Mios调节小胶质细胞对病理刺激的反应

作为中枢神经系统中驻留的免疫细胞，小胶质细胞在神经系统发育成 熟过程以及维持内环境稳态中发挥着至关重要的作用。生理状态下脑组织 中小胶质细胞具有细小的胞体，长而复杂的分支，但在受到损伤、病原菌 侵袭等病理刺激时，胞体变大，分支缩短、复杂度降低，抵抗病理刺激产 生的负效应。已有研究表明，小胶质细胞的形态变与其功能变化具有一定 联系。细胞的形变和功能改变与营养物质的摄取、蛋白质的合成以及能量 代谢等过程具有密不可分的关系，mTOR 信号通路作为细胞生长、代谢等 生命过程中不可缺少的信号通路之一，在小胶质细胞的形态和功能改变中 起着重要作用，但目前关于该信号通路的正向调控蛋白复合体 GATOR2的 组分—MIOS，对小胶质细胞形态和功能的影响还不清楚。所以我们假设小 胶质细胞中敲除Mios基因会抑制小胶质细胞的形态改变以及功能发挥。 为了验证猜测，我们构建了 TMEM119-CreER/TMEM119-Cre 介导的 小胶质细胞特异性敲除 Mios 的基因工程小鼠，通过构建 LPS 刺激模型以 及 EAE 病理模型，在免疫荧光染色、qRT-PCR、ELISA 等实验方法的辅 助下，检测在小胶质细胞敲除 Mios对其生理状态以及病理刺激下的形态和 功能影响（包括形态变化、增殖能力、炎症因子分泌等），并探究 Mios敲 除对小胶质细胞功能产生影响的作用机制。 我们研究发现小胶质细胞中特异性敲除 Mios，和野生型相比在生理状 态下，分支轻微缩短，胞体轻微变大，但在 LPS 刺激后两者形态变化不明 显。和野生型相比，LPS刺激后小胶质细胞敲除Mios增殖能力没有发生改 变，Mios 敲除组的炎症因子的产生减少，并且吞噬能力受到抑制。这说明 Mios 敲除会抑制小胶质细胞的功能发挥。NF-κB信号通路作为调控多种炎 症因子产生的经典通路，我们猜测 Mios 敲除可能通过抑制 NF-κB信号通 路的激活抑制炎症因子产生，但结果显示 Mios敲除抑制炎症因子的产生和 NF-κB 信号通路无关。研究 Mios 对小胶质细胞对病理刺激反应的调节作 用，有助于我们对小胶质细胞在炎症状态下的形态和功能改变的理解加深， 为研究神经退行性疾病和神经炎症的致病机制和治疗方案奠定理论基础。

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