褪黑素通过MTNR1B/Gαi2/YAP调控炎症微环境下髓核细胞基质代谢的作用及机制研究

如何调控炎症微环境下髓核细胞代谢紊乱是延缓椎间盘退变（IDD）的重点、难点问题。申报人前期开展系列研究，发现褪黑素可作为防治骨软骨退变性疾病的候选药物（已发表5篇 J Pineal Res. IF:15.221）。本项目预实验结果显示，IDD患者中存在血清褪黑素水平及褪黑素信号通路异常，在大鼠IDD模型中给予褪黑素治疗可显著改善IDD；进一步发现褪黑素可通过膜受体MTNR1B调控炎症微环境下髓核细胞基质代谢，该作用与募集Gαi2蛋白，维持YAP蛋白活性，并抑制NF-κB通路有关。本项目拟在前期研究基础上，通过临床标本利用多组学测序分析等明确褪黑素相关通路与椎间盘退变的相关性；并通过体外细胞实验及体内动物模型研究系统阐明褪黑素通过MTNR1B/Gαi2/YAP调控炎症微环境下髓核细胞基质代谢的作用及具体机制，为褪黑素作为防治IDD的候选药物提供必要的理论依据，为IDD的防治提供新的靶点。

How to regulate the metabolic disorder of nucleus pulposus cells in the inflammatory microenvironment is the key and difficult issue in delaying intervertebral disc degeneration (IDD). The applicant has carried out a series of previous studies and found that melatonin can be used as a candidate drug for the prevention and treatment of osteochondral degenerative diseases. Preliminary experiment of our project found that there were abnormal levels of serum melatonin and melatonin signaling pathway in IDD patients. Treatment with melatonin in rat IDD models can significantly ameliorate the IDD process. Further study showed that melatonin can regulate the matrix metabolism of nucleus pulposus cells in the inflammatory microenvironment through the membrane receptor MTNR1B. This effect may be related to the recruitment of Gαi2 protein, maintenance of YAP protein activity and inhibition of the NF-κB pathway. Based on the previous research, our project intends to determine the correlation between melatonin and its membrane receptor-related pathways and intervertebral disc degeneration through clinical specimens using multi-omics sequencing analysis; systematically clarify the role and specific mechanism of melatonin in regulating matrix metabolism of nucleus pulposus cell through MTNR1B / Gαi2 / YAP axis by cell experiments and animal models. It can provide the necessary theoretical basis for melatonin as a candidate drug for IDD prevention and treatment. It can also provide new therapeutic targets for the prevention and treatment of IDD.