MECHANISMS OF CANALICULAR BILE FORMATION

胆管形成机制

• 批准号: 3151608
• 负责人: BRUCE F SCHARSCHMIDT
• 金额: $ 16.13万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-07-01 至 1986-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3151608
• 关键词: acidity /alkalinity; adenosine triphosphate; adenosinetriphosphatase; anions; autoradiography; bile; biological fluid transport; cations; cell membrane; cell morphology; chlorpromazine; corticosteroids; cystic fibrosis; electron spin resonance spectroscopy; epithelium; estrogens; ethylene glycols; galactose; gluconeogenesis; glucose; glucose transport; hypertension; inulin; ion transport; liver function; liver metabolism; magnesium; mannitol; membrane activity; membrane lipids; membrane model; membrane permeability; monosaccharides; muscle relaxation; orphan disease /drug; passive transport; phenobarbital; radiotracer; thyroid hormones

We propose to investigate two new hypotheses based on recent work by ourselves and others which pertain to cellular mechanisms of canalicular bile formation and their relationship to regulation of intracellular pH, intracellular volume, Na,K-ATPase cation pumping and sodium-coupled solute transport. First, we postulate that active proton transport across the hepatocyte plasma membrane mediates hepatic bicarbonate secretion and much of bile acid-independent bile formation and is involved as well in regulation of hepatic intracellular pH. Second, we postulate that Na,K-ATPase cation pumping is regulated by the rate of transport of sodium-coupled solutes such as bile acids via changes in intracellular sodium concentration so as to maintain the electrochemical sodium gradient, and that certain hormones and drugs have a primary effect on Na,K-ATPase cation pumping which in turn affects the electrochemical sodium gradient, transport of sodium-coupled solutes and bile formation. These hypotheses will be investigated by studies of transport and/or electrophysiology in the intact perfused liver, cultured rat hepatocytes and liver plasma membrane vesicles using techniques developed by the investigators. The findings are expected to provide important new insight into cellular mechanisms of canalicular bile formation and into the pathophysiology of intrahepatic cholestasis. They will also clarify the nature of the dynamic relationship between Na,K-ATPase cation pumping and sodium-coupled solute transport. Such fundamental information is necessary for a complete understanding of important processes other than bile formation which are dependent on sodium-coupled transport and are common to all animal cells or are characteristic of specialized tissues. These processes include regulation of intracellular pH and volume, gluconeogenesis, muscle relaxation, and transepithelial transport of water, sodium, bicarbonate, chloride and glucose. Information derived from these studies is also expected to aid in understanding the pathophysiology of human diseases other than cholestasis which are associated with abnormal active and passive ion transport including cystic fibrosis, obesity, cancer, and hypertension.

我们建议根据基于最新工作的两个新假设 我们和他人和其他与管道的蜂窝机理有关的 胆汁形成及其与细胞内pH的调节的关系， 细胞内体积，Na，K-ATPase阳离子泵送和钠耦合溶质 运输。 首先，我们假设主动质子在 肝细胞质膜介导肝碳酸氢盐分泌和很多 与胆汁酸无关的胆汁形成的形成，也参与 肝内pH的调节。 其次，我们假设 Na，K-ATPase阳离子泵泵受运输速率调节 钠耦合溶质，例如胆汁酸，细胞内的变化 钠浓度以维持电化学钠梯度， 并且某些激素和药物对Na，K-ATPase具有主要作用 阳离子抽水反过来影响电化学钠梯度， 钠耦合溶质和胆汁形成的运输。 这些假设 将通过对运输和/或电生理学的研究研究 完整的灌注肝，培养的大鼠肝细胞和肝等离子体 使用研究人员开发的技术的膜囊泡。 这 期望发现将为细胞提供重要的新见解 大口径胆汁形成的机制以及进入病理生理学的机制 肝内胆汁淤积。 他们还将阐明动态的本质 Na，K-ATPase阳离子泵送和钠耦合溶质之间的关系 运输。 这样的基本信息对于完整的 了解胆汁形成以外的重要过程 取决于钠耦合的运输，并且是所有动物细胞或 是专业组织的特征。 这些过程包括 调节细胞内pH和体积，糖异生，肌肉 放松和水，钠，碳酸氢盐的旋转运输 氯化物和葡萄糖。 这些研究得出的信息也是 期望有助于理解人类疾病的病理生理学 除了胆汁淤积与异常活跃和 被动离子运输，包括囊性纤维化，肥胖，癌症和 高血压。

项目成果

Oxygen consumption by rat liver: effects of taurocholate and sulfobromophthalein transport, glucagon, and cation substitution.

大鼠肝脏的耗氧量：牛磺胆酸盐和磺溴酞运输、胰高血糖素和阳离子替代的影响。

• DOI: 10.1152/ajpgi.1983.244.5.g523
• 发表时间: 1983
• 期刊: The American journal of physiology
• 作者: vanDyke,RW;Gollan,JL;Scharschmidt,BF
• 通讯作者: Scharschmidt,BF

Intracellular chloride activity in intact rat liver: relationship to membrane potential and bile flow.

完整大鼠肝脏中的细胞内氯离子活性：与膜电位和胆汁流量的关系。

• DOI: 10.1152/ajpgi.1987.252.5.g699
• 发表时间: 1987
• 期刊: The American journal of physiology
• 作者: Fitz,JG;Scharschmidt,BF
• 通讯作者: Scharschmidt,BF

ATP-dependent proton transport by isolated brain clathrin-coated vesicles. Role of clathrin and other determinants of acidification.

通过分离的脑网格蛋白包被的囊泡进行 ATP 依赖性质子运输。

• DOI: 10.1016/0005-2736(85)90317-7
• 发表时间: 1985
• 期刊: Biochimica et biophysica acta
• 作者: VanDyke,RW;Scharschmidt,BF;Steer,CJ
• 通讯作者: Steer,CJ

Clathrin-coated vesicles from rat liver: enzymatic profile and characterization of ATP-dependent proton transport.

大鼠肝脏的网格蛋白包被的囊泡：ATP 依赖性质子运输的酶谱和表征。

• DOI: 10.1073/pnas.81.10.3108
• 发表时间: 1984
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: VanDyke,RW;Steer,CJ;Scharschmidt,BF
• 通讯作者: Scharschmidt,BF