二甲双胍上调少突胶质细胞自噬水平保护脊髓继发性损伤及机制研究

Spinal cord injury (SCI) is a severe orthopedic disease, control the damage of secondary injury can effectively prevent or even slow down SCI aggravation. We found from our previous research results that metformin abolished diabetic SCI, meanwhile our results showed that it reduced non-diabetic SCI damage. Moreover, our preliminary study indicated that metformin reduced white matter damage and oligodendrocyte apoptosis after SCI, however the underlying mechanism is unclear. Recent studies showed that metformin could up-regulate autophagy in adult cells and up-regulation of autophagy has been proved to be protective in SCI recovery, based on these theories we hypothesize that metformin could reduce spinal cord secondary injury through up-regulation of autophagy in oligodendrocytes. So in this proposal, 1) mice spinal cord will be impacted to induce SCI animal models, and the effect of metformin on the SCI secondary damage will be evaluated in vivo; 2) autophagy-deficient mice and autophagy gene knock down oligodendrocytes will be used to verify the effect of metformin on autophagy; 3) key molecules of AMPK signaling pathway will be detected and manipulated to elucidate the underlying mechanism of the effect of metformin on autophagy; 4) examine whether local delivery of metformin with polycaprolactone (PCL) membrane could reduce secondary damage in SCI animal models. This study will potentially find a new indication of metformin in SCI, thus provide new knowledges and methods for SCI therapy.

脊髓损伤（SCI）是严重骨科疾病，对其继发性损伤的控制是降低其进一步恶化的防治重点。课题组前期在研究二甲双胍减轻糖尿病SCI大鼠继发性损伤的同时，发现其对非糖尿病SCI也具有保护作用。预实验表明，二甲双胍可减轻脊髓白质损伤，减少少突胶质细胞凋亡，但是具体机制不明。文献表明二甲双胍在其他体细胞中可上调自噬，而自噬上调可保护脊髓损伤。由此提出假说：二甲双胍通过上调少突胶质细胞自噬减少其凋亡保护脊髓继发性损伤。本课题首先采用脊髓打击方法构建SCI动物模型，检测二甲双胍对SCI继发性损伤的作用；其次通过自噬缺陷小鼠及自噬基因敲降脊髓少突胶质细胞，研究二甲双胍的作用是否通过自噬途径；再者通过AMPK信号通路的干预，探讨二甲双胍调控自噬的分子机制；最后采用小鼠脊髓损伤模型，研究聚已内酯(PCL)膜控释二甲双胍对脊髓继发损伤的作用。本研究可拓展二甲双胍药物新用途，为SCI治疗提供新的理论支持。

脊髓损伤（SCI）是严重骨科疾病，对其继发性损伤的控制是降低其进一步恶化的防治重 点。课题组前期在研究二甲双胍减轻糖尿病SCI大鼠继发性损伤的同时，发现其对非糖尿病SCI 也具有保护作用。预实验表明，二甲双胍可减轻脊髓白质损伤，减少少突胶质细胞凋亡，但是 具体机制不明。文献表明二甲双胍在其他体细胞中可上调自噬，而自噬上调可保护脊髓损伤。本课题首先采用脊髓打击方法构建SCI动物模型，发现二甲双胍对SCI继发性损伤的保护作用；其次通过基因敲降脊髓少突胶质细胞，表明二甲双胍的作用是通过自噬途径；再者通过AMPK信号通路的干预，进一步发现二甲双胍调控自噬的分子机制；最后采用小鼠脊髓损伤模型，发现聚已内酯(PCL)膜控释二甲双胍对脊髓继发损伤的体内保护作用作用。本研究可拓展二甲双胍药物新用途，为SCI治疗提供新的理论支持。