FOXA3抑制非酒精性脂肪肝炎(NASH)炎症与纤维化的机制研究与靶标验证

非酒精性脂肪肝炎NASH的发病机理与肝脏炎症密切相关。同时NASH诱导心血管风险增高，因此理想的NASH药物靶点应既抑制肝脏炎症又降低心血管风险。目前全世界NASH患者数量巨大且无上市药物，发现这样新颖的多效性靶点具有迫切的临床需求。前期研究申请人发现肝脏FOXA3可降低小鼠动脉粥样硬化风险(ATVB, 2019)。预实验发现FOXA3在NASH病人以及NASH小鼠模型肝脏下调，提示其可能参与NASH发病机理；同时，RNA-Seq预实验表明肝脏FOXA3下调多种炎症与纤维化通路。因此FOXA3非常有潜力成为治疗NASH与其心血管并发症的多效性药物靶标。然而FOXA3如何抑制肝脏炎症的机理目前尚不清楚。本课题拟在NASH细胞和动物模型中敲低或过表达FOXA3，研究其对NASH的影响，揭示其抑制NASH炎症的分子机制。本项目将为确立FOXA3作为治疗NASH的新靶点提供实验基础和理论依据。

The pathogenesis of non-alcoholic steatohepatitis(NASH) is closely associated with liver inflammation. Meanwhile, NASH promotes the risk of cardiovascular diseases(CVD). Therefore, an idea NASH drug target should be able to inhibit liver inflammation and reduce CVD risk at the same time. At present, due to the huge population of NASH patients around the world and lack of approved drugs, identification of such multi-effect novel drug targets is an urgent clinic need. In a previous study, the applicant found that liver FOXA3 reduced the risk of atherosclerosis in mice(ATVB, 2019). Preliminary study found that hepatic FOXA3 expression was lowered in NASH patients and in NASH mouse models, suggesting that it might be involved in the pathogenesis of NASH. Moreover, RNA-Seq preliminary study showed that hepatic FOXA3 reduced multiple inflammatory and fibrotic pathways. FOXA3 therefore has great potential to be a multi-effect drug target for the treatment of NASH and its cardiovascular complication. However, it is not clear how FOXA3 inhibits liver inflammation. In this project, we plan to knockdown or overexpress FOXA3 in NASH cell and animal models, to study its effect on NASH progression and to elucidate the specific molecular mechanisms behind it. This project will provide experimental basis and theoretical basis for establishing FOXA3 as a novel target for the treatment of NASH.