缓释bpV(pic)复合脊髓脱细胞支架调控mTORC1信号通路在修复脊髓损伤中的作用及机制

After spinal cord injury, limited CNS cell regeneration capacity and damaged microenvironment lead to difficulties in repairing. PTEN was originally identified as a negative regulator of PI3K/AKT mTORC1 signaling, a main regulator of cell growth, metabolism and survival. Recent study reported PTEN deletion could enhance the regenerative ability of adult corticospinal neurons, which provide us a potential therapeutic strategy for adult spinal cord injury. Sustained releasing PTEN specific inhibitor - bpV(pic) composite embedded in the spinal cord acellular scaffold may could promote neural network reconstruction. But the mechanism of action is unclear. Using polylactic acid (PLA) nanospheres coated bpV(pic) composite embedded in the spinal cord highly biomimetic acellular scaffold which inhibit PTEN signaling through axonal transportation. We want to use it to repair rat spinal cord injury, by means of cell and molecular biology, especially using tracer technology to observe axonal regeneration whether it reconstruct reflex loop, we assessed clinical efficacy in rat spinal cord injury. Here we want to build a therapeutic platform of PLA nanoparticles coated molecules regulating scaffold for the treatment of spinal cord injury. It is hoped that inhibitor composite which regulate cell signaling pathway embedded in the spinal cord acellular scaffold would be used for basic clinical research. It maybe provide new ideas for treatment of spinal cord injury.

脊髓损伤后中枢神经细胞有限的再生能力及局部抑制再生的微环境是导致脊髓损伤修复再生困难的主要原因。PTEN是PI3K/AKT/mTORC1信号通路的负性调节因子，PTEN基因敲除显著增强神经元轴突自我再生能力，给脊髓损伤治疗带来希望。但通过PTEN特异抑制剂bpV(pic)复合高度仿生的脊髓脱细胞支架对脊髓损伤后神经网络重建的作用与机制尚不清楚。本项目拟通过聚乳酸（PLA）纳米微球包被BPV(Pic) 复合高度仿生脊髓脱细胞支架修复脊髓损伤，即通过轴浆转运抑制中枢神经元PTEN活化经mTORC1信号通路强烈激活神经元轴突自我再生能力，结合支架改善局部微环境作用修复大鼠脊髓损伤。并分别在分子、细胞与整体水平研究进行评估，重点通过示踪技术观察轴突再生重建神经反射环路的效果，目标是建立PLA纳米微球包被细胞信号调控分子的支架作为平台治疗脊髓损伤，为脊髓损伤的防治提供新思路。

脊髓损伤是脊柱神经系统严重的创伤，损伤后局部组织破坏和微循环障碍，引起局部损伤加重和周围神经细胞广泛坏死。脊髓损伤后中枢神经细胞有限的再生能力及局部抑制再生的微环境是导致脊髓损伤修复再生困难的主要原因。本项目通过PLGA纳米微球包被bpv(pic) 复合高度仿生脊髓脱细胞支架修复脊髓损伤，通过轴浆转运抑制中枢神经元PTEN活化经mTORC1信号通路强烈激活神经元轴突自我再生能力，发现bpv(pic) 可以明显改善脊髓损伤的修复，构建的药物缓释新材料能够增强修复效果。深入分析发现推测bpv（pic）是通过抑制PTEN的活性，激活mTOR和ERK信号，进而增强细胞的自噬，抑制细胞的凋亡水平，从而能够促进神经元的修复减少神经元的丢失；同时发现在脊髓损伤部位巨噬细胞的M1/M2极化受到一定影响，M1极化出现一定的减弱，M2极化出现增强，促进脊髓损伤后的运动功能恢复。我们的发现说明PTEN可以作为脊髓损伤的潜在治疗靶点，同时PLGA复合脊髓脱细胞支架在治疗脊髓损伤中可以为药物提供更好的承载作用。