MK2和MSK1/2在颈椎后纵韧带骨化症脊髓慢性压迫损伤中作用及其分子机制研究

Inflammation factors of chronic spinal cord compression injury in ossification of posterior longitudinal ligament (OPLL) of cervical spine were the research focus at home and abroad in recent years. The p38a mitogen-activated protein kinase (p38a MAPK) as key links involved in inflammatory reaction signaling pathways, combining its important downstream kinases that is mitogen-activated protein kinase-activated protein kinase 2 (MK2) and mitogen and stress-activated protein kinase-1/2(MSK1/2), could regulate nerve inflammation bilaterally. Nevertheless, their role in the chronic inflammation injury caused by mechanical pressure remains unclear. Our preliminary work indicates that MSK1 could intervene the inflammatory responses of microglial/macrophage. In this study, homozygous twy/twy mice were set as the model of cervical OPLL. Based on this model, we will use flow cytometry, immunofluorescence, Western blot technologies, combining with mouse kinematics, spinal cord MRI, electrophysiological methods in order to clarify the molecular mechanism and function of MK2 and MSK1/2 pathways in the cervical spinal cord compression inflammation injury of OPLL. The research results will help us to understand the signal transduction mechanisms in chronic spinal cord compression inflammation injury and provide a new target molecule for drug treatment of cervical OPLL.

颈椎后纵韧带骨化症(OPLL)中脊髓慢性压迫损伤的炎症因素是近年来国内外关注的焦点。作为参与炎症反应重要信号通路的p38a丝裂原激活蛋白激酶（p38a MAPK），以及其下游中的关键激酶—MAPK激活的蛋白激酶2（MK2）、丝裂原和应激激活的蛋白激酶1/2 (MSKl/2)，可能双向调控炎症反应，但这一信号通路在脊髓慢性机械压迫炎症损伤中的作用尚不清楚。前期工作表明MSK1调节了脊髓小胶质/巨噬细胞的炎症反应。据此，本课题拟以twy/twy小鼠为颈椎OPLL模型，采用流式细胞术、免疫荧光、蛋白印迹等技术，结合小鼠运动学、脊髓MRI、电生理等方法，明确MK2和MSK1/2在颈椎OPLL脊髓慢性压迫炎症损伤中的作用及其分子机制。所获研究成果，将丰富人们对脊髓慢性压迫损伤信号转导机制的认识，同时为颈椎OPLL的药物治疗提供新的靶分子。

颈椎后纵韧带骨化症(OPLL)中脊髓慢性压迫损伤的炎症因素是近年来国内外关注的焦点。作为参与炎症反应重要信号通路的p38a丝裂原激活蛋白激酶（p38a MAPK），以及其下游中的关键激酶—MAPK激活的蛋白激酶2（MK2），可能调控炎症反应，但这一信号通路在脊髓慢性机械压迫炎症损伤中的作用尚不清楚。本课题拟以twy/twy小鼠为颈椎OPLL模型，采用蛋白印迹等技术，结合小鼠运动学、脊髓MRI检查等方法，探讨MK2在颈椎OPLL脊髓慢性压迫炎症损伤中的作用及其分子机制。结果显示与对照组相比，twy/twy小鼠步长及肢体协调性下降，使用抑制剂4周后，肢体运动功能明显改善。twy/twy小鼠受压颈脊髓中炎症相关因子（IL-1β、TNF-α、NF-κB、MK2 and p-MK2）、凋亡相关蛋白（caspase-8和bax/bcl-2比值）表达明显增高，使用MK2抑制剂4周后，twy/twy小鼠受压颈脊髓中上述炎症相关因子和凋亡相关蛋白表达明显降低。本研究首次提示MK2信号通路参与了OPLL颈脊髓慢性压迫损伤中的炎症反应，使用抑制剂通过调控MK2信号通路可能调控脊髓损伤炎症反应，促进脊髓慢性压迫损伤恢复。我们的发现将有助于认识OPLL脊髓慢性压迫损伤信号转导机制，并为颈脊髓慢性压迫损伤的药物治疗提供新的靶分子。