内源性修复失效是椎间盘退行性变的主要原因。我们前期研究发现，过度压力诱导的髓核干细胞坏死性凋亡在椎间盘内源性修复失效过程中发挥重要作用，但其调控机制仍未完全阐明。线粒体分裂和融合是细胞应对不利刺激、调控线粒体数量和功能的重要机制。申请者前期预实验发现，线粒体分裂融合失衡参与了压力诱导的髓核干细胞死亡。本课题拟以线粒体分裂融合现象为切入点，以髓核干细胞为研究对象，着眼于坏死性凋亡这一新型细胞程序性死亡方式，深入研究压力诱导线粒体分裂融合失衡的具体机制及其关键靶点，探讨线粒体分裂融合失衡对压力诱导的髓核干细胞坏死性凋亡的调控作用，进而阐明线粒体分裂融合重要调控蛋白INF2对压力诱导的髓核干细胞线粒体分裂融合失衡及坏死性凋亡的调控作用。本课题不但有望为抑制压力诱导的髓核干细胞坏死性凋亡继而挽救髓核内源性修复能力提供全新调控靶点，而且可能为其他疾病的相关研究提供新思路。

The failure of endogenous repair is the main cause of intervertebral disc (IVD) degeneration. Our previous studies have demonstrated that excessive compression-induced necroptosis of nucleus pulposus stem cells (NPSCs) plays a vital role in the failure of endogenous repair of IVD. However, the regulatory mechanisms of necroptosis have not been clearly elucidated. Mitochondrial fission and fusion are essential mechanisms for cells to cope with adverse stimuli and regulate the quantity and quality of mitochondria. The pilot experiments indicated that the imbalance of mitochondrial fission and fusion participated in compression-induced death of NPSCs. Thus, the current project is designed to choose the mitochondrial fission and fusion as the breakthrough point, take NPSCs as the research object, and focus on necroptosis which is a novel manner of programmed cell death. We try to systematically investigate the specific mechanisms and key targets of compression-induced imbalance of mitochondrial fission and fusion, and explore the regulatory effects of the imbalance on compression-induced NPSCs necroptosis. Further, we intend to elucidate the regulatory effects of INF2, an important protein regulating the mitochondrial fission and fusion, on compression-induced imbalance of mitochondrial fission and fusion, as well as the necroptosis of NPSCs. This project is expected to provide novel targets for inhibiting compression-induced necroptosis of NPSCs, and further restoring the endogenous repair capacity of IVD. In addition, it might provide related researches of other diseases with a new perspective.