髓核细胞功能丧失是椎间盘退变（IDD）的主要病理学基础，其具体分子机制尚待阐明。糖酵解代谢失衡对髓核细胞功能有显著负面影响。课题组前期发现，临床退变髓核组织存在细胞外基质硬度增高并伴有分解代谢激活的特征。预实验结果显示，基质硬度的增高激活髓核细胞内糖酵解并促进退变表型，其机制可能是通过诱导机械感受因子MRTF-A的核转位进而抑制代谢催化酶AMPD1所实现；阻断MRTF-A或过表达AMPD1则抑制糖酵解。据此项目组提出假说：退变椎间盘中增加的基质硬度可通过MRTF-A/AMPD1信号过度激活髓核细胞内糖酵解导致代谢失衡，加速椎间盘退变。本研究拟采用硬度梯度水凝胶、IDD动物模型及MRTF-A基因敲除小鼠，结合病毒转染、免疫共沉淀测序和位点敲除等技术分别从分子、细胞和动物水平解析基质硬度对糖酵解和IDD发生发展的影响及相关信号通路的调控作用，为IDD防治提供新靶点。

Nucleus pulposus cell dysfunction is the main pathological feature of intervertebral disc degeneration (IDD). However, the underlying molecular mechanisms remain to be explored. The imbalanced glycolysis has a marked negative impact on the function of nucleus pulposus cells. Our previous studies demonstrated that the clinical nucleus pulposus degeneration was characterized by increased matrix stiffness and activated catabolic metabolism. Furthermore, preliminary data showed that matrix stiffness downregulated the expression of AMPD1 and promoted glycolysis and degenerative phenotype in nucleus pulposus cells by translocating mechanical sensing factor MRTF-A, and silencing MRTF-A or overexpressing AMPD1 inhibited glycolysis. Therefore, we propose that the increased matrix stiffness in IDD leads to metabolic imbalance by excessive activation of glycolysis in nucleus pulposus cells via the MRTF-A/AMPD1 signaling, thereby accelerating the development of IDD. In this project, we will employ virus transfection, ChIP-Seq, CRISPR-Cas9 and other experimental methods to analyze the impact of matrix stiffness on glycolysis and IDD at animal, cellular and molecular levels. We will also investigate the regulation of associated signaling pathways which will promote the discovery of novel therapeutic targets of IDD.