信号转导子和转录激活子STAT4信号通路在T细胞介导的肝炎中保护机制的研究

JAK-STAT信号通路在肝脏炎症中至关重要。而STAT4作为其成员之一,却较少受到关注。我们前期研究发现几种慢性肝炎患者肝内均有大量STAT4激活，而健康者肝内鲜有STAT4激活现象，证实STAT4在肝炎中亦起重要作用。在进一步研究中，我们得到出人意料的发现：在ConA诱导的肝炎模型中，STAT4并不促炎，而是起到保护作用。由此我们推测:在肝脏炎症过程中，免疫细胞中的STAT4一方面通过调控细胞因子间接影响肝细胞损伤；同时STAT4还可能影响免疫细胞直接对靶细胞的杀伤作用。为验证此观点，本项目计划检测肝炎患者血清和肝内STAT4的活化情况，评价STAT4激活与肝脏炎症反应程度的相关性；同时在STAT4缺陷和野生型小鼠上建立ConA模型；建立体外原代肝细胞培养体系，明确STAT4激活的调控机制以及在疾病发展过程中的重要临床意义，为进一步寻找治疗肝脏炎症的新靶向药物提供理论和实验基础。

Most cases of the chronic hepatitis are liver injury and inflammation caused by T cell-mediated immune response. The Janus Kinase-signal transducers and activators of transcription (JAk-STAT) signaling pathway has been shown to play crucial roles in hepatitis including viral hepatitis and autoimmune hepatitis. The roles of STAT4 in the pathogeneses of liver diseases are largely unknown, even though STAT1/2, STAT3 and STAT6 have been well proved to be very important in the progress of liver inflammation, fibrosis and cancer. In our previous study, we found much more activated STAT4 in the liver of patients with autoimmune hepatitis、hepatitis B and hepatitis C than that of health controls. Besides that, it is unexpected that more liver injury was found in STAT4 knockout mice compared with wild type mice. Based on these phenomenons, our hypothesis is: STAT4 is activated in the immune cells in ConA-induced hepatitis model and plays a protective role via regulation of inflammatory cytokines and inhibition of Fas/FasL in liver inflammatory response and liver injury. To validate the hypothesis, we plan to detect the level of activation of STAT4 in immune cells of serum and liver in various patients with hepatitis to evaluate the correlation of activated STAT4 and liver injury. To establish the animal model of ConA induced hepatitis and mouse primary hepatocyte culture system to identify the critical roles of STAT4 in the control of liver injury and liver inflammation. The project will be focus on the mechanisms of the activation and immune regulation of STAT4 in liver inflammatory response in order to provide theoretical and experimental evidences for the exploration of new drugs which target to STAT4 in the therapy of hepatitis.