基于 ERK/p38 MAPK 信号通路探讨Foxb1基因调控早产儿脑室周围白质软化后髓鞘修复的机制

Periventricular leukomalacia (PVL) is a major disease of hypoxic-ischemic encephalopathy. The pathology is demyelination due to the damage of oligodendrocyte precursor cells (OPC), that results in cognitive and movement disorders. It's difficult to interpose and treat PVL by inhibiting demyelination. Our previous results show that inactivation of Foxb1 could accelerate the proliferation and differentiation of oligodendroglia, however, the mechanism is mainly unknown. MAPK signalling pathway has a key role in OPC development. Many factors maintain homeostasis of oligodendroglia through MAPK pathway. The present study will cultivate neural stem cells (NSC) and OPC from Foxb1-Cre mice, and then generate PVL mouse model for in-vivo experiment. After adding the inhibitors of different MAPK pathway respectively, we attempt to find the crucial signalling pathway in regulating oligodendroglia development. Moreover,we will reversly validate the MAPK mechanism by in-vivo experiment, and then to elucidate the roles of Foxb1 in PVL. Eventually, this study could provide theoretical basis for molecular targeting therapy and novel pharmaceutical studies to treat PVL.

脑室周围白质软化(PVL)是早产儿缺血缺氧性脑损伤最主要的类型,病理表现为少突胶质前体细胞(OPC)受到破坏引起神经轴突脱髓鞘及髓鞘化障碍,而发生认知及运动障碍等。如何阻止少突胶质细胞系受损和加速髓鞘修复是治疗PVL迫切待解决的难题。前期发现Foxb1基因的失活可以促进OPC增殖并分化为成熟的少突胶质细胞,但具体机制未知。MAPK信号通路在OPC增殖分化中发挥重要作用,许多因子通过调节MAPK通路以维持OPC的稳态。本项目拟培养Foxb1基因敲除小鼠的神经干细胞(NSC)和OPC细胞,建立PVL动物模型,利用不同亚族的MAPK通路抑制剂阻断特定亚型信号观察OPC增殖与髓鞘化情况，借助动物模型论证Foxb1基因的下调能否延缓PVL的疾病进展，明确Foxb1调节髓鞘形成与MAPK通路的上下游关系,揭示Foxb1影响PVL进展的机制，为PVL的诊治提供新靶点。

脑室周围白质软化(PVL)是早产儿缺血缺氧性脑损伤最主要的类型,病理表现为少突胶质前体细胞(OPC)受到破坏引起神经轴突脱髓鞘及髓鞘化障碍,而发生认知及运动障碍等。如何阻止少突胶质细胞系受损和加速髓鞘修复是治疗PVL迫切待解决的难题。前期发现Foxb1基因的失活可以促进OPC增殖并分化为成熟的少突胶质细胞,但具体机制未知。MAPK信号通路在OPC增殖分化中发挥重要作用,许多因子通过调节MAPK通路以维持OPC的稳态。本项目培养Foxb1基因敲除小鼠的神经干细胞(NSC)和OPC细胞,建立PVL动物模型,利用不同亚族的MAPK通路抑制剂阻断特定亚型信号观察OPC增殖与髓鞘化情况，借助动物模型论证Foxb1基因的下调能否延缓PVL的疾病进展，明确Foxb1调节髓鞘形成与MAPK通路的上下游关系,揭示Foxb1影响PVL进展的机制，为PVL的诊治提供新靶点。