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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 胆盐输出泵（BSEP）作为一种限速性小管流出器，控制肝内胆汁酸和胆汁胆汁酸水平。妊娠期肝内胆汁淤积症（ICP）和胆石病分别是肝内胆汁酸和胆汁胆汁酸失衡引起的病理状态。ICP主要发生在妊娠晚期，与雌激素水平升高相关。胆石病表现出明显的性别偏好，女性比男性易感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。该提案的目的是扩展我们的初步研究结果，并获得额外的证据来支持或反驳我们的中心假设，即雌激素下调BSEP表达是ICP和胆石病的共同危险因素，并且这种下调是通过一种新的非经典反式阻遏途径介导的。在这个项目中，将追求两个具体目标：具体目标1是确定雌激素反式抑制BSEP的BSEP启动子中的顺式元件;具体目标2是确定雌激素发挥其抑制作用所需的ER α的功能特征。完成这项研究后，我们将确定BSEP启动子中的新顺式元件和ER α介导ICP和胆石病中雌激素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.