锌指蛋白A20对髓核细胞炎症反应的调控在椎间盘退变机制中的保护作用研究

The cascade of inflammatory cytokines of nucleus pulposus cells are core to the pathogenesis of disc degeneration, the inflammatory cytokines plays a key role in the pathogenesis of disc degeneration by promoting extracellular matrix degradation and accumulation of immune cells. Our previous studies have shown that: zinc finger protein A20 is an important regulatory protein to prevent uncontrolled inflammatory response in vivo, and it related to inflammatory cytokines production of nucleus pulposus cells during disc degeneration. In order to further clarify the protective role of zinc finger protein A20 in regulating the inflammation response in nucleus pulposus cells during intervertebral disc degeneration, the cell culture, morphology, Northern Blot, Western Blot, gene transfection, RNA interference, animal experiments and other technical methods will be used to study the role of NF-κB inflammatory signaling pathways and secondary release of proinflammatory cytokines in intervertebral disc degeneration mechanisms, as well as through negative feedback regulate to NF-κB inflammatory signaling pathway and proinflammatory cytokine secondary release by the key regulatory protein zinc finger protein A20, to further explore the protective role of zinc finger protein A20 in regulating the inflammation response in nucleus pulposus cells during intervertebral disc degeneration. It will be helpful to find a new breakthrough for effective treatment of degenerative disc disease.

髓核细胞产生的炎性细胞因子及其级联反应是椎间盘退变发病机制的核心，炎性细胞因子通过促进细胞外基质的降解和免疫细胞的聚集，在椎间盘退变的发病中起关键作用。我们的前期研究已表明：锌指蛋白A20是防止体内炎症反应失控的重要调节蛋白，且锌指蛋白A20与椎间盘退变时髓核细胞内炎性细胞因子的产生有关。为了进一步明确锌指蛋白A20对髓核细胞炎症反应的调控在椎间盘退变机制中的保护作用，本研究拟采用细胞培养、形态学观察、Northern Blot、Western Blot、基因转染、RNA干扰、动物实验等技术方法，探讨髓核细胞NF-κB炎症信号通路及其继发性释放的致炎因子在椎间盘退变机制中的作用，并通过研究锌指蛋白A20对NF-κB炎症信号通路及炎性细胞因子的负反馈抑制，进一步明确锌指蛋白A20对髓核细胞炎症反应的调控在椎间盘退变机制中的关键保护作用，为有效治疗椎间盘退变性疾病寻找新的突破口。

本课题较系统地研究了锌指蛋白A20对髓核细胞炎症反应的调控在椎间盘退变机制中的保护作用。在椎间盘受到刺激因素作用时，锌指蛋白A20阻断了髓核细胞NF-κB炎性信号通路及其炎性细胞因子TNF-α和IL-1β等的产生，抑制了髓核细胞内外炎性环境的发生，干扰了椎间盘退变进程中免疫细胞的浸润和活化，阻断了炎症级联反应的放大及炎性细胞因子的继发性释放，从而达到对髓核细胞NF-κB炎性信号通路的关键调控，抑制了椎间盘组织的炎症反应升级，延缓了细胞外基质的降解，最终减轻了椎间盘退变的发生、发展。从而为临床有效治疗椎间盘退变性疾病，最大可能的保留椎间盘组织使其继续发挥重要功能，最终保持脊柱活动度及运动功能等目前这一脊柱外科临床亟待解决的关键科学问题提供了新的思路。