Drp1介导的线粒体动力学失衡在EV71致中枢神经病变中的作用机制研究

以中枢神经系统损害为主要表现的重症手足口病严重威胁婴幼儿健康，而发病机制不清是制约抗病毒药物研发的主要因素。肠道病毒71型（EV71）是引起重症手足口病的重要病原体，其感染细胞后导致线粒体功能受损，但机制不详。我们通过体内外模型发现EV71能影响神经组织/细胞的线粒体动力学蛋白Drp1、Drp1-Ser616以及Opa1的表达，使线粒体形态和运动改变，破坏了线粒体动力学平衡，最终导致细胞病变死亡。然而，EV71是如何影响Drp1的功能？这种Drp1介导的线粒体动力学失衡对于EV71的致中枢神经病变作用和机制是什么？以及干预Drp1活性对EV71的复制有何影响均不清楚。故本项目拟通过体内外模型，系统分析EV71致中枢神经病变中线粒体动力学的改变特征及Drp1的调控机制，同时观察干预Drp1活性对EV71致中枢神经病变可能的治疗作用，以期为研发靶向线粒体动力学的新型抗EV71药物提供理论基础。

The central nervous system damage is the main manifestation of severe hand-foot-mouth disease(HFMD), which seriously threatens the health of infants and children. The unclear pathogenesis is the main factor restricting the development of antiviral drugs. In vivo and in vitro models, we found that EV71 can affect the expression of Drp1, Drp1-Ser616 and Opa1 of nerve tissues/cells, so as to change the mitochondrial morphology and movement, disrupt the balance of mitochondrial dynamics, and eventually lead to cell death. However, how does EV71 affect the function of Drp1? What is the role and mechanisms of Drp1 mediated mitochondrial dynamic imbalance in EV71? What is the effect of intervening Drp1 activity on EV71 replication? None of this is clear. So the project is proposed on the basis of past research, through the central nervous system infection in vivo and in vitro model to analyze the change of mitochondrial dynamics in the central nervous pathological changes caused by EV71 characteristics and regulatory mechanism of Drp1, at the same time observe the intervention Drp1 active effect on the treatment of central nervous pathological changes caused by EV71. The research works will provide some evidences for developing effective anti-EV71 drugs based on mitochondrial dynamics as the new therapeutic targetegy and provide new ideas and methods for clinical treatment of EV71 infection.