巨噬细胞集落刺激因子受体调控脊髓小胶质细胞增生参与复杂性局部疼痛综合征Ⅰ型中枢敏化形成机制的研究

Microgliosis,which is known as the rapid changes of functional behaviors such as microglial quantity and immune profile,plays a key role in central sensitization of complex regional pain syndrome I (CRPS I ),one of the most challenging clinical neuropathic pain syndromes.Macrophage colony stimulating factor receptor (CSF-1R) is primarily expressed by microglia in the spinal cord,and regulates the migration,chemotaxis,proliferation and differentiation of microglia.However,the effects of CSF-1R on microglial activation in CRPS I have not been investigated.Our preliminary studies have demonstrated that the CSF-1R on the spinal microglia may be involved in the central sensitization of CRPS I,as the immunofluorescence intensity of microglial marker and CSF-1R both increased greatly,consisted with the decreased tactile allodynia and thermal hyperalgesia in 14d after CRPS I.PI3K/Akt is a major downstream pathway from the CSF-1R,and it remains unclear whether and how CSF-1R/PI3K/Akt pathway in microglia mediates the central sensitization of CRPS I. Therefore,in this study,we will use the state-of-art behavior and molecular techniques to investigate the possible influences of CSF-1R/PI3K/Akt pathway on the microgliosis,such as phagocytosis,migration,chemotaxis,proliferation,differentiation and immunity of microglia in vivo and in vitro.The goals of this project are to identify new pathological mechanisms and to develop novel therapies for CRPS I.

脊髓小胶质细胞增生是复杂性局部疼痛综合征Ⅰ型（CRPSⅠ）中枢敏化形成的主要机制。小胶质细胞增生是指小胶质细胞激活后在数量和免疫功能等方面的迅速改变。巨噬细胞集落刺激因子受体（CSF-1R）主要分布在小胶质细胞上，具有调控小胶质细胞的吞噬、趋化、增殖和免疫等功能的作用。PI3K/Akt是CSF-1R主要胞内信号通路。我们前期试验结果提示：脊髓小胶质细胞上的CSF-1R可能与CRPSⅠ中枢敏化的形成有关。CSF-1R是否以及如何调控包括CRPSⅠ中枢敏化的机制尚不清楚。本课题将结合在体和离体实验，采用疼痛行为学和分子生物学等实验技术，从脊髓小胶质细胞的吞噬作用、趋化运动、增殖分化和免疫功能等方面入手，研究CSF-1R/PI3K/Akt信号通路调控脊髓小胶质细胞增生参与CRPSⅠ中枢敏化的形成，为更好的阐明神经病理性疼痛中枢敏化形成机制，靶控治疗CRPSⅠ提供实验依据。

脊髓后角小胶质细胞与慢性疼痛中枢敏化的形成密切相关，但机制不清。当机体出现病理损伤或外界病原体刺激时，作为中枢神经系统巨噬细胞的小胶质细胞能迅速激活，并在数量、趋化增殖和免疫效应等功能行为方面发生改变。巨噬细胞集落刺激因子（Macrophage colony stimulating factor, CSF1）是一重要的血源性巨噬细胞生长因子，其受体CSF1R在中枢神经系统内仅分布在小胶质细胞。既往研究显示：CSF1/CSF1R信号通路调控小胶质细胞的发育和存活。本项目主要研究了CSF1/CSF1R信号通路通过调控脊髓后角小胶质细胞的增殖和免疫特性参与慢性缺血性疼痛中枢敏化的形成。主要研究结果如下：①下肢缺血时间长短和疼痛行为学与脊髓后角小胶质细胞数量增多有关，下肢缺血6h较缺血3h明显促进脊髓后角小胶质细胞增殖和疼痛阈值的下调；②下肢缺血6h能激活脊髓后角星形胶质细胞分泌CSF1，同时促进小胶质细胞CSF1R含量表达上调；③CSF1/CSF1R促进脊髓后角小胶质细胞增殖(Ki67标记)；④CSF1/CSF1R激活脊髓后角小胶质细胞分泌神经生长因子BDNF，同时小胶质细胞趋化受体CX3CR1表达上调；⑤CSF1/CSF1R促进脊髓后角神经元c-Fos表达增强，同时GluR1和NR2b受体表达上调；⑥抑制CSF1/CSF1R能明显缓解小胶质细胞的增殖和趋化能力，减少BDNF的生成，逆转脊髓后角神经元兴奋性的传导，从而缓解慢性疼痛症状。上述研究结果表明：CSF1/CSF1R信号通过促进小胶质细胞增殖，趋化和分泌BDNF参与慢性疼痛中枢敏化的形成。

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