内向整流钾通道在髓鞘发育及损伤修复中的作用及机制

少突胶质前体细胞（OPC）分化为成熟的少突胶质细胞（OL）是神经元髓鞘发育的重要环节。研究OPC分化与髓鞘发育的调控对于髓鞘损伤的防治和修复具有重要意义，但目前OPC发育与髓鞘损伤修复的机制仍不清楚。最近新英格兰医学杂志报道Kir4.1通道在多发性硬化症表达异常，但其机制未见报道。我们前期实验在OPC和OL中记录到Kir4.1电流，抑制Kir4.1通道活性显著降低髓鞘蛋白表达，提示Kir4.1可能在OPC分化、髓鞘发育及损伤修复中有重要作用。本项目在前期基础上，通过在培养细胞干扰Kir4.1表达和建立Kir4.1条件性基因敲除小鼠模型，结合生物化学、RNA干扰、免疫荧光染色、电镜、神经电生理等多种方法研究Kir4.1通道在OPC分化和髓鞘发育中的作用及机制，并利用小鼠脱髓鞘模型研究Kir4.1在髓鞘损伤修复和再生中的作用。本课题的研究将为髓鞘相关疾病的治疗及新药的筛选鉴定提供潜在的新靶点。

Differentiation of oligodendrocyte precursor cells (OPC) into oligodendrocytes (OL) is a crucial step for the myelin formation in the central nervous system. Thus, investigation of the regulatory mechanisms of OPC differentiation and myelin formation is very important to myelin-related diseases and the repair of myelin injury. Recent research from New England Journal of Medicine showed that inwardly rectifying K channel Kir4.1 abnormally expressed in multiple sclerosis (MS), but its mechanism is unclear. Our preliminary data showed that Kir4.1 current exists in OPC and OL. Inhibiting Kir4.1 channel suppressed the expression of myelin proteins, indicating that Kir4.1 may play an important role in regulating OPC differentiation and myelin formation and myelin injury and repair. In this project, we will continue to study how Kir4.1 regulates the differentiation of OPC and the development of myelin using combined techniques including biochemistry, immunocytochemistry, electron microscope and electrophysiology et al. by interfering Kir4.1 expression in primary cultured OPC cells and Kir4.1 cconditional knockout mouse model. We will also study the role of Kir4.1 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.