癫痫相关基因LGI1在髓鞘发育和损伤中的作用

Remyelination and repair of myelin injury is one of the important projects in neuron injury repair. Myelins are formed by oligodendrocytes (OLs) and OLs are differentiated from oligodendrocyte precursor cells (OPCs) in the CNS. The studies on the regulation of OPC differentiation and myelin formation are quite lack, so more factors need to be found. Our recent research showed that epilepsy related gene LGI1 plays an important role in the development of cerebellum. As a widespread neuron secretory protein in the brain, the role of LGI1 in myelin formation is still unknown. Our preliminary data showed that LGI1 expresses in both OPC and OL. The structure of myelin is abnormal in LGI1 knockout mice brain indicating that LGI1 may play an important role in regulating OPC differentiation and myelin formation and myelin injury repair. In this project, we will continue to study how LGI1 regulates the differentiation of OPC and the development of myelin using combined techniques including primary OPC cells culture, LGI1 completely and cconditional knockout mice model, biochemistry, immunocytochemistry, and electron microscope et al. We will also study the role of LGI1 in myelin injury and repair by building mouse demyelination models. This project will provide new potential treatment targets for myelin-related diseases and the new drug screening.

髓鞘再生和损伤修复是神经损伤修复的一个重要课题。中枢神经系统中髓鞘由少突胶质细胞（OL）形成，OL由少突胶质前体细胞（OPC）分化而来。目前关于OPC分化和髓鞘发育机制的研究涉及面很窄，更多的相关信号分子有待研究。我们最近的一项工作首次表明，癫痫相关基因LGI1在小脑发育中十分重要。作为一种人类大脑中广泛存在的神经元分泌蛋白，LGI1在髓鞘发育中的作用尚未见报道。我们前期工作发现LGI1表达在体外培养的OPC和分化后的OL中，LGI1全身敲除的小鼠髓鞘结构异常，提示LGI1可能在髓鞘形成过程中起着重要调控作用。本项目将综合利用体外OPC原代细胞培养、LGI1全敲小鼠和条件性基因敲除小鼠模型，结合分子生化、电镜、免疫荧光染色等方法研究LGI1在OPC分化和髓鞘发育中的作用及其机制，并利用小鼠脱髓鞘模型来研究LGI1在髓鞘损伤修复中的作用。本课题的研究将为髓鞘相关疾病的治疗提供潜在的新靶点。

髓鞘再生和损伤修复是神经损伤修复的一个重要课题。目前关于OPC分化和髓鞘发育机制的研究涉及面很窄，更多的相关信号分子有待研究。我们前期研究首次表明，癫痫相关基因LGI1在小脑发育中十分重要。作为一种人类大脑中广泛存在的神经元分泌蛋白，LGI1在髓鞘发育中的作用尚未见报道。本项目综合利用体外OPC原代细胞培养、LGI1全敲小鼠和条件性基因敲除小鼠模型，结合分子生化、电镜、免疫荧光染色等方法研究了LGI1在OPC分化和髓鞘发育中的作用及其机制，并利用小鼠脱髓鞘模型来研究LGI1在髓鞘损伤修复中的作用。体外研究结果显示LGI1表达在体外培养的OPC和分化后的OL中，LGI1基因敲除抑制了OPC分化，对OPC增殖没有影响。LGI1缺失激活了mTOR信号通路，抑制了OL中脂质的合成，说明LGI1参与了OL中蛋白和脂质的合成，对OL的作用可能是通过调控TSC1-mTORC1信号通路完成的。体内研究表明LGI1基因敲除小鼠髓鞘结构异常，抑制了脑中OPC的分化，抑制了白质束和髓鞘纤维的形成，进一步说明LGI1对OPC的分化和髓鞘损伤修复具有重要作用。本课题的研究将为髓鞘相关疾病的治疗提供潜在的新靶点。