髓核细胞数量下降是椎间盘退行性变的主要特征，与细胞程序性死亡密切相关。坏死性凋亡和凋亡、自噬、坏死等传统死亡方式不同，是一种全新的程序性死亡方式，近两年受到国际学术界高度重视，可能为多种疾病提供全新治疗策略。但是，坏死性凋亡的调控机制尚需进一步研究，其与凋亡、特别是自噬间的串扰影响尚不清楚，在椎间盘退行性变领域更未见报道。申请者前期预实验发现，坏死性凋亡确实参与了髓核细胞坏死过程。本课题拟在以往研究髓核细胞自噬的多项国家自然基金的基础上，采用特异性抑制剂、SiRNA干扰、基因过表达等手段，深入研究RIPK1-RIPK3-MLKL信号途径在压力诱导的髓核细胞坏死性凋亡中的分子机制及其与自噬的串扰影响，明确椎间盘退行性变的关键调控靶点，探讨协同调控坏死性凋亡和自噬的可行性。本课题不仅可能为椎间盘退行性变的分子靶向治疗和创新药物研发奠定基础，而且可能为其他疾病的相关研究提供新思路。

The decline of the number of nucleus pulposus(NP) cells,the main feature of intervertebral disc degeneration(IVDD), is closely related to programmed cell death. Unlike traditional manners of death, such as apoptosis,autophagy and necrosis, necroptosis is an entirely new manner of programmed cell death, highly valued by international academia, and it is possible to provide utterly new treatment strategies for various diseases. Nevertheless, there are uncertainties about the regulation mechanism of necroptosis and the crosstalk between it and apoptosis,especially autophagy, as well as a lack of relative report in the field of IVDD.Our previous studies have discovered that necroptosis is involved in the death process of NP cells. Based on our previous National Natural Science Foundation of China(NSFC) about studying NP cells autophagy, this project will adopt special inhibitor, SiRNA interference technology,and the gene overexpression technology,to systematically investigate the molecular mechanism of RIPK1-RIPK3-MLKL pathway in compression induced necroptosis and its crosstalk with autophagy, determine the key target of regulation of IVDD and discuss the possibility of coordinated regulation of necroptosis and autophagy.This study is expected to not only contribute to the theoretical foundation of molecular targeted treatment of IVDD and innovative medicinal development, but provide relative researches of other diseases with a new perspective.