基于TSC1/mTOR通路调控巨噬细胞线粒体氧化应激在脊髓损伤修复中的作用及机制研究

脊髓损伤是骨科临床亟待解决的难题之一。其中，巨噬细胞在脊髓损伤修复中发挥了重要的调控作用。脊髓损伤后线粒体氧化应激导致了巨噬细胞极化障碍，是影响脊髓损伤修复效果的重要原因。然而，线粒体氧化应激对巨噬细胞极化的影响及其机制尚不明确。基于此，课题组前期观察到脊髓损伤后改善线粒体功能可缓解氧化应激介导的巨噬细胞极化障碍。本研究拟进一步探讨线粒体氧化应激对巨噬细胞功能的调控及其潜在机制。本课题拟从体内体外实验多层次验证脊髓损伤后巨噬细胞功能状态的改变，以及应用线粒体移植术或线粒体保护剂MitoQ改善线粒体氧化应激后，多角度综合评价对巨噬细胞极化的影响及对神经功能恢复的作用。最后通过建立Lyz2-CreERT2-TSC1flox/flox转基因小鼠模型，进一步验证TSC1/mTOR通路是否参与了线粒体氧化应激介导的巨噬细胞极化障碍，从而可望为临床脊髓损伤患者的修复重建提供理论依据及实验基础。

Spinal cord injury (SCI) remains a serious clinical challenge for orthopedic surgeons globally. Macrophage plays an important role in the regulation of SCI and repair. Recent studies have revealed that mitochondrial oxidative stress in the spinal cord injury impairs the polarization of macrophages, which further leads to unfavorable repair of SCI. However, the effect of mitochondrial oxidative stress on macrophage polarization in SCI regeneration and its mechanism remains unknown. In light of this, our previous study confirmed that improving mitochondrial function could alleviate oxidative stress-mediated impaired macrophage polarization. The main purpose of this study is to further explore the role and potential mechanism of mitochondrial oxidative stress on macrophage function. This study intends to confirm the function of macrophages after SCI both in vitro and in vivo. Moreover, this study also intends to evaluate the effect of attenuating mitochondrial oxidative stress by mitochondrial transplantation or mitochondrial oxygen free radical scavenger (MitoQ) on macrophages polarization and functional recovery of nerve. Finally, the involvement of TSC1/mTOR signaling pathway in the relationship between mitochondrial oxidative stress and macrophage polarization dysfunction is further explored by Lyz2-CreERT2-TSC1flox/flox genetically modified mouse models. This study is expected to elucidate the mechanistic role of mitochondrial oxidative stress on macrophages in SCI repair and provide theoretical basis and fundamental knowledge for the treatment of spinal cord injury.