RUNX1调控NFκB信号通路介导线粒体动力学失衡在急性肺损伤中的作用

气道上皮细胞损伤导致的炎症反应是ARDS/ALI关键环节。我们前期发现小鼠气道上皮细胞RUNX1下调可加重LPS诱导ALI肺部炎症并增加死亡率；深入研究发现RUNX1下调可活化NFκB通路并伴线粒体动力学异常。为研究RUNX1/NFκB介导的线粒体动力学异常在ALI中作用，我们拟构建RUNX1气道上皮细胞定向上调/下调小鼠ALI模型，以线粒体形态和相关基因表达为指标，分析线粒体动力学与ALI炎症反应相关性，探讨其在ALI中的作用。再通过基因编辑、小分子药物等干预，观察RUNX1/NFκB对线粒体动力学及ALI炎症反应的影响，确立RUNX1/NFκB通路对线粒体动力学失衡调控机制，并发现关键靶点；最后从线粒体自身生物活性及细胞死亡方式两方面探索线粒体动力学失衡影响ALI的途径。通过上述研究揭示RUNX1/NFκB/线粒体通路在ALI中的作用及分子机制，为临床开发新的ARDS干预靶点奠定基础。

The inflammatory response caused by airway epithelial cell injury is key in ARDS/ALI. Although our previous data indicated that deletion of RUNX1 in mice airway epithelial cells promoted lung inflammation in ALI induced by LPS and increased the mortality, the mechanism is unknown. Further study demonstrated that down-regulation of RUNX1 resulted into activation of NFΚB signaling and abnormality mitochondrial dynamics. To investigate the role of RUNX1/NFκB/mitochondrial dynamics in ALI, the association between abnormal mitochondrial dynamics and lung inflammation, survival time of mice, will be analyzed in ALI with RUNX1 down or up-regulation. In vitro experimental will also be carried out at the same time. CRISPR and small molecular substances will be used to block RUNX1/NFκB pathway for evaluating the effect of RUNX1/NFκB on the abnormality of mitochondrial dynamics. The influence of mitochondrial dynamics on the function of mitochondria, the expression of inflammatory cytokines and the death of airway epithelial cells, will also be investigated. The study will put new insight into the mechanism of ALI regulated by RUNX1/NFκB/mitochondrial dynamics and may discover new targets for the treatment of ARDS/ALI, a syndrome with high mortality.