Gab在中枢神经系统髓鞘发育与髓鞘损伤修复中的功能及其机制

项目名称： Gab在中枢神经系统髓鞘发育与髓鞘损伤修复中的功能及其机制

项目编号： No.31200818

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 神经、认识与心理学

项目作者： 周亮

作者单位： 浙江大学

项目金额： 25万元

中文摘要： 中枢神经系统的髓鞘由少突胶质细胞形成。髓鞘缺陷常见于多发性硬化症、白质损伤、精神分裂症等疾病中。形成髓鞘的少突胶质细胞由少突胶质细胞前体细胞（OPC）分化并进一步发育成熟产生。研究髓鞘发育和OPC细胞分化调控的机制对髓鞘相关疾病以及髓鞘损伤后的修复治疗具有重要意义。目前对髓鞘发育和OPC细胞分化的调控机制了解仍不完全。我们发现一类锚定蛋白Gab可能参与调节中枢神经系统髓鞘形成，在Gab条件性敲除小鼠脑中存在髓鞘相关蛋白表达的显著下调。本项目将在前期研究基础上，综合利用分子，生化和细胞生物学等实验技术研究Gab条件性敲除小鼠是否存在中枢神经系统髓鞘发育和OPC细胞分化缺陷及其可能的分子机制，并以此为基础利用小鼠脱髓鞘模型来研究Gab在髓鞘损伤修复中的作用。该项目将揭示Gab对中枢神经系统髓鞘发育，OPC细胞分化及髓鞘损伤修复的调控及其分子机制，为髓鞘相关疾病及新药的筛选鉴定提供潜在治疗靶点。

中文关键词： Gab1；髓鞘；少突胶质细胞；分化；转录

英文摘要： Oligodendrocytes (OLs) form myelin in the central nervous system. Myelin defect is one of important symptoms in many brain diseases, such as multiple sclerosis, white matter injury, autism and schizophrenia. The proliferation of oligodendrocyte precursor cells (OPCs) and their timely differentiation into mature OLs play critical roles in myelination. Although previous studies show that the myelination is regulated by multiple cell-intrinsic and extracellular factors, the mechanisms of myelination are not fully understood. Our preliminary work first showed that an membrane anchoring protein, Gab, regulated the myelination in CNS. Myelin-related proteins, such as MBP, MOG, MOBP, CNPase, were significantly reduced in Gab1/Gab2 conditioning knock-out mice. In this project, we continue to utilize molecular biology, biochemistry, immunochemistry and Cre-Loxp-based knock out mice to investigate the defects of myelination and OPC differentiation in the Gab1 and/or Gab2 conditioned knock-out mice and underlying mechanisms. We also investigate the action of Gab signaling in the injury of myelin and remyelination using the cuprizone-induced demyelination model.Our results may reveal the roles and mechanisms of Gab in myelination,OPC differentiation and remyelination in CNS and may supply a new therapeutic target and an ani

英文关键词： Gab1；myelination；oligodendrocyte；differentiation；transcription