接头蛋白Numb在髓鞘发育和髓鞘损伤修复中的作用及机制

Oligodendrocytes (OLs) are generated by the differentiation and maturation of oligodendrocyte precursor cells (OPCs). The failure of OPC differentiation is a major cause of demyelinating diseases; thus, identifying the molecular mechanisms that affect OPC differentiation is critical for understanding the myelination process and repairing after demyelination. Although prevailing evidence shows that OPC differentiation is a highly coordinated process controlled by multiple extrinsic and intrinsic factors, the signaling in OPC differentiation is still unclear. Our preliminary work showed myelin deficiency in mouse with deletion of Numb/Numblike specifically in OPCs. In present project, we will utilized genetic methods, cell biology, biochemistry and behavior analysis to study: 1) function of Numb in CNS myelin development or maintenance ; 2)function of Numb in myelin disease model and remyelination; 3)Regulatory mechanism of Numb in myelination.Our results will reveal the novel functions of Numb in nerve system and give a new sight in myelin disease therapy and drug development.

少突胶质细胞(OL)由少突胶质前体细胞(OPC)分化成熟而来。OPC分化障碍是许多脱髓鞘疾病的主要原因之一，因此寻找并确定影响OPC分化的分子机制对于理解髓鞘化的过程以及脱髓鞘的修复都是非常重要的。尽管之前有研究证据表明OPC的分化是一个高度协调的过程，受多种内在和外在因素的调控，但是OPC分化的信号传导机制仍不清楚。Numb作为一个内吞蛋白在神经元发育中起重要作用，但未见其在髓鞘相关细胞中功能的报道。我们前期研究表明在小鼠OPC中条件性敲除Numb会造成小鼠中枢神经系统（CNS）中髓鞘的缺失，提示Numb参与调节CNS中的髓鞘发育或维持。本课题利用遗传生物学、分子生物学、细胞生物学、生物化学和动物行为学等技术，研究1）Numb在CNS髓鞘发育中或维持中的功能；2）Numb在髓鞘疾病模型以及损伤修复中的作用；3）Numb调节髓鞘形成的分子机制。课题研究成果将进一步揭示Numb在神经系统中的新功能以及对髓鞘疾病的药物开发和治疗都提供新的方向。