高负荷压应力是椎间盘退变的重要外部病理因素，可促进髓核细胞发生凋亡和衰老样命运改变，但机制尚未阐明。既往国内外研究提示SIRT1可减轻氧化应激反应进而抑制细胞凋亡和衰老。我们前期研究发现高负荷压应力促进髓核细胞凋亡和衰老时，伴随SIRT1表达下调和胞内活性氧蓄积。因此，我们推测高负荷压应力是通过降低SIRT1表达增强氧化应激反应，继而导致髓核细胞凋亡和衰老样命运改变。为证实该假设，本项目拟在椎间盘器官培养和髓核细胞三维培养模型中，通过特异性阻断、基因过表达等技术，探讨高负荷压应力下SIRT1表达下调介导的氧化应激损伤在促进髓核细胞凋亡和衰老中的作用及机制；并观察高负荷压应力下，SIRT1过表达能否减轻氧化应激反应进而抑制髓核细胞凋亡和衰老；另外，动物模型中探讨SIRT1过表达能否减缓动物体内椎间盘退变进程。本研究将有助于阐明椎间盘退变的病理机制，为探索新的防治策略提供理论依据。

High compressive stress is a crucial pathological factor of intervertebral disc degeneration, which can promote apoptosis- and senescence-like cellular fate of nucleus pulposus (NP) cells. However, the potential mechanism is not fully understood. Previous studies suggest that SIRT1 can alleviate NP cell apoptosis and senescence through inhibiting oxidative-stress damage. Our preliminary experiments show that the aggravated NP cell apoptosis and senescence are accompanied by the up-regulated SIRT1 expression and the intracellular reactive oxygen species (ROS) accumulation under high compressive stress. Therefore, we deduce that high compressive stress may promote the apoptosis- and senescence-like cellular fate of NP cells through down-regulating SIRT1 expression and thus aggravating oxidative-stress damage. To verify this hypothesis, this study will using technologies, including specific intervention and gene overexpression, to investigate the role and signal transduction of SIRT1 down-regulation in enhancing oxidative stress and than promoting the apoptosis- and senescence-like cellular fate of NP cells under high compressive stress in the disc organ culture and NP cell 3D culture. Meanwhile, we will observe that whether SIRT1 overexpression can alleviate oxidative stress and then alleviate apoptosis- and senescence-like cellular fate of NP cells. Additionally, we will observe that whether SIRT1 overexpression can retard intervertebral disc degeneration in vivo. This study will be helpful to understand the pathogenesis of disc degeneration and provide theoretical evidence for the prevention and therapy of disc degeneration.