15-PGDH通过抑制NLRP3炎症小体活化而保护LPS所致急性肾损伤的机制研究

目前，15-PGDH在LPS诱导的AKI中的生物学功能尚不清楚。申请者在发现15-PGDH可通过抑制NLRP3炎症小体-IL-1β/IL-18通路活化而保护LPS诱导的AKI的基础上，进一步研究发现15-PGDH对自噬具有促进作用。自噬是NLRP3炎症小体活化的一个重要调控因素，因此，本项目提出“15-PGDH通过促进自噬而抑制NLRP3炎症小体-IL-1β/IL-18通路活化从而保护LPS诱导的AKI”的工作假说。本项目拟在此基础上，深入探讨15-PGDH在LPS所致AKI中的表达模式；采用慢病毒注射的方法从整体动物水平探讨15-PGDH在LPS诱导的AKI中的功能；采用15-PGDH基因过表达及RNA干扰从细胞水平探讨其对LPS所致NLRP3炎性小体活化及肾小管上皮细胞损伤的影响；并通过深入探讨15-PGDH对自噬的调节作用从而阐明15-PGDH调控NLRP3炎性小体活化的机制。

Now the role of 15-PGDH during LPS-induced acute kidney injury is not clear yet. In this study 15-PGDH is found to protect against LPS-induced AKI by inhibiting NLRP3 inflammasome--IL-1β/IL-18 pathway activation; our further study indicates that 15-PGDH regulates renal autophagy in response to LPS stimuli. As autophagy is an important regulator of NLRP3 inflammasome--IL-1β/IL-18 pathway, it is supposed that 15-PGDH regulates LPS-induced NLRP3 inflammasome--IL-1β/IL-18 pathway activation and subsequent AKI via autophagy. In this project we will further detect the expession of 15-PGDH in LPS-induced AKI; illustrate the effect of 15-PGDH on NLRP3 inflammasome--IL-1β/IL-18 pathway activation and subsequent AKI in vitro and in vivo; determine whether 15-PGDH regulates LPS-induced NLRP3 inflammasome--IL-1β/IL-18 pathway activation and subsequent AKI via autophagy. In together, we expect to illustrate the function of 15-PGDH and its mechanism in LPS-induced AKI.