Rab18-Rab7互作调控内质网应激保护脓毒症急性肺损伤的作用及机制研究

内质网应激诱导肺泡上皮细胞凋亡是脓毒症急性肺损伤（ALI）的重要机制。我们初步研究发现Rab18与Rab7在脓毒症ALI中显著低表达，Rab18的下调激活内质网应激PERK-eIF2α通路促进细胞凋亡；过表达Rab18可增强线粒体自噬减轻细胞损伤；且Rab18可能与Rab7存在互作。据此提出假说Rab18与Rab7互作维持内质网稳态与线粒体自噬，保护脓毒症ALI。本项目拟进一步：从临床样本分析Rab18、Rab7与脓毒症ALI的相关性；在细胞和动物水平明确Rab18与Rab7互作的模式，揭示Rab18-Rab7互作缓解内质网应激，增强线粒体自噬，减轻细胞损伤的作用；阐明脓毒症时Rab18下调，其与Rab7解离，激活UPR信号通路和增强ROS的产生，促进细胞凋亡的分子机制。本项目提出Rab18-Rab7互作维持内质网稳态减轻脓毒症ALI，具有机制创新意义，有望为脓毒症ALI的诊治提供新策略。

Alveolar epithelial cell apoptosis which mediated by endoplasmic reticulum stress apoptosis plays a critical role in the pathogenesis of septic acute lung injury (ALI). In our preliminary study, we found that Rab18 and Rab7 were significantly down-regulated in septic ALI. Downregulation of Rab18 activated endoplasmic reticulum stress pathway PERK‐eIF2α mediated apoptosis. Rab18 overexpression induces mitochondrial autophagy and improves cell survival. Rab18 may interact with Rab7. We speculate that Rab18 interacts with Rab7 to maintain endoplasmic reticulum homeostasis and mitochondrial autophagy and protect against lung injury. The purpose of this project is to further analyze the correlation between Rab18/Rab7 and septic ALI in clinical samples. To clarify the mode of interaction between Rab18 and Rab7 at the cellular and animal level. To reveal the role of Rab18-Rab7 interaction in relieving endoplasmic reticulum stress, enhancing mitochondrial autophagy, and alleviating cell injury. To further clarify the molecular mechanism of down-regulation of Rab18, dissociation from Rab7 which would activate UPR signal pathway, augment ROS production, and promote apoptosis in sepsis. This project proposes a new mechanism of Rab18-Rab7 interaction in sepsis to maintain endoplasmic reticulum homeostasis which may improve cell survival, and is expected to become an important target for diagnosis and treatment of septic ALI.