GDF11在多发性硬化症中的作用及机制研究

Promoting remyelination is an important strategy for multiple sclerosis treatment. However, little is known about the detailed mechanisms underlying remyelination process. Growth differentiation factor 11 (GDF11) is a secreted signaling molecule that belongs to transforming growth factor beta superfamily. It is an important anti-aging protein. Recently, we found that GDF11 improved behavioral outcome, alleviated demyelination area and promoted the remyelination of axons on spinal cord in experimental autoimmune encephalomyelitis (EAE) model. Furthermore,GDF11 could promote the differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocyte in vitro. These results suggest that GDF11 is a critical extracellular signaling protein that could regulate the development of oligodendrocyteand promoteremyelination. Therefore, the aim of the project is to explore the promoting effects of GDF11 on OPCs differentiation and myelination in vitro and vivo and associated molecular mechanisms. Using EAE model and lysophosphatidyl choline-induced demyelination model, we will examine the effects of GDF11 on myelin repair. Our project will further reveal the molecular and cellular mechanisms that regulate the development of oligodendrocyteand remyelination, and will provide novel therapeutic target for multiple sclerosis.

促进髓鞘再生是治疗多发性硬化症的一个重要策略，但目前对中枢神经系统髓鞘再生的调控机制尚不十分清楚。GDF11是转化生长因子β超家族中的一种分泌型信号分子，具有抗衰老作用。我们最近发现：在实验性自身免疫性脑脊髓炎（EAE）脱髓鞘模型中GDF11可以改善小鼠的神经功能评分，减少脱髓鞘区域和促进轴突的再髓鞘化；在体外细胞实验中GDF11能促进少突胶质前体细胞（OPCs）分化成成熟的少突胶质细胞。以上预实验提示GDF11可能是调控少突胶质细胞发育的一种重要的细胞外信号分子，对髓鞘再生具有促进作用。因此本项目将在整体动物和细胞水平上，研究GDF11对OPCs分化过程的调控作用及其可能的分子机制，并在此基础上利用EAE模型和溶血卵磷脂诱导的脱髓鞘模型研究GDF11对髓鞘再生的调控作用。该项目有助于加深我们对少突胶质细胞发育以及髓鞘再生机制的理解，为多发性硬化症的治疗提供新靶点。

促进髓鞘再生是治疗多发性硬化症的一个重要策略。GDF11是转化生长因子β超家族中的一种分泌型信号分子，具有抗衰老作用。我们的研究结果发现：GDF11能促进少突胶质前体细胞（OPCs）分化成成熟的少突胶质细胞，其作用途径是通过作用于OPCs上的ALK5和ActRⅡB受体而激活smad2/3和CREB信号转导途径来实现的。利用EAE脱髓鞘模型和溶血卵磷脂诱导的脱髓鞘模型，证实了GDF11对髓鞘再生的促进作用，其作用机制是通过促进少突胶质前体细胞的分化来实现的，而并非通过抑制外周免疫系统的应答过程来实现。本项目为阐明少突胶质细胞发育、髓鞘形成以及髓鞘再生的调控机制提供全新的证据，为多发性硬化的治疗提供新思路和药物作用的新靶点。