miR-146a靶向SENP6抑制NEK7/NLRP3调控炎症与细胞转分化修复在机械通气相关性肺损伤中的作用及机制

机械通气相关性肺损伤（VILI）主要以肺泡膜破坏和炎性损伤为主；前期研究发现机械牵张导致炎性损伤，同时伴有II型肺泡上皮细胞转分化为I型的肺泡膜修复趋势，但机制未明。已知NEK7参与有丝分裂，预实验证实其还激活NLRP3炎性小体致炎，有报道SENP6致NLRP3去SUMO化调控炎症，筛选并验证调控炎症的miR-146a与SENP6有结合位点。由此假设：NEK7参与肺炎症和修复，且通过miR-146a调控SENP6介导NLRP3去SUMO化抑制NEK7/NLRP3结合、促进NEK7参与细胞转分化修复而减轻VILI。本课题拟从分子、细胞及动物水平，采用活体成像、RIP、KD/KO等技术，首次从基因靶向翻译后修饰调控炎症与修复角度，揭示VILI发生发展机制，阐明机械通气早期抑制炎症可促进肺组织修复，为临床VILI防治提供新思路。

Ventilator-induced lung injury (VILI) is characterized by destruction of alveolar membrane and inflammatory injury; Previous studies have found mechanical stretch led to inflammatory injury, accompanied by the transdifferentiation of type II alveolar epithelial cells into type I, but the mechanism is not clear. NIMA-related kinase 7 (NEK7) was known to be involved in mitosis, and preliminary studies confirmed it also activated NLRP3 inflammasome. SUMO-specific protease 6 (SENP6) has been reported to regulate inflammation by mediating desumoylation of NLRP3. Moreover, miR-146a that regulates inflammation has binding sites with SENP6. It is hypothesized that NEK7 is involved in inflammation and repair, miR-146a targeting SENP6 mediates desumoylation of NLRP3 to promote NEK7 involvement in transdifferentiation by inhibiting NEK7/NLRP3 interaction, alleviating VILI. In this study, we use in vivo imaging, RNA binding protein immunoprecipitation, knock down/out techniques to reveal the mechanism of VILI development from the perspective of the regulation of inflammation and repair by gene targeted post-translational modification. It is clarified that the early inhibition of inflammation can promote lung tissue repair, providing new ideas for the prevention and treatment of VILI.