ROLE OF H+/HCO3- TRANSPORT IN BILE FORMATION

胆汁的形成是一个重要但知之甚少的问题。 肝功能。胆汁的形成始于 小管和申请人和其他人最近的研究表明 胆小管胆汁的形成部分是由于 肝细胞对HCO3-的转运。风管和风管也是 据信通过分泌HCO3-有助于胆汁的形成-- 富含流体，但对其机制知之甚少(S)或 对导管分泌的调节，很大程度上是因为缺乏 合适的实验模型。这项提案概述了研究， 根据首席调查员最近的观察， 一般与溶质和水的运动机制有关 肝脏，并特别关注H和HCO3转运的作用 在肝细胞和胆管细胞的胆汁形成中。申请人 建议(A)进一步表征肝脏的Na/HCO3-符号， 一种以前未知的肝脏HCO3转运机制 他和他的同事最近在肝细胞中发现了这种物质，(B) 检验这一假设，即高胆汁酸的作用部分是通过 促肝细胞H和HCO3转运的途径 调节细胞内pH的机制也有可能 (Phi)，(C)定义细胞内pH和 胆汁酸的葡萄糖醛酸化作用，(D)制定一项制度，以建立 原代培养的胆管上皮细胞，以及(E)定义 导管细胞中H和HCO3-转运机制(S) 并确定对这些转运机制的影响。 据信能促进胆管分泌的利胆药物。 研究将采用既定的方法和模型，并 申请人最近开发的技术(例如荧光 培养的肝细胞PHI的测量)，以及模型 和技术(例如，肝小管细胞的原代培养， 单个肝细胞或导管细胞的phi测定) 目前正在开发中。

The formation of bile is an important yet poorly understood hepatic function. Bile formation begins at the level of the canaliculus and recent studies by the applicant and others suggest that formation of canalicular bile results, in part, from active transport of HCO3- by hepatocytes. Ducts and ductules are also believed to contribute to bile formation via secretion of a HCO3-- rich fluid, yet little is known regarding the mechanism(s) or regulation of ductular secretion, largely because of the lack of an appropriate experimental model. This proposal outlines studies, base on recent observations by the Principal Investigator, which relate generally to mechanisms of solute and water movement by liver and focus specifically on the roles of H+ and HCO3-transport in bile formation by hepatocytes and ductular cells. The applicant proposes to (a) further characterize hepatic Na+/HCO3- symport, a previously unrecognized mechanism of hepatic HCO3- transport which he and his colleagues recently identified in hepatocytes, (b) test the hypothesis that hypercholeretic bile acids act, in part, by stimulating H+ and HCO3- transport by hepatocytes via mechanisms also involved in the regulation of intracellular pH (pHi), (c) define the relationship between intracellular pH and glucuronidation of bile acids, (d) develop a system for establishing bile ductular epithelial cells in primary culture, and (e) define the mechanism(s) of H+ and HCO3- transport present in ductular cells and determine the effects on these transport mechanism of choleretic agents believed to enhance ductular secretion. The studies will employ established methods and models and techniques recently developed by the applicant (e.g. fluorescence measurement of pHi in cultured hepatocytes), as well as models and techniques (e.g., primary cultures of hepatic ductular cells, measurement of pHi in individual hepatocytes or ductular cells) currently under development.