MST1调控线粒体自噬在LPS所致急性肺损伤中的作用及机制研究

线粒体自噬在急性肺损伤(ALI)发病过程中发挥着重要的作用。哺乳动物STE20样激酶1（MST1）是一种蛋白激酶，通过JNK/p53信号通路调控线粒体功能和自噬，参与细胞凋亡、炎症反应、氧化应激等过程，但MST1在ALI中的作用及机制研究未见报道。我们前期研究发现MST1在ALI小鼠肺组织中表达明显增加，抑制MST1减轻ALI的炎症反应、氧化应激与损伤，与线粒体自噬相关。在此基础上提出假说ALI时，MST1异常活化，通过JNK/p53信号通路的活化下调BNIP3表达抑制了线粒体自噬，参与了ALI的炎症反应、氧化应激和细胞凋亡，促进了ALI的发生和发展。本项目在前期基础上，通过基因沉默技术、过表达和小分子抑制剂调控MST1的水平和活性，从动物以及细胞水平来研究MST1调控线粒体自噬在ALI中的作用及其机制。本项目的实施将为ALI的防治提供新的靶点和理论基础。

Mitophagy plays an important role in the pathogenesis of acute lung injury (ALI). Mammalian STE20-like kinase 1 (MST1) is a protein kinase which can regulate mitochondrial function and autophagy through the JNK/p53 signaling pathway, and takes part in apoptosis and inflammatory response, but little research has been performed regarding the role and mechanisms of MST1 in ALI. Our previous research found that MST1 expression was significantly increased in the lung tissue of ALI mice and that inhibiting MST1 could reduce the inflammation, oxidative stress and injury of ALI. Therefore, we hypothesized that aberrantly activated MST1 can activate JNK/p53 signaling pathway that can down-regulate BNIP3 expression, which leads to decrease in mitophagy and participates in inflammatory response, oxidative stress and apoptosis in ALI. In this study, we will examine the role of MST1 on mitophagy in ALI and the mechanisms through manipulating the gene level and activity of MST1 using gene silencing technology, construction of overexpression vectors and pharmacological inhibitor in animal and cell models. The implementation of this study will provide a new target and theoretical basis for the prevention of ALI.