REGULATION OF SECRETION BY BILE DUCT EPITHELIAL CELLS

描述：肝内胆管对肝脏的体积和 由肝脏分泌的胆汁的成分。在这篇文章中描述的研究 建议解决胆管细胞的特殊功能，上皮细胞 排列在这些导管管腔内的细胞，负责胆汁 队形。胆管细胞顶膜上氯离子通道的开放 代表一个点的分泌调节，并涉及氯离子外流 通过CFTR，囊性纤维化基因的蛋白产物。孤立 胆管细胞还表达丰富的其他通道，这些通道 受受体依赖性(促胰液素、ATP)和非受体依赖性(胆汁)调节 酸、细胞体积)途径。建议的研究将评估 工作假说，氯离子的跨上皮运输代表一种 肝内胆管上皮细胞分泌的重要推动力； 局部(自分泌、旁分泌)因素和全身(激素)因素 多种因素共同作用，调节胆汁的体积和组成。 通过直接作用于导管细胞。膜片钳和其他技术将 被用来评估分离的胆管细胞的转运电流 胆汁细胞的极化模型，以前几乎没有应用到 对这些问题的调查。具体目标是：1)本地化 膜离子通道通向顶端或基底区并进行批判性评估 氯离子转运作为导管分泌的驱动力的作用；2) 评估钙/钙调蛋白依赖的蛋白激酶在脑内的互补作用 分泌调节，蛋白激酶C调节细胞体积； 并评估细胞外三磷酸腺苷和胆汁酸作为局部调节 膜氯离子通透性的调节因子对变化的响应 生理需求。这些研究的长期目标是确定 参与调节导管分泌的细胞机制。 总而言之，这些发现与诊断和 以精神障碍为特征的一系列疾病的管理 胆管细胞转运与新疗法的发展 调节胆汁容量和成分的途径 对导管细胞的直接影响。

DESCRIPTION: Intrahepatic ducts contribute importantly to the volume and composition of bile secreted by the liver. The studies described in this proposal address the specialized functions of cholangiocytes, the epithelial cells that line the lumen of these ducts and are responsible for bile formation. Opening of Cl- channels in the apical membrane of cholangiocytes represents one point for regulation of secretion and involves Cl- efflux through CFTR, the protein product of the cystic fibrosis gene. Isolated cholangiocytes also express a rich array of other channels that are regulated by both receptor-dependent (secretin, ATP) and -independent (bile acids, cell volume) pathways. The proposed studies will evaluate the working hypothesis that transepithelial transport of Cl- ions represents an important driving force for secretion across intrahepatic duct epithelium; and that both local (autocrine, paracrine) factors and systemic (hormonal) factors work in concert to modulate the volume and composition of bile through direct effects on duct cells. Patch clamp and other techniques will be utilized to evaluate transport currents in isolated cholangiocytes and polarized models of biliary cells which have had little prior application to investigation of these issues. The specific aims are 1) to localize membrane ion channels to the apical or basal domains and critically evaluate the role of Cl- transport as a driving force for ductular secretion; 2) to assess the complementary roles of Ca2+/calmodulin-dependent kinases in regulation of secretion, and protein kinase C in regulation of cell volume; and to evaluate 3) extracellular ATP and 4) bile acids as local regulatory factors which modulate membrane Cl-permeability in response to changing physiologic demands. The long-term goal of these studies is to define the cellular mechanisms involved in regulation of ductular secretion. Collectively, the findings are directly relevant to the diagnosis and management of a broad range of disorders characterized by impaired cholangiocyte transport, and to the development of new therapeutic approaches aiming to modulate the volume and composition of bile through direct effects on duct cells.