Rheb 在小胶质细胞对脑损伤应答反应的 调节作用

小胶质细胞是大脑主要的免疫细胞，在大脑正常发育和维持及神经退 行性疾病的发病机理中发挥关键作用。小胶质细胞的形态具有多变性，功 能具有多样性。当脑内出现如损伤、病原体侵染等异常时，小胶质细胞能 及时响应，形态上由静息状态向激活状态转变，伴随增殖、迁移、吞噬、 促炎/抑炎等生理功能层面相应的改变。目前认为，小胶质细胞形态转变和 功能改变具备偶联性，且对小胶质细胞生理功能的正常执行至关重要。然 而，目前对调控小胶质细胞形态和功能转换的分子机制知之甚少。细胞形 态的转变和功能的正常进行离不开大量蛋白质的合成和能量的正常供应， 所以我们推测调节蛋白质合成及能量代谢的信号通路很可能参与小胶质细 胞功能及组织损伤的应答的调节。Rheb 是这些信号通路的关键因子，Rheb 是否参与小胶质细胞形态与功能的调节呢？是否通过 mTORC1 通路调控小 胶质细胞形态及功能改变介导其对脑损伤的应答？ 为了探究 Rheb 对小胶质细胞的调节，在小胶质细胞（Cx3CR1-Cre） 特异性敲除 Rheb，构建 Cuprizone 脑损伤、LPC 脑损伤、LPC 脊髓损伤多 种损伤模型，利用免疫荧光染色、BlackGold、LFB 等技术手段，检测在小 胶质细胞敲除 Rheb 对小胶质细胞脑损伤应答反应（如形态改变、增殖能力、 吞噬功能、髓鞘再生）的调节。之后我们还构建了 mTOCR1 重要成分 Raptor 敲除小鼠，探讨 Rheb 对小胶质细胞脑损伤应答反应的调节是否是 mTOR 依赖路径调控。 我们的研究发现特异性敲除 Rheb，并不影响小胶质细胞形态，也不影 响静息状态下小胶质细胞的增殖和吞噬功能；但在小胶质细胞敲除 Rheb 会 抑制小胶质细胞对损伤应答反应的增殖能力和吞噬功能，也会因此影响小 胶质细胞在髓鞘再生中的作用，抑制髓鞘再生。说明 Rheb 参与小胶质细胞 的功能和脑损伤应答的调节。研究 Rheb 对小胶质细胞的调节，有助于我们 加深理解小胶质细胞形态和功能的调节机制，对阐明退行性疾病的致病机 理以及治疗具有潜在价值。

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