prr5l对中枢神经系统髓鞘形成与再生的调控作用

促进内源性少突胶质细胞分化和髓鞘再生是治疗多发性硬化的重要策略之一。然而目前调控髓鞘形成及损伤修复的分子机制仍不完全清楚，尤其是控制髓鞘生长（长度和厚度）的机理。基于再生髓鞘的形态和厚度与生理状态下产生的髓鞘存在差别，我们通过分析小鼠出生后髓鞘形成的高峰期和成年小鼠髓鞘损伤后再生阶段的基因表达差异发现：髓鞘再生阶段，prr5l的表达水平显著降低；在少突胶质细胞（OL）条件性敲除prr5l基因的小鼠中，胼胝体髓鞘的厚度显著降低。为了深入研究prr5l在髓鞘形成与再生中的作用及机制，本项目将通过建立OL条件性prr5l基因敲除的小鼠模型、铜腙或溶血卵磷脂诱导的脱髓鞘模型和实验性自身免疫性脑脊髓炎模型，结合磷酸化蛋白质组学、RNA-seq技术和电镜等多种方法研究prr5l对OL分化、髓鞘形成及损伤修复过程的影响。本项目有助于阐明调控中枢髓鞘形成与再生的分子机制，为多发性硬化的药物开发提供新靶点。

Promoting endogenous oligodendrocytes formation and remyelination is one of the important strategies in the treatment of multiple sclerosis. However, the molecular mechanism regulating myelin formation and repair is still not clear, especially the mechanism regulating myelin growth (length and thickness). Based on the difference between the shape and thickness of the regenerated myelin and the myelin produced in physiological state, we analyzed the gene expression difference between the peak period of myelin formation after birth and the regeneration stage after myelin injury in adult mice, and found that: prr5l expression was significantly reduced in the myelin regeneration stage; The myelin thickness was significantly decreased in mice with conditional deletion of prr5l in oligodendrocyte. To further study the role and mechanism of prr5l in the formation and regeneration of myelin, this project will study the effect of prr5l on OL differentiation, myelination and myelin repair using mice with conditional deletion of prr5l in oligodendrocyte, cuprizone or lysolecithin-induced demyelination model and experimental autoimmune encephalomyelitis model, combined with phosphorylated proteomics, RNA-seq technology and electron microscopy. This project is helpful to elucidate the molecular mechanism regulating the formation and regeneration of myelin and provide new targets for drug development of multiple sclerosis.