HIPK2-Sox10/Zfp488通路在七氟醚致少突胶质细胞发育障碍中的作用及机制研究

全麻药物对婴幼儿神经发育的影响备受关注，然而机制不清。近年来少突胶质细胞分化成熟异常被证明在七氟醚神经毒性中发挥重要作用。我们前期研究发现七氟醚暴露导致海马少突胶质细胞分化成熟障碍，揭示少突胶质细胞发育障碍可能是七氟醚毒性作用的发生原因，但少突胶质细胞发育障碍的特征与机制及在认知损伤中的作用仍需深入研究。同源结构域相互作用蛋白激酶2（HIPK2）作为转录抑制因子在神经发育过程中具有很重要的作用，我们通过HIPK2-ChIP-qPCR发现HIPK2可结合于调控少突胶质细胞分化/成熟的转录因子Sox10/Zfp488的启动子区。我们将利用HIPK2 flox小鼠，综合应用神经形态、发育生物学等技术系统研究七氟醚致少突胶质细胞分化成熟等特征，探讨其分子机制。验证发育阶段少突胶质细胞功能修复对七氟醚致认知行为的改善效应。本课题将为临床上寻求相应的小儿脑保护措施提供新的思路。

The effect of general anesthesia on the neurodevelopment of infants has attracted much attention, but the mechanism is unclear. In recent years, the abnormal differentiation and maturation of oligodendrocytes has been shown to play an important role in the neurotoxicity of sevoflurane. Our previous study found that sevoflurane exposure leads to dysdifferentiation and maturation of hippocampal oligodendrocytes, revealing that dysplasia of oligodendrocytes may be the cause of the toxic effects of sevoflurane, but the characteristics and mechanism of dysplasia of oligodendrocytes and its role in cognitive impairment still need further study. Homologous domain interacting protein kinase 2 (HIPK2) plays an important role in neural development as a transcriptional suppressive factor. Through HIPK2-ChIP-qPCR, we found that HIPK2 can bind to the promoter region of Sox10 / Zfp488, a transcription factor that regulates the differentiation/maturation of oligoendrocytes. We will use HiPK2 Flox mice to systematically study the differentiation and maturation of oligodendrocytes induced by sevoflurane and explore its molecular mechanism by using neuromorphologic and developmental biology techniques. To investigate the effect of functional repair of oligodendrocytes during development on sevoflurane-induced cognitive behavior improvement. This study will provide a new idea for seeking the corresponding protective measures for children's brain in clinic.