mGluR5调控Activin A信号通路参与脊髓损伤修复的机制研究

脊髓损伤的治疗为学界难题，归因于损伤周围微环境的不利因素。M2型小胶质/巨噬细胞介导的神经炎症反应的保护作用为促进修复指明了方向。但如何维持M2型小胶质/巨噬细胞的持续极化仍存在挑战。我们前期研究表明mGluR5调控小胶质/巨噬细胞的极化而可能具有神经保护作用，调控Activin A信号通路介导神经元存活可能是其分子机制。本项目拟从调控小胶质/巨噬细胞极化出发，借助条件性敲除、小胶质细胞/神经元共培养、神经行为学/形态学/机能学等方法，研究脊髓损伤后mGluR5在小胶质/巨噬细胞极化调控中的作用；分析Activin A信号通路介导神经保护的具体途径；探讨mGluR5调控Activin A信号通路参与小胶质/巨噬细胞极化的具体机制；从而明确调控mGluR5及Activin A信号通路在脊髓损伤修复和功能恢复中的作用。以期望阐明小胶质/巨噬细胞在体极化机制，并为脊髓损伤修复提供新的视点和策略。

The treatment of spinal cord injury has little effect on the injury repair. The main reason lies in the difficulty of regenerating inner mature neurons and adverse factors of surrounding microenvironment. With the appearance of neuroprotective effect of neuroinflammation, especially M2 microglial/macrophage, it is possible for us to improve the microenvironment and promote repair. However, how to sustained polarization of M2 microglia/macrophages in the local microenvironment has remained largely unknown. Our previous studies showed that mGluR5 may play a neuroprotective role through the regulation of microglial/macrophage polarization, but the exact mechanism remains unclear. Our recent results indicate that mGluR5 is involved in regulating the expression of Activin A receptor, and Activin A signaling pathway mediates neuronal survival. In this study, we will make all effort to clarify the molecular mechanism of mGluR5-mediated microglial/macrophage polarization after spinal cord injury by using mGluR5 conditional knock-out mice, cell culture, virus injection and molecular biological methods. Meanwhile, the role of Activin A signaling pathway mediating neuroprotection will be studied. Additionally, the role of mGluR5 and Activin A in the modulation of injury repair and functional recovery in vivo will also be investigated in this study by using neuromorphological and behavioral methods. It is expected to offer more valuable information for the polarization mechanisms of microglia/macrophage in vivo and the establishment of therapeutic strategies for nerve regeneration after spinal cord injury.