ATF3负调控髓系抑制性细胞氧化应激及其介导NASH形成的机制研究

Liver local immune regulation disorder is an important pathogenesis of nonalcoholic steatohepatitis (NASH). In our preliminary study myeloid-derived suppressor cell (MDSC) could promoting the development of NASH, and the activation transcription factor 3 (ATF3) is an important participator (J Biol Chem, 2016), the specific regulatory mechanism remains to be elucidated. We further found that the oxidative stress activation was significantly increased in NASH model mice or ATF3 knockout mice derived MDSC. In contrast, inhibiting the activity of ROS could eliminate the effect of MDSC mediated NASH. Based on these observations, we propose that activation of MDSC oxidative stress causes NASH regulated by ATF3. In order to verify this hypothesis, we intend to investigate the mechanism of ATF3 regulation of oxidative stress. Determine the MDSC mediated the effect of oxidative stress causes NASH. Demonstrate the mechanism of ATF3 in regulate MDSC oxidative stress. Demonstrate the pathological significance of MDSCs oxidative stress in NASH patient. The implantation of this proposal will uncover a novel mechanism dictating MDSC promotes the occurrence of NASH, and also provide potential therapeutic target for MDSC-based immunotherapy.

肝脏局部免疫调节紊乱是非酒精性脂肪性肝炎（NASH）的重要致病机制。我们前期发现：髓系抑制性细胞（MDSC）可促进NASH发生，ATF3通过调控MDSC功能参与NASH的发生（J Biol Chem, 2016），但具体调控机制尚待阐明。我们进一步研究发现，NASH模型小鼠或ATF3基因缺陷小鼠来源MDSC细胞中与氧化应激活性相关的ROS表达显著升高；而抑制ROS活性则可消除MDSC对NASH的促进作用。据此提出“ATF3通过调控MDSC氧化应激介导NASH形成”。本项目拟从以下四方面对此进行研究：研究ATF3对氧化应激的调控作用；研究MDSCs介导氧化应激对NASH的促进作用；ATF3调控MDSCs氧化应激分子机制研究；最后利用临床NASH患者样品对其病理意义进行研究。项目的实施将揭示MDSC促进NASH发生的分新机制，为靶向MDSC的NASH免疫治疗提供干预靶标。

肝脏局部免疫调节紊乱是非酒精性脂肪性肝炎（NASH）的重要致病机制。我们前期发现：髓系抑制性细胞（MDSC）可促进NASH发生，ATF3通过调控MDSC功能参与NASH的发生，但具体调控机制尚待阐明。本项目研究表明：NASH模型小鼠或ATF3基因缺陷小鼠来源MDSC细胞中与氧化应激活性相关的ROS表达显著升高；而抑制ROS活性则可消除MDSC对NASH的促进作用。项目的实施将揭示MDSC促进NASH发生的分新机制，为靶向MDSC的NASH免疫治疗提供干预靶标。