ICK调控少突胶质细胞发育的机制研究

In vertebrate central nervous system (CNS), oligodendrocytes (OLs) form myelin sheaths around axons to ensure the rapid saltatory and faithful transmission of electrical signals. In addition, myelin sheaths provide neurotrophic support for neuronal axons. Loss of myelin sheaths can lead to impaired body movement, paralysis or even death. One strategy for therapeutic treatment of demyelinating diseases is to stimulate the de novo differentiation of oligodendrocytes from undifferentiated oligodendrocyte progenitor cells (OPCs) that remain present in the adult CNS. Our previous studies have identified ICK as the first reported non-receptor serine/threonine kinase that displays a dramatic and specific upregulation in differentiating OLs. Also, our preliminary data provided evidences that ICK is required for oligodendrocyte differentiation. To elucidate the role of ICK in controlling oligodendrocyte development and myelin repair, we will investigate the functions of ICK in regulating oligodendrocyte differentiation and remyelination in vivo in Ick gene ablation and overexpression mouse models, and identify the upstream/downstream factors involved in ICK pathway. The proposed studies will yield novel insights into the molecular regulation of oligodendrocyte development and provide guidance for the therapeutic treatments of demyelinating diseases.

脊椎动物中枢神经系统中，由少突胶质细胞（oligodendrocytes, OLs）形成的髓鞘保证神经冲动沿神经元轴突的快速准确传导，并为轴突提供营养支持。髓鞘损伤和病变会引起严重的运动障碍甚至瘫痪和死亡。治疗脱髓鞘疾病的一个主要策略是促进中枢神经系统中尚未分化的少突胶质细胞前体细胞（oligodendrocyte progenitor cells, OPCs）的再分化。我们前期结果首次发现一个在正在分化的OLs中特异性表达的非受体型丝氨酸/苏氨酸激酶ICK，并初步证明其参与调控OLs的分化。我们拟通过条件性基因敲除和过表达小鼠模型，在体内水平研究ICK在OLs发育和髓鞘再生过程中的功能，并鉴定ICK通路上下游相关蛋白，以便阐明ICK调控OLs发育和髓鞘再生的机制。这些研究将丰富OLs发育的相关调控机制，为脱髓鞘相关疾病的治疗提供新的理论基础和实践依据。

脊椎动物中枢神经系统中，由少突胶质细胞（oligodendrocytes, OLs）形成的髓鞘保证神经冲动沿神经元轴突的快速准确传导，并为轴突提供营养支持。髓鞘损伤和病变会引起严重的运动障碍甚至瘫痪和死亡。治疗脱髓鞘疾病的一个主要策略是促进中枢神经系统中尚未分化的少突胶质细胞前体细胞（oligodendrocyte progenitor cells, OPCs）的再分化。我们前期结果首次发现一个在正在分化的OLs中特异性表达的非受体型丝氨酸/苏氨酸激酶ICK，推测该基因可能参与少突胶质细胞的发育调控。为了验证这一假设，我们通过条件性基因敲除小鼠模型，在体内水平证明Ick基因缺失是发育过程中中枢神经系统维持正常数量的成熟少突胶质细胞所必需的，且该基因的缺失会显著阻碍髓鞘损伤小鼠的髓鞘再生过程。同时，我们的体内体外水平的过表达实验则证实Ick基因不直接诱导少突胶质细胞的成熟。这些研究丰富了OLs发育的相关调控机制，为脱髓鞘相关疾病的治疗提供新的理论基础。

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