MECHANISMS FOR ESTROGEN-MEDIATED TRANSREPRESSION OF HUMAN BILE SALT EXPORT PUMP

雌激素介导的人胆汁盐输出泵转阻滞的机制

• 批准号: 7960151
• 负责人: Ruitang Deng
• 金额: $ 2.49万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-04 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7960151
• 关键词: Behavioral Research; Bile Acids; Biliary; Cholelithiasis; Computer Retrieval of Information on Scientific Projects Database; Disease; Down-Regulation; Elements; Estrogen Receptor alpha; Estrogens; Exhibits; Funding; Grant; Human; Indium; Institution; Mediating; Pathway interactions; Play; Pump; Repression; Research; Research Personnel; Resources; Risk Factors; Role; Source; Third Pregnancy Trimester; Time; United States National Institutes of Health; Woman; bile salts; gender preference; intrahepatic; intrahepatic cholestasis of pregnancy; men; novel; promoter

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. As a rate-limiting canalicular effluxer, the bile salt export pump (BSEP) controls both intrahepatic and biliary bile acid levels. Intrahepatic cholestasis of pregnancy (ICP) and gallstone disease are pathological conditions resulting from an imbalance of intrahepatic and biliary bile acids, respectively. ICP predominantly occurs during the third trimester of pregnancy, correlating with elevated estrogen levels. Gallstone disease exhibits clear gender preference, with women being 2-3 times more susceptible than men. Studies have demonstrated that estrogen plays a key role in the induction of the two diseases. In our preliminary studies, we found that estrogen transrepressed human BSEP via estrogen receptor-alpha (ERalpha), but the repression was not mediated through the classical estrogen responsive element (ERE)-dependent pathway. The objective of this proposal is to extend our preliminary findings and obtain additional evidence to support or refute our central hypothesis that down-regulation of BSEP expression by estrogen is a common risk factor for both ICP and gallstone disease and that such down-regulation is mediated through a novel nonclassical transrepression pathway. In this project, two specific aims will be pursued: Specific Aim 1 is to identify the cis-element in the BSEP promoter for estrogen to transrepress BSEP; and Specific Aim 2 is to determine the functional features of ERalpha required for estrogen to exert its repressive effect. Upon completion of the proposed study, we will have defined the novel cis-element in the BSEP promoter and functional features of ERalpha required for mediating estrogen's actions in ICP and gallstone disease.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 作为限速小管流出器，胆盐输出泵 (BSEP) 控制肝内胆汁酸和胆汁胆汁酸水平。妊娠期肝内胆汁淤积（ICP）和胆石病分别是由于肝内胆汁酸和胆汁胆汁酸失衡引起的病理状况。 ICP 主要发生在妊娠晚期，与雌激素水平升高相关。胆结石疾病表现出明显的性别偏好，女性的易感性是男性的 2-3 倍。研究表明，雌激素在这两种疾病的诱发中起着关键作用。在我们的初步研究中，我们发现雌激素通过雌激素受体α（ERα）反式抑制人类BSEP，但这种抑制不是通过经典的雌激素反应元件（ERE）依赖性途径介导的。本提案的目的是扩展我们的初步发现并获得更多证据来支持或反驳我们的中心假设，即雌激素对 BSEP 表达的下调是 ICP 和胆结石疾病的常见危险因素，并且这种下调是通过一种新型非经典反式抑制途径介导的。在该项目中，将追求两个具体目标： 具体目标 1 是确定 BSEP 启动子中雌激素反式抑制 BSEP 的顺式元件；具体目标2是确定雌激素发挥其抑制作用所需的ERα的功能特征。完成拟议的研究后，我们将确定 BSEP 启动子中的新顺式元件以及介导雌激素在 ICP 和胆石病中的作用所需的 ERalpha 功能特征。