Regulation of cholangiocytes by InsP3 receptor isoforms

InsP3 受体亚型对胆管细胞的调节

• 批准号: 7168859
• 负责人: BARBARA E. EHRLICH
• 金额: $ 30.43万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7168859
• 关键词: Bicarbonates; Bile Duct Epithelium; Bile fluid; Binding; Calcium; Cell Line; Cells; Childhood; Cholestasis; Chronic; Condition; Cystic Fibrosis; Disease; Epithelial Cells; Epithelium; Hepatic; Hepatocyte; Inherited; Inositol 1,4,5-Trisphosphate; Lead; Liver diseases; Measures; Mediating; Mediator of activation protein; Modeling; Molecular; Molecular Models; Numbers; Organ; Pattern; Play; Primary biliary cirrhosis; Property; Protein Isoforms; Regulation; Sclerosing Cholangitis; Series; Shapes; Signal Pathway; Signal Transduction; Testing; Time; Transplant Recipients; Work; base; bile duct; cholangiocyte; improved; liver function; liver transplantation; receptor; research study; response

Bile secretion is one of the principal functions of the liver. In order to maintain bile flow, not only must hepatocytes secrete bile, but this must then be modified and conditioned further by bile duct epithelial cells, or cholangiocytes. Abnormal cholangiocytes function results in cholestasis, which is a cardinal manifestation of liver disease. Cholestatic liver diseases are responsible for 20% of liver transplants in the US, and are the most common cause of liver disease among pediatric transplant patients. In addition, abnormal cholangiocyte function is responsible for the hepatic manifestations of cystic fibrosis, one of the most common inherited diseases. Bile secretion in cholangiocytes is regulated in part by cytosolic Ca2+. In general, cells are regulated both by the pattern of Ca2+ signals over time and by the regions of the cells in which Ca2+ signals occur. However, little is known about temporal or spatial aspects of Ca2+ signaling in cholangiocytes, and nothing is known about how these Ca2+ signals are regulated. Inositol 1,4,5-trisphosphate receptors (InsP3R) mediate Ca2+ signaling in epithelia, and cholangiocytes express all three isoforms of this receptor. The hypothesis of this proposal is that Ca2+ signals in the cholangiocyte are regulated by the subcellular distribution of the InsP3R isoforms. This hypothesis will be investigated through the following specific aims: 1. The function and regulation of the InsP3Rs will be compared at the single channel level. 2. The contribution that each of the receptors plays to Ca2+ signaling in cholangiocytes will be examined in a bile duct cell line modified to express either one or a combination of these receptors. 3. These findings will be related to the organization of Ca2+ signals and secretory function in native cholangiocytes, as determined in isolated microperfused bile duct segments. This work should not only identify the molecular mechanisms responsible for Ca2+ signaling in cholangiocytes, but serve as a model for how the molecular organization of signaling pathways is responsible for regulation of ductular secretion.

胆汁分泌是肝脏的主要功能之一。为了保持胆汁流，不仅必须 肝细胞分泌胆汁，但必须对此进行修改并通过胆管上皮进一步调节 细胞或胆管细胞。异常的胆管细胞功能导致胆汁淤积，这是红衣主教 肝病的表现。胆汁淤积性肝病是导致20％的肝移植 美国，是小儿移植患者中肝病的最常见原因。此外， 异常的胆管细胞功能是囊性纤维化的肝表现，是其中之一 最常见的遗传疾病。 胆管细胞中的胆汁分泌部分由胞质Ca2+调节。通常，细胞受调节 随着时间的流逝，CA2+信号的模式以及发生Ca2+信号的细胞区域的模式。 但是，关于胆管细胞中Ca2+信号传导的时间或空间方面知之甚少，以及 对于如何调节这些CA2+信号，尚不了解。肌醇1,4,5-三磷酸受体 （insp3r）介导上皮中的Ca2+信号传导，而胆管细胞表达这三种同工型 受体。该提议的假设是胆管细胞中的Ca2+信号受 INSP3R同工型的亚细胞分布。该假设将通过以下调查 具体目的： 1。将在单个通道级别上比较INSP3R的功能和调节。 2。将检查每个受体对胆管细胞中Ca2+信号传导的贡献 在胆管管细胞系中，被修饰以表达这些受体的一种或组合。 3。这些发现将与本机中CA2+信号和分泌功能的组织有关 胆管细胞，如在分离的微灌注胆管段中确定的。 这项工作不仅应确定负责Ca2+信号传导的分子机制 胆管细胞，但作为信号通路分子组织的模型 负责调节导管分泌。