CBP/p300抑制椎间盘退变和减轻椎间盘源性腰痛的机制研究

椎间盘退变(IVDD)及其引起的腰痛是重要临床问题，髓核细胞(NPC)数量减少和功能下降是直接诱因；CBP/p300具有多种生物学功能，在炎症、退变、肿瘤等过程中起关键作用。申请人预实验发现随年龄增加IVD内CBP/p300表达呈递减趋势，IVDD时CBP/p300表达显著降低，CBP/p300沉默后NPC凋亡增加且细胞外基质合成分泌下降，提示CBP/p300在IVDD进程中至关重要。我们假设：CBP/p300参与调节IVDD进程，调控椎间盘NGF等疼痛相关因子分泌，从而影响椎间盘退变相关疼痛，为此我们设计实验：①明确CBP/p300调控NPC增殖凋亡和合成分泌细胞外基质的具体作用及机制；②阐明其在椎间盘内诱导NGF等疼痛因子分泌的机制；③阐述其在疼痛性IVDD内低表达和调节疼痛阈值的分子机制。本研究有望揭示CBP/p300在IVDD相关腰痛中的作用，为IVDD相关腰痛的生物治疗提供依据。

Intervertebral disc degeneration (IVDD) and related diseases are important clinical problems, mainly caused by nucleus pulposus cells (NPC) reduction and dysfunction. CBP/p300 are macromolecular proteins with many biological functions, which plays a key role in the physiology and pathology of inflammation, degeneration and cancer. It was found that CBP/p300 showed a decreasing trend with age in IVD, significantly lower CBP/p300 expression in IVDD, CBP/p300 silence increased NPC apoptosis and decreased synthesis and secretion of extracellular matrix, suggesting CBP/p300 plays crucial role in the process of IVDD. We hypothesized: CBP/p300 regulates the process of IVDD, together with the secretion of NGF and other cytokines. To verify the hypothesis we designed the following topics: ①explore the function and mechanism of CBP/p300 in regulation of NPC proliferation and apoptosis, as well as synthesis and secretion of extracellular matrix; ②clarify the mechanism of CBP/p300 in regulation of NGF and pain factor secretion related to discogenic pain; ③elaborate the molecular mechanism of low CBP/p300 expression in the IVDD and the regulation of pain threshold. This study is expected to reveal the role of CBP/p300 in IVDD related pain and provides a new direction for biological treatment of IVDD associated with low back pain.