轴突再生抑制因子Nogo-A在少突胶质细胞分化和髓鞘化中的作用和机理

项目名称： 轴突再生抑制因子Nogo-A在少突胶质细胞分化和髓鞘化中的作用和机理

项目编号： No.30800325

项目类型： 青年科学基金项目

立项/批准年度： 2009

项目学科： 医药、卫生

项目作者： 赵湘辉

作者单位： 中国人民解放军第四军医大学

项目金额： 18万元

中文摘要： 中枢神经系统髓鞘来源的Nogo-A分子是一种重要的神经元轴突再生抑制分子。在创伤性脊髓损伤动物模型中，抑制Nogo-A/Nogo受体信号途径可显著增强受损神经元的轴突再生并促进神经功能恢复。我们前期研究表明，Nogo-A在少突胶质细胞体外分化成熟过程中维持高水平表达，应用具有功能封闭活性的抗体作为Nogo-A的拮抗剂处理少突前体细胞可引起细胞发育不良，并抑制细胞的分化。本课题计划探讨在调控少突细胞内源性Nogo-A表达水平的条件下，是否对细胞分化存活、或者胶质细胞－神经元共培养系统中髓鞘化程度有影响，并对可能参与调节的相关信号分子进行研究。目前取得的结果主要有：下调培养细胞中内源性Nogo-A分子的表达对于少突细胞的分化没有显著影响，但将促进细胞的突起分支和形态分化，该功能与RhoGTPase家族分子的活性变化并没有关系；在氧化应激损伤诱导的少突细胞凋亡模型中，由TAT-M9蛋白转导介导的胞内Nogo-A截短体水平升高，将促进细胞的存活。因此，据我们和他人的结果，我们推测Nogo-A可能并不影响少突胶质细胞的分化成熟，而与该细胞的存活有一定关系。这为今后研究的方向提供了重要实验依据。

中文关键词： 少突胶质细胞；Nogo-A；分化；凋亡

英文摘要： The myelin protein Nogo-A is one of the most important axonal outgrowth inhibitors in the central nervous system. Blocking Nogo-A/Nogo receptor signaling pathway will greatly enhance axon regeneration and neuronal function recovery. Our previouse work have found that Nogo-A is highly expressed during the development of oligodendrocyte and application of inhibitory antibody against Nogo-A in the culture system will block the differentiation of oligodendrocytes. In current project, we aim to investigate the effect of modulating the expression level of Nogo-A, especially on the differentiation of oligodendrocyte and on the involvement of possibly associated signaling factors. By silencing the expression of Nogo-A, we found that the differentiation of oligodendrocytes was not influenced, but the process branching was greatly enhanced. And this effect was RhoGTPase activity independent. In an oxidative stress induced apoptosis model, the transduction of TAT-M9 fusion protein, which contains Nogo-A short form, protected oligodendrocyte from death. Therefore, according to our work and others' reports, we speculate that endogenous Nogo-A is not involved in the maturation of oligodendrocytes, but is associated with its apoptosis, at least in current models. These data have set important foudations for our further research.

英文关键词： Oligodendrocyte; Nogo-A; Differentiation; Apoptosis