Sirt1 通过分子伴侣介导的自噬调控脑损伤后星形胶质细胞活化的机制

创伤性脑损伤后星形胶质细胞过度活化可引起神经元死亡而阻碍神经修复，Sirt1被认为是损伤后保护神经元的重要分子之一，但具体作用机制尚未明确。前期工作中发现脑损伤后上调Sirt1表达可减弱星形胶质细胞活化。另外，Sirt1可通过去乙酰化LC3参与巨自噬过程，但其是否参与其它两种自噬尚未有明确报道。自噬的发生可有效的保护损伤周边的神经组织，且参与星形胶质细胞的活化过程。预实验显示星形胶质细胞中Sirt1和分子伴侣介导的自噬相关蛋白DNAJB1直接结合。由此我们设想：Sirt1减弱星形胶质细胞活化的作用机制，可能与调控分子伴侣介导的自噬有关。因此，我们通过体内外上调Sirt1的表达并沉默DNAJB1，观察分子伴侣介导的自噬相关信号蛋白的表达和星形胶质细胞的活化情况，探究Sirt1和DNAJB1之间通过何种作用关系参与分子伴侣介导的自噬从而影响星形胶质细胞的活化，从中探讨Sirt1的神经保护机制。

Over activated astrocytes directly or indirectly cause neuronal death and exhibit neuronal regeneration after traumatic brain injury. Sirt1 is considered to be one of the important molecules to protect neurons after injury, but the mechanism of its protective effect on neuronal regeneration has not been clarified. Our previous study reported that up-regulation of Sirt1 expression could attenuate the astrocytes activation after traumatic brain injury. In addition，Sirt1 has been identified to play an important role in the process of LC3 deacetylation, which can effectively protect the injured peripheral nerve tissue, but whether it is involved in the other two autophagy has not been clearly reported. Autophagy occurred in neurons showing neuroprotective effect and also participated in the astrocyte activation after injury. The result of Co-Immunoprecipitation (Co-IP) shows that Sirt1 and DNAJB1, a molecular chaperon-mediated autophagy associated protein, bind directly in astrocytes in vitro. We propose that the mechanism of Sirt1 attenuating the astrocyte activation after brain injury may be related to the interaction with DNAJB1 and the regulation of molecular chaperone mediated autophagy. Therefore, we will observed the expression of molecular chaperon-mediated autophagy associated proteins and the activation of astrocytes via up-regulating Sirt1 expression and silencing DNAJB1 in vivo and in vitro, to explore the relationship between Sirt1 and DNAJB1 involved in molecular chaperon-mediated autophagy and astrocyte activation and discuss the neuroprotective mechanism of Sirt1. This study will provide a solid theoretical basis for neuronal rehabilitation after traumatic brain injury.