基于iNKT17细胞功能调控的雌激素诱导肝内胆汁淤积新靶点发现

肝内胆汁淤积（IHC）是许多肝病共有的基础病变，未经有效干预时可发展为肝纤维化、肝硬化，甚至肝癌。IL-17与IHC炎症密切相关，胆汁酸代谢产物直接影响RORγt活性，靶向IL-17与RORγt可改善小鼠胆汁淤积，但IHC相关的IL-17的来源、作用、效应通路和潜在药物靶标均不明确。本项目拟以雌激素诱导的IHC为研究对象，探索iNKT17细胞经由CXCL9/10-CXCR3信号通路调控雌激素诱导IHC的作用机制，论证iNKT17细胞功能调控作为潜在治疗靶标的可行性。采用化学干预、基因操纵等技术确证iNKT17细胞在雌激素诱导IHC病程中的作用及效应通路；应用大数据人工智能辅助分子对接、微量热泳动分析等手段筛选靶向抑制RORγt的活性化合物，通过在体内外模型中验证活性化合物的药效作用论证靶点的可及性。综上，本项目研究雌激素诱导IHC的病理机制和治疗靶点，为IHC的药物开发和合理防治提供支撑。

Intrahepatic cholestasis (IHC) is a common clinical symptom of liver diseases. If patients don’t receive effective treatment, IHC can develop into liver fibrosis, cirrhosis and liver cancer. IL-17 is positively related to the inflammation of IHC. Bile acid metabolites directly affect the activity of RORγt. Targeting IL-17 and RORγt improves cholestasis in mouse model. However, the source, effect, signaling pathway and potential drug target of IL-17 in IHC are still not clear. In the present study, we aim to explore the mechanism of iNKT17 cells through CXCL9/10-CXCR3 signaling pathway in estrogen-induced IHC and demonstrate the feasibility of iNKT17 cell function regulation as a potential therapeutic target. The effect and mechanism of iNKT17 cells in the pathogenesis of estrogen-induced IHC are studied by chemical intervention and gene manipulation. The active compounds targeted to inhibit RORγt are screened by big data and artificial intelligence assisted molecular docking, microscale thermophoresis analysis and other methods. The efficacy of the active compounds is investigated in vitro and in vivo models to verify the target. In conclusion, the present study investigates the pathological mechanism and therapeutic target of estrogen-induced IHC, contributing to the drug development and reasonable prevention and treatment of IHC.