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

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.

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。

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。. 通过研究本项目（1）发现了肺上皮细胞中线粒体动力学失衡与LPS诱导的ALI的发生和发展密切相关；（2）阐明了肺上皮细胞RUNX1表达缺失可加重LPS诱导的线粒体损伤和炎症反应；（3）证明了定向上调肺上皮细胞RUNX1可部分缓解LPS诱导的线粒体损伤和炎症反应；（4）揭示了RUNX1一方面可通过影响DRP1的表达和磷酸化水平调节线粒体的分裂，进而实现维持线粒体动力学平衡，减轻肺损伤；另一方面，RUNX1还可通过促进损伤线粒体的清除缓解肺部损伤；（5）拓展了RUNX1是一种可调控线粒体的新分子，为防治ALI提供策略。. 既往针对急性炎症性疾病的研究多聚焦于经典的炎症相关信号通路，本研究基于前期研究，从核心结合因子RUNX1入手，持续探讨ALI的分子机制。研究发现，RUNX1是一种调控线粒体蛋白，且肺上皮细胞RUNX1表达缺失介导的线粒体动力学水平失衡和线粒体自噬抑制是LPS诱导致ALI的重要病理分子机制。线粒体已成为多种疾病的潜在治疗靶点，因此，本研究揭示了ALI新的病理分子机制和拓展了RUNX1的生物学功能之外，还揭示了RUNX1及RUNX1调控的线粒体靶点可能为防治ALI提供创新切实的新视角。