M1-Th17免疫微环境调控Notch通路抑制TBI后内源性NSCs分化成熟的机制研究

颅脑创伤（TBI）诱导新生神经干细胞（NSCs）分化成熟为有功能的神经元，是内源性成体NSCs修复神经功能的首要前提。经证实，内源性新生NSCs分化成熟的能力非常有限。微环境影响着新生NSCs的命运。炎症反应在TBI继发性脑损伤进程中占据主导作用，因此TBI后的免疫微环境是阻碍新生成体NSCs分化成熟的关键因素。本项目拟从明确TBI后免疫微环境动态变化及其影响内源性神经新生机制的角度出发，在TBI临床病例分析的基础上，利用TBI动物模型探讨巨噬细胞/小胶质细胞M1/M2极化影响Th17/Treg分化，及后续调控Notch信号通路对海马新生NSCs分化成熟的作用；通过体外细胞实验进一步阐明巨噬细胞/小胶质细胞M1-Th17-Notch轴对NSCs分化成熟的作用及机制，从而为更有效诱导内源性神经再生以及建立适宜的分化微环境提供理论指导。

That traumatic brain injury (TBI) induces the differentiation of newborn neural stem cells (NSCs) into functional neurons is the primary premise for endogenous NSCs to repair neurological function. It has been proved that the ability of differentiation and maturation of endogenous newborn NSCs is very limited. Microenvironment affects the fate of newborn NSCs. Inflammatory reaction plays a leading role in the process of secondary brain injury of TBI, so the immune microenvironment after TBI is the key factor to hinder the differentiation and maturation of newborn NSCs. To clarify the change of immune microenvironment and its effects on endogenous neurogenesis after TBI, based on TBI analysis of clinical cases, how M1/M2 polarization of macrophages/microglia affects Th17/Treg differentiation, and its subsequent regulation of Notch signaling pathway in hippocampus of newborn NSCs differentiation and its mechanism is investigated with a TBI model in rats. The role of macrophage/microglia M1-Th17-Notch axis on NSCs differentiation and maturation and mechanism is further elucidated in cells. The aim of this study is to provide theoretical guidance for more effective induction of endogenous neurogenesis and establishment of suitable differentiation microenvironment.