血红素氧合酶-1通过调控AMPK信号通路对脊髓损伤的保护机制研究

脊髓损伤（SCI）是一种高致残性疾病，磷酸腺苷激活的蛋白激酶（AMPK）是细胞内重要的能量代谢和应激感受器，在SCI发病中具有重要作用。前期我们研究发现腺相关病毒（AAV）介导的血红素氧合酶-1（HO-1）基因过表达（AAV-HO-1）通过抑制Cdc42/MLK3/MKK7/JNK3信号通路促进大鼠SCI的神经功能恢复。文献报道MLK3可以直接活化AMPK，是AMPK信号途径的上游信号分子。我们的预实验结果提示AAV-HO-1能抑制SCI大鼠中AMPK信号通路的活化，并且AMPK基因沉默对大鼠SCI具有神经保护作用。综上，调控AMPK通路可能是HO-1对SCI保护作用的一个重要机理。为了验证这一假说，我们将从分子、细胞、组织以及动物整体水平等多方面探讨HO-1对SCI后AMPK信号通路的调控作用及机制。我们的研究将为SCI的治疗研究提供新思路和新靶点，以期促进临床转化。

Spinal cord injury (SCI) is a leading cause of disability. AMP-activated protein kinase (AMPK) is an important energy metabolism and stress sensor in the cell, which plays an important role in the pathogenesis of SCI. Our previous study indicated that overexpression of heme oxygenase-1 (HO-1) gene mediated using adeno-associated virus (AAV) promoted the recovery of neurological function after SCI in rats by inhibiting Cdc42/MLK3/MKK7/JNK3 signaling pathway. Previous study has indicated that MLK3 can directly activate AMPK, serving as an upstream signal molecule of the AMPK signaling pathway. Our preliminary study showed that AAV-HO-1 inhibited activation of AMPK signaling pathway after SCI and AMPK gene silencing had neuroprotective effect against SCI in rats. In summary, regulating AMPK activation after SCI may be an important mechanism of the protective effect of HO-1 after SCI. To verify the hypothesis, we will examine the effect of HO-1 on AMPK signaling pathway activation after SCI and the potential mechanism from molecular, cellular, tissue and whole animal levels; our study will provide new ideas and new targets for SCI treatment and promote clinical translation.