原发性硬化性胆管炎（PSC）是最常见的胆汁淤积性疾病，以慢性炎症、进行性纤维化和胆管狭窄为特征，最终导致肝硬化和肝功能衰竭，且极易诱发胆管癌的发生。PSC的发病机制尚未阐明而临床治疗措施非常有限。我们的前期实验发现，与细胞衰老密切相关的microRNA-34a（miR-34a）在PSC的动物模型—多药耐药基因2敲除（Mdr2-/-）小鼠肝脏的表达较对照组显著升高而其调控的去乙酰化酶1（SIRT1）显著降低，提示miR-34a可能参与了PSC的发生。因此，本项目首先观察抑制或促进miR-34a的表达后对Mdr2-/-小鼠肝损伤和纤维化的影响，然后探讨miR-34a促进PSC肝损伤的机制是否与miR-34a下调SIRT1引起肝内细胞衰老的改变和NF-κB信号通路介导的炎症反应改变有关，最终阐明miR-34a/SIRT1信号轴在PSC发生发展中的调控作用，为PSC的治疗提供新的靶点和理论基础。

Primary sclerosing cholangitis is one kind of the most common cholestatic diseases, which is characterized by chronic inflammation, progressive fibrosis and biliary stricture, eventually developing into cirrhosis and hepatic failure. The patients with PSC are prone to cholangiocarcinoma. The mechanisms of PSC are not fully elucidated and there is still lack of effective therapy for PSC. Our preliminary data demonstrated that microRNA-34a (miR-34a) which is associated with cellular senescence was expressed much higher in the liver of multiple drug resistance gene 2 knockout (Mdr2-/-) mice which is a typical model of PSC than that in control mice, but the expression of Sirtuin 1(SIRT1) targeted by miR-34a was decreased compared to control mice, suggesting that miR-34a may be involved in the development of PSC. Therefore, this project will first observe the changes of liver function and fibrosis due to inhibition or overexpression of miR-34a in Mdr2-/- mice. Then, the mechanism related to the promotion effect of miR-34a on liver injury in PSC will be further explored, especially for the effect of down-regaulation of SIRT1 caused by increased expression of miR-34a on cellular senescence in the liver and inflammation mediated by NF-κB signaling pathway. Finally, the regulation effect of miR-34a/SIRT1 axis in the development of PSC will be elucidated, which can provide the novel theoretic basis and a promising target for the therapy of PSC.