电刺激诱导的靶源性信号对周围神经再生选择性和功能恢复的影响及机制

Promoting the selective regeneration of axons and function recovery are the core issues in regard of periphery nerve repair. The target-derived signals play the key role in promoting axon selective regeneration. Our previous works indicated that the correct projection rate of motor neurons is reduced after muscle deprivation. After periphery nerve injury, the muscles become atrophy and fibrosis. However, electrical stimulation can make denervated muscles atrophy reversal and improve its function. So far there is no report about muscles electrostimulation enhancing target-derived signals and promoting axon selective regeneration. Recently, studies showed that electrical stimulation upregulates the expression of PSA on axons. PSA can conduct axon selective regeneration, and there is an increase in the expression of PSA after periphery nerve injury. These researches suggest that electrical stimulation might induce PSA expression in muscles in order to promote axon selective regeneration. Therefore, based on our previous works, this study would observe axon regeneration and selectivity in vivo and in vitro by muscles electrostimulation in order to clarify the effect of target organ electrostimulation on functional recovery of injured nerve. Meanwhile, the role and the mechanisms of PSA will also be analyzed in this work. This study would reveal the signal conducting axon selective regeneration and the regulation mechanism and provide a new method for solving the tough problem of selective regeneration and function recovery.

促进神经选择性再生，提高功能恢复是周围神经损伤(PNI)治疗康复的核心问题和难题。靶源性信号在促进神经选择性再生中具有至关重要的作用。前期研究发现失肌肉联系的神经存在较低的再生选择性，错误投射率较高。PNI后，肌肉出现萎缩、纤维化，影响了神经选择性再生。然而电刺激可逆转失神经肌肉萎缩，改善其功能。但电刺激肌肉能否促进神经再生及其选择性、提高功能恢复却未见报道。最近研究显示电刺激能上调神经PSA表达。而PSA可引导神经选择性再生；PNI后，肌组织中PSA表达上调。提示电刺激可能促进肌细胞表达PSA以促进神经选择性再生。所以本项目在前期研究基础上，从预防肌肉萎缩方面入手，以电刺激为手段，观察神经再生及其选择性，明确电刺激靶器官对神经功能恢复的作用；并以PSA为切入点，分析PSA在其中的作用及调节机制，了解引导神经选择性再生的信号分子及调控机制，为解决当前神经损伤治疗康复难题提供新的思路。

促进神经再生、提高功能恢复是周围神经损伤(PNI)治疗康复的核心问题和难题。而影响周围神经再生的因素包括内在因素神经元本身、外在因素Schwann细胞、靶器官信号等。靶源性信号在促进神经再生中具有至关重要的作用。前期研究发现失肌肉联系的神经存在较低的再生选择性，错误投射率较高。PNI后，肌肉由于缺乏神经的电信号和营养而出现萎缩、纤维化，影响了神经选择性再生。而模拟电信号的电刺激可逆转失神经肌肉萎缩，改善其功能。所以本项目在前期研究基础上，从预防肌肉萎缩方面入手，以电刺激为手段，观察神经再生及其选择性，探讨电刺激靶器官对神经功能恢复的作用。结果表明电刺激可提高肌细胞的活性、改变其生长周期，提高成肌因子表达；并提高神经损伤后骨骼肌肌纤维直径、湿重、成肌因子表达，减缓其萎缩，增强其收缩功能。电刺激靶器官可提高再生神经纤维数量、纤维直径、髓鞘厚度，增加骨骼肌内运动终板的形成，并通过提高PSA-NCAM信号促进周围神经选择性再生，促进神经功能恢复；而且还表明电刺激可通过ERK/Ca2+信号上调成肌因子表达并提高再生神经内促神经生长因子如BDNF、IGF、GDNF及受体TrkB等表达。本项目的研究明确了电刺激可减缓神经损伤后的骨骼肌萎缩，促进神经再生，提高神经功能恢复，并阐明了促进神经选择性再生的分子基础，为临床电刺激治疗周围神经损伤、促进神经功能恢复提供了理论基础和实验依据。