"FXR-SOCS3信号通路"的确立及其在抗肝脏炎症中的作用及机制研究

细胞因子信号抑制蛋白3（SOCS3）与核受体FXR均具有重要抗肝脏炎症的功能，但前者是否受到FXR的调控（即Socs3是否为FXR的新靶基因），目前未见报道。本项目在创新性发现"FXR能在肝细胞中显著诱导SOCS3表达，并能明显抑制STAT3磷酸化"的基础上，拟借助报告基因实验、蛋白质与DNA相互作用分析等技术，精细解析出FXR在Socs3基因启动子区中的具体反应元件，率先将Socs3鉴定为FXR的一个新靶基因，从而阐明FXR诱导SOCS3表达的分子机制，揭示肝细胞中"FXR-SOCS3信号通路"的存在；进而在体外肝细胞和小鼠体内肝脏炎症及全身性炎症模型上，探讨通过诱导SOCS3表达而发挥抗炎作用（即"FXR-SOCS3通路"）在FXR抗炎作用中的重要地位，以期揭示"FXR-SOCS3通路"是FXR抗肝脏炎症的新机制，为探索以"FXR-SOCS3通路"为靶标的抗肝脏炎症新措施提供科学依据。

Both suppressor of cytokine signaling 3（SOCS3）and nuclear receptor FXR (farnesoid X receptor) play important roles in suppression of hepatic inflammation. However, it is unclear whether SOCS3 is regulated by FXR (Namely, it is unknown whether Socs3 is a novel target gene of FXR). Our preliminary study for the first time showed that FXR activation could dramatically induce SOCS3 expression and significantly repress the phosphorylation of STAT3(signal transducer and activator of transcription 3) in hepatocytes. In the present study, we will verify that Socs3 is a novel target gene of FXR by screening and identifing the exact FXR response element in Socs3 gene promoter region using a number of technologies such as reporter assy, analyzing the interaction between protein and DNA, and so on. The above studies will reveal the mechanism by which FXR induces SOCS3 expression, and confirm the existence of FXR-SOCS3 sinaling pathway in hepatocyte. Subsequently, we will investigate the significance of FXR-mediated SOCS3 upregulation (FXR-SOCS3 pathway) in the anti-inflammatary function of FXR in hepatocytes in vitro and in mice hepatic and systemic inflammation models in vivo, so that we hope to reveal that FXR-SOCS3 pathway is a novel mechansim of FXR-mediated anti-hepatic inflammation. Our study may provide a new sight for searching novel strategy to the inhibition of hepatic inflammation by targeting FXR-SOCS3 signaling pathway.