miR-200b-PDZK1介导转运体定位在雌激素所致胆汁淤积中的作用及黄芩苷干预

雌激素所致胆汁淤积（EIC）危害性大，缺乏特效药物。基于激动核受体改善胆汁酸平衡的传统研究策略效果欠佳。我们前期发现EIC机体异常高表达的miR-200b与下调支架蛋白PDZK1以及肝脏转运体定位异常相关，而黄芩苷激动sirt1后可改善EIC中上述通路的异常现象。国内外最新报道也证实雌激素与miRNAs异常表达和部分肝脏转运体内化密切相关，但机制不清，且PDZK1调控转运体定位的关键作用也待全面阐明。因此我们提出假说，miR-200b-PDZK1通路介导的转运体定位异常促进EIC胆汁酸失衡，且可被黄芩苷通过sirt1逆转。本项目拟采用基因敲除动物结合体外细胞实验，确证miR-200b-PDZK1在EIC胆汁酸失衡中的关键作用，筛选并验证该通路可调控的肝脏转运体，揭示黄芩苷通过sirt1调控miR-200b-PDZK1而改善EIC的作用并明确其内在机制，为EIC病理和药物干预研究提供新思路。

Estrogen-induced cholestasis (EIC) is harmful and there is still no specific medicine. The benefit of current research strategies on EIC is unsatisfied, which mainly focuse on activating nuclear receptors to maintain bile acid homeostasis. We have previously found that the abnormally elevated miR-200b in EIC animals was related to the down-regulation of the scaffold protein PDZK1 and the abnormal location of hepatic transporters, while these aberrant manifestations could be reversed by baicalin via sirt1 activation. Recent international and domestic studies showed that estrogen was responsible for the abnormal miRNAs and the internalization of liver transporters with an unclear mechanism, and the key roles of PDZK1 involving in the localization of liver transporters should also be fully elucidated. Therefore, we propose that miR-200b-PDZK1 pathway mediates abnormal transporter localization and promotes the imbalance of bile acid homeostasis in EIC, which can be reversed by baicalin via sirt1. In this project, we will use gene knockout animals combined with in vitro experiments to confirm the key role of miR-200b-PDZK1 pathway in bile acid homeostasis in EIC, to screen and verify the liver transporters regulated by miR-200b-PDZK1 pathway, and to demonstrate the role of baicalin in regulating miR-200b-PDZK1 pathway via sirt1 to improve EIC and its underlying mechanisms. Our project will provide new strategy for the pathology and drug intervention research in EIC.