CircSPG21靶向SIRT2抑制髓核细胞衰老在椎间盘退变中的作用和机制

椎间盘退变是一种衰老相关疾病，常导致腰痛及劳动能力丧失，加重社会负担。髓核细胞衰老是椎间盘退变的重要致病因素，靶向髓核细胞衰老有望为诊治椎间盘退变提供新思路。研究显示环状RNA在椎间盘退变中发挥重要作用，但其是否参与髓核细胞衰老的调控尚不明确。申请人前期研究发现，环状RNA circSPG21在退变椎间盘的髓核细胞中表达显著下调，在髓核细胞中沉默circSPG21则可诱导髓核细胞衰老；筛选并验证circSPG21可结合SIRT2蛋白，抑制其泛素化修饰。由此申请人提出科学假说：circSPG21可能结合SIRT2蛋白并抑制其降解，从而抑制下游p53-p21信号通路，进而发挥抗衰老作用，延缓椎间盘退变。本项目旨在前期研究的基础上，通过体外实验及动物模型研究circSPG21/SIRT2/p53-p21信号轴对髓核细胞衰老的作用及调控机制，从而为以环状RNA为靶点的椎间盘退变防治提供理论依据。

Intervertebral disc degeneration (IDD) is an aging-related disease, which often leads to low back pain and disability, and increases social burden. The senescence of nucleus pulposus cell is a leading pathogenic factor of IDD. Targeting nucleus pulposus cell senescence is expected to provide new ideas for the diagnosis and treatment of IDD. Studies have shown that circRNA plays an important role in IDD, but whether it is involved in the regulation of nucleus pulposus cell senescence has not been reported. Our previous research found that the expression of circRNA circSPG21 was significantly down-regulated in nucleus pulposus cells of degenerated disc, and silencing circSPG21 in nucleus pulposus cells could induce senescence; Screen and verify that circSPG21 can bind to SIRT2 protein and inhibit its ubiquitination. Based on this, the applicant proposes a new hypothesis: circSPG21 may inhibit the ubiquitination and degradation of RNA-binding protein SIRT2, thereby inhibiting its downstream p53-p21 signaling pathway, exerting anti-aging effects and delaying the process of IDD. This project intends to investigate the effect and regulatory mechanism of circSPG21/SIRT2/p53-p21 axis on the senescence of nucleus pulposus cells through in vitro experiments and animal model based on previous work, so as to provide theoretical basis for prevention and treatment of IDD.