Netrin-1-DSCAM-AMPK-mTOR信号通路对脊髓损伤后自噬的调节作用及机制研究

The regeneration of axon in the central nervous system can be promoted by the Netrin-1 protein via phosphorylation of the AMPK, at the same time, the AMPK-mTOR signal pathway plays an important role in the regulation of autophagy after spinal cord injury (SCI). Our previous studies have shown the positive correlation between Netrin-1 protein and Beclin-1 protein expression, on the contrary, the negative correlation between Netrin-1 protein and mTOR protein expression also been shown, besides, the autophagosome expression also been increased by the Netrin-1 protein after SCI, which may imply the potential effect of the Netrin-1 on autophagy through regulating the mTOR after SCI. Based on the above foundation, the Netrin-1 gene knockout rats and the various factors of the Netrin-1-DSCAM-AMPK-mTOR signal pathway will been utilized to reveal the regulation and molecular mechanism of Netrin-1-DSCAM-AMPK-mTOR signal pathway on autophagy and verify the neuroprotection of autophagy regulated by Netrin-1-DSCAM-AMPK-mTOR signal pathway on the functional and pathological recovery after SCI. Ultimately, the fundamental research on SCI will been promoted, and the potential clinical therapeutic target and scheme for SCI may been provided by our study.

Netrin-1蛋白可使AMPK磷酸化并促进轴突再生，而AMPK-mTOR信号通路对脊髓损伤后自噬的调节发挥重要作用。前期研究发现：脊髓损伤后Netrin-1蛋白与自噬标志性蛋白Beclin-1的表达呈正相关，相反的是，Netrin-1蛋白与mTOR蛋白的表达水平呈负相关，经过透射电镜也可以观察到Netrin-1重组蛋白提高了自噬小体的表达水平，提示Netrin-1可能通过调节mTOR而影响脊髓损伤后自噬的表达水平。基于以上研究基础，本项目将利用Netrin-1基因缺陷大鼠以及细胞水平上Netrin-1-DSCAM-AMPK-mTOR信号通路标志性蛋白的不同处理因素，揭示脊髓损伤后该信号通路对自噬的调节作用及具体分子机制；验证该信号通路调控的自噬对脊髓损伤后神经功能恢复的作用。本课题的顺利开展将为脊髓损伤提供新的治疗靶点及方案，为脊髓损伤的基础研究提供有力的理论学依据和实验学基础。

Netrin-1蛋白可使AMPK磷酸化并促进轴突再生，而AMPK-mTOR信号通路对脊髓损伤后自噬的调节发挥重要作用。前期研究发现：脊髓损伤后Netrin-1蛋白与自噬标志性蛋白Beclin-1的表达呈正相关，相反的是，Netrin-1蛋白与mTOR蛋白的表达水平呈负相关，经过透射电镜也可以观察到Netrin-1重组蛋白提高了自噬小体的表达水平，提示Netrin-1可能通过调节mTOR而影响脊髓损伤后自噬的表达水平。基于以上研究基础，本项目将利用Netrin-1基因缺陷大鼠以及细胞水平上Netrin-1-DSCAM-AMPK-mTOR信号通路标志性蛋白的不同处理因素，揭示脊髓损伤后该信号通路对自噬的调节作用及具体分子机制；验证该信号通路调控的自噬对脊髓损伤后神经功能恢复的作用。本课题的顺利开展将为脊髓损伤提供新的治疗靶点及方案，为脊髓损伤的基础研究提供有力的理论学依据和实验学基础。