脂酰辅酶A硫酯酶7在中枢髓鞘形成中的作用及机制研究

Myelin, formed by the wrapping of axons with the processes of oligodendrocytes, is vital for maintaining normal physiological function in the central nerve system. Lipid is the main component of myelin, but the role of synthesis and metabolism of myelin lipid in myelination is not fully understood yet. In the preliminary study. we found that Acyl-CoA thioesterase 7 (ACOT7), a major isoform of the ACOT family, was highly expressed in the oligodendrocytes in vitro and in vivo. The expression of Acot7 was significantly increased during the development of mouse white matter and as the remyelination occurred after demyelination. Acot7 was found to promote the differentiation and maturation of primary cultured oligodendrocyte precursor cells. Importantly, after conditional knockout of Acot7 in oligodendrocytes, the myelin generation during development was greatly inhibited. Our preliminary data strongly indicate that Acot7 play a crucial role in myelination. In this proposal, we aim to further analyze the role and the underlying mechanism of Acot7 in myelination. The goal of this research is to establish the role of Acot7 in the regulation of myelination and to open up new possibilities to achieve successful therapeutic explorations for demyelinating diseases.

中枢髓鞘是由少突胶质细胞突起包绕轴突形成的螺旋样多层生物膜结构，是维持神经正常生理活动的基础。脂质是髓鞘的主要成分，但是目前尚不清楚髓鞘特征性脂质代谢在髓鞘形成中的作用。我们的前期研究显示：脂酰辅酶A硫酯酶7（Acot7）在少突胶质细胞中特异性表达；在小鼠白质发育成熟阶段和脱髓鞘后再髓鞘化过程中，Acot7的表达量显著升高；Acot7对体外原代培养的少突胶质前体细胞分化成熟，具有促进作用；在少突胶质细胞中条件性敲除Acot7，会显著抑制小鼠中枢髓鞘生成。这些研究结果强烈提示Acot7在髓鞘形成中具有重要作用。本项目拟在前期实验基础上，深入、系统地分析Acot7在中枢髓鞘发育和再生过程中的作用，并阐明其发挥作用的机制。这项研究不仅有可能揭示Acot7的新功能，而且有助于深入认识髓鞘形成的调控机制，并可能为脱髓鞘相关疾病的治疗研究提供新思路。

中枢髓鞘是由少突胶质细胞突起包绕轴突形成的螺旋样多层生物膜结构，是维持神经正常生理活动的基础。脂质是髓鞘的主要成分，但是目前尚不清楚髓鞘特征性脂质代谢在髓鞘形成中的作用。脂酰辅酶A硫酯酶(Acot7)通过催化脂酰辅酶A水解生成自由脂肪酸和辅酶A，参与维持胞内脂酰辅酶A、自由脂肪酸和辅酶A的平衡。我们的研究显示，在小鼠中枢神经系统，Acot7在成熟的少突胶质细胞和神经元中高表达，而在星形胶质细胞、小胶质细胞中鲜有表达；在小鼠白质发育成熟过程中，Acot7的表达模式与髓鞘发育过程密切相关。运用溶血卵磷脂诱导的脱髓鞘模型和铜腙脱髓鞘模型，我们发现Acot7的表达变化与再髓鞘化过程相关。Acot7 可以促进体外原代培养OPCs分化成熟，但是并不影响OPCs增殖、凋亡和迁移能力。通过构建的OL谱系细胞中特异性敲除Acot7的转基因小鼠(Acot7cKO)，我们发现Acot7cKO小鼠在出生后早期，中枢髓鞘发育相较于对照明显减缓。在老年期，Acot7cKO小鼠和对照小鼠相比，有髓轴突的比例明显低于对照小鼠，呈现低髓鞘化表型。运用脂质组学分析显示，Acot7可能通过调节棕榈酰辅酶A的含量影响髓鞘鞘磷脂合成。RNA-Seq分析显示，Acot7还可能通过激活PI3K-Akt信号通路促进少突胶质细胞分化，从而促进髓鞘形成。这项研究不仅揭示了Acot7的新功能，而且有助于深入认识髓鞘形成的调控机制，并为脱髓鞘相关疾病的治疗研究提供新思路。相关研究发表SCI论文3篇,授权专利1项。培养博士研究生1名、硕士研究生2名。