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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 胆盐输出泵(BSEP)作为一种限速小管流出器，控制着肝内和胆汁中的胆汁酸水平。妊娠期肝内胆汁淤积症和胆石症分别是由肝内胆汁酸和胆汁酸失衡引起的病理状态。肝内胆汁淤积症主要发生在妊娠晚期，与雌激素水平升高有关。胆石症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(ER-α)反式抑制人的BSEP，但这种抑制不是通过经典的雌激素反应元件(ERE)依赖的途径来介导的。这项建议的目的是扩大我们的初步发现，并获得更多的证据来支持或驳斥我们的中心假设，即雌激素下调BSEP的表达是ICP和胆结石疾病的共同危险因素，并且这种下调是通过一种新的非经典反式抑制途径介导的。在本项目中，将追求两个特定的目标：特定的目标1是确定雌激素反式抑制BSEP的BSEP启动子中的顺式元件；特定的目标2是确定雌激素发挥其抑制作用所需的ERα的功能特征。在拟议的研究完成后，我们将确定BSEP启动子中的新顺式元件和ERα在介导雌激素在肝内胆汁淤积症和胆石病中的作用所需的功能特征。

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.