Notch2/γ-secretase抑制人椎间盘髓核细胞凋亡及细胞外基质降解的分子机制研究

椎间盘退变及其继发疾病是腰痛发生的主要病因。椎间盘退变主要表现为髓核细胞数量减少及功能下降。Notch信号通路在多种生理病理过程具有重要作用。申请人预实验结果显示Notch受体家族中Notch2在人椎间盘中显著表达，将Notch/γ-secretase通路阻断后髓核细胞凋亡显著增加且细胞外基质显著下降。结合以上结果和文献复习，我们提出科学假设：Notch2/γ-secretase通过抑制髓核细胞凋亡及细胞外基质降解，抑制椎间盘退变的发生；为验证此假设，我们设计了本课题：①明确Notch2/γ-secretase在抑制髓核细胞凋亡及细胞外基质降解方面的具体作用；②研究Notch2/γ-secretase此方面作用的详细作用机制；③探讨Notch2保护性高表达的分子调控机制。本研究有望揭示Notch通路在椎间盘退变中发挥的重要保护作用和具体分子机制，为治疗椎间盘退变及相关性腰痛提供理论。

Intervertebral disc degeneration is the main cause of low back pain and showed as nucleus pulposus(NP) cells apoptosis and dydfunction. Nocth signaling plays important role in many pathophysiological processes. Our prior data showed that,Notch2 gene highly expressd in NP cells,NP cells apoptosis decreased and extrocellular matrix degradation decreased while Notch/γ-secreatase was inhibited. According to these, we bring up the hypothesis: Notch2/γ-secretase inhibite disc degeneration by inhibiting NP cells apoptosis and extrocellular matrix degradation. Then we design this project: including: ①to study the function pattern of Notch2/γ-secretase in inhibiting NP cells apoptosis and extrocellular matrix degradation. ②to explore the detailed mechanism of Notch2/γ-secretase inhibiting disc degeneration.③to investigate the regulation molecular mechanism of protective high expression of Notch2. This project is designed to investigate the role of Notch signaling in disc degeneration and find out its molecular mechanisms, and provides a new target for biological treatment for intervertebral disc degeneration.