与少突胶质细胞分化相关的microRNA分子对脊髓损伤后再髓鞘化和神经功能恢复的作用研究

Demyelination is one of the most significant pathological changes following spinal cord injury (SCI). Studies have indicated that preservation of as few as 5% of descending brainstem systems to the lumbar cord will retain the function of the segmental systems that control hindlimb movement. But chronic demyelination greatly destroies the electronic activity transduction alone the remaining axons and thereafter inhibits the recovery of hindlimb movement. In order to improve remyelination and motor function after SCI, strategies designed for promoting endogenous remyelination or replenishing the lost myelinating cell by transplantation are highly favored. In our previous work, we have identified the essential role of several microRNAs (miRs) in regulating the generation, differentiation and myelination process of developing oligodendrocyte, which is the myelinating cell in the central nervous system. In current study, we plan to apply these critical molecules in spinal cord contusion model by transfecting endogenous progenitor cell with these miR genes and by transplanting oligodendrocyte precusor cell overexpressing these genes, then examine the motor function recovery of animals and study the related mechanisms,especially myelination. It is conceivable that the manipulation of miRNA genes modulating the developmental process in the study of SCI therapy will provide new therapeutic targets for myelin repair after injury and is important for further theoretical and experimental research.

脊髓损伤(SCI)后的轴突脱髓鞘是最重要的病理特征之一。研究表明大鼠SCI后，损伤区若残存一定数量的下行纤维就可以维持基本运动功能；但神经纤维脱髓鞘往往使得神经元轴突的传导能力受损，并显著限制运动功能恢复。因此，通过动员内源性或移植补充外源性的中枢神经系统髓鞘形成细胞-少突胶质细胞，并促进其再髓鞘化，对神经功能恢复非常重要。我们前期的研究证实，几种微小RNA分子在少突细胞的发生、分化和髓鞘化过程中发挥重要的调控作用，这为我们应用基因修饰的方法促进SCI后少突细胞的分化成熟提供了崭新的思路。本研究我们计划利用SCI动物模型，从诱导内源性神经前体细胞向少突细胞分化，以及移植基因修饰的少突前体细胞并促进其成熟两方面，探讨对神经纤维功能恢复的影响及损伤区的髓鞘化等组织学变化。我们将发育过程中重要的基因表达调控事件应用到SCI修复的研究中，为今后开展相关疾病的治疗研究提供了重要的实验基础和理论依据。

我们前期的工作观察到miR-219分子在中枢神经系统发育过程中发挥了重要的调控少突胶质细胞分化成熟的作用，这为该分子应用于治疗一些相关的脱髓鞘疾病提供了重要的理论基础。我们计划将编码该分子的逆转录病毒颗粒注射到局部脱髓鞘动物的损伤区，观察过表达miR-219是否可以促进内源性NG2胶质细胞向成熟少突胶质细胞的分化，以及是否可以促进损伤后的再髓鞘化。我们已经成功制备表达miR-219的逆转录病毒颗粒，而且成功建立了脑白质局部注射LPC毒剂诱导脱髓鞘的损伤模型。为了更加方便、直接的观察发育和损伤过程中中枢神经系统髓鞘形成细胞的膜结构变化，我们还制作了CNP-mEGFP转基因小鼠，利用该小鼠观察过表达miR-219对LPC损伤后脱髓鞘病变的影响作用正在研究中。我们的工作将为以microRNA作为治疗靶点，促进脱髓鞘疾病的成功再髓鞘化提供重要的实验依据和理论基础。