phospholipid composition in a spectrum of vertebrates will be defined to develop principles of BA evolution An attempt will be made to develop a cell culture technique for studying biliary secretion since available techniques are unsatisfactory. If successful, experiments proposed in this application should give rise to new methods for studying biliary secretion and should permit biliary bile flow and biliary lipid secretion to be described by general principles; elucidation of these principles should lead to new prophylactic and therapeutic approaches to cholelithiasis and cholestasis, and possibly to liver cell injury.

提出了一项综合的多学科研究计划 其目的是制定肝的一般原则 胆汁酸（BA），胆汁酸生物转化的肠道转运 在肝和肠道运输以及原理中 胆汁酸依赖性胆汁流和胆道脂质的机理 分泌。 为此，将购买自然和新颖的BA或 合成及其生理特性定义。 肝运输和肠肝中的生物转化 将使用包括男人在内的哺乳动物骑自行车 色谱和光谱法。 这些效果 将测量胆汁流和胆汁脂质分泌的胆汁酸 使用胆道瘘动物（包括人）以及孤立的 灌注肝。 实验将继续验证（或 驳斥）Cholehepatic骑自行车的存在作为一种机制 高质学；实验方法将涉及 药物学，生理和成像方法。 在 协作研究，将尝试确定 使用光接亲和力的胆汁酸葡萄糖醛酸糖苷的口管载体 标记技术和口腔膜制剂。 将进行研究以测试是否有效导管 重吸收被过滤到口腔胆汁中的溶质（例如 葡萄糖和氨基酸会影响胆汁流。 被动的各个方面 和包括人在内的哺乳动物中BA的主动肠道运输 将通过一种新型的肠道灌注技术进行研究。 将尝试隔离参与活性的蛋白质 末端回肠运输。 多班子建模 在人类中的代谢和肠道疾病循环中 继续进行协作研究。 胆汁胆酸和 一系列脊椎动物中的磷脂组成将是 定义为制定BA进化原则的尝试将尝试 制造用于研究胆道的细胞培养技术 分泌由于可用技术不令人满意。 如果 成功的，本应用程序中提出的实验应给予 提升了研究胆道分泌的新方法，应 允许描述胆汁胆流量和胆道脂质分泌 一般原则；阐明这些原则应该领导 采用新的预防性和治疗方法 和胆汁淤积，可能是肝细胞损伤。