强啡肽通过线粒体自噬途径缓解脓毒症中枢神经系统炎症的机制研究

脓毒症病死率高，其中脓毒症相关性脑病（SAE）是导致脓毒症病死的重要原因，降低炎症水平被认为是治疗SAE的关键。我们在前期研究中发现强啡肽可显著降低脓毒症小鼠中枢神经系统的炎症水平；在分子水平上，强啡肽可促进自噬相关蛋白的表达，抑制NLRP3炎症小体的表达；强啡肽还可以挽救脓毒症模型细胞的线粒体膜电位下降，而依赖于线粒体膜电位的PINK1/Parkin信号可激活线粒体自噬。我们因此推测：强啡肽通过PINK1/Parkin信号通路诱导线粒体自噬，修复损伤线粒体，进而抑制NLRP3炎症小体激活，减轻脓毒症中枢神经系统的炎症水平。本项目拟从细胞和动物水平，明确强啡肽对脓毒症中枢神经系统炎症水平的抑制作用，并探讨其分子机制，为脓毒症的临床治疗提供新的有效药物和治疗靶点。

Sepsis has a high mortality rate, among which sepsis associated encephalopathy (SAE) is an important cause of death from sepsis, and reducing inflammation is considered to be the key to treatment of SAE. Previous studies have found that dynorphin can effectively reduce central nervous system (CNS) inflammation. At the molecular level, dynorphin can promote the expression of autophagy-related proteins and inhibit the expression of NLRP3 inflammasome. Dynorphin can also rescue the mitochondrial membrane potential decreasing of cell model of sepsis, and PINK1/Parkin signal which dependent on the mitochondrial membrane potential can activate mitochondrial autophagy. Therefore, a scientific hypothesis is proposed: dynorphin induces mitochondrial autophagy through PINK1/Parkin signaling pathway to repair damaged mitochondria, thereby inhibiting the activation of NLRP3 inflammasome and reducing the inflammatory level of sepsis central nervous system. This project aims to clarify the inhibitory effect of dynorphin on the inflammatory level of central nervous system in sepsis from the cellular and animal levels, and explore its molecular mechanism. So as to provide new effective drugs and therapeutic targets for the clinical treatment of sepsis.