GCH1与小胶质细胞在腰段脊神经慢性压迫性疼痛中的相关性机制研究

GTP cyclohydrolase 1(GCH1) mediated neuropathic pain through inflammation factors, however, the exact mechanism is unclear. In our earlier studies, we found that silencing the expression of GCH1 gene can release the neuropathic pain caused by spinal nerve compression, and the aggregated microglia around spinal nerves disappeared. It is unclear that whether GCH1 were involved in the process of neuropathic pain by activating microglia cells or not. Here we screened the related inflammatory factors by stimulating the neurons and studied the changes of releasing of these factors at different times after the expression of GCH1 gene changed. Meanwhile, we studied the role of these factors on chemotaxis and activation of microglia in a neuropathic pain model of rats. Also the molecular mechanism of GCH1 on chemotaxis and activation of microglia were studied during the neuropathic pain produced by chronic compression of lumbar nerves. We expect to find out the mechanism of neuropathic pain induced by chronic Lumbar spinal nerve compression, and shed light on targeted therapy for the chronic spinal nerve compression pain.

三磷酸鸟苷环化水解酶1（GTP cyclohydrolase 1 GCH1）通过调节相关炎症因子的表达介导神经性疼痛的发生，但确切机制尚不完全明确。在研究GCH1与脊神经疼痛的关系时，发现沉默GCH1基因表达后伴随疼痛缓解，同时神经元外周小胶质细胞聚集消失。GCH1是否通过活化小胶质细胞参与疼痛的产生尚不明确。本研究通过改变GCH1基因表达，在不同时相点检测神经元受炎性刺激释放的炎症因子的变化并筛选出对小胶质细胞具有趋化作用的炎症因子。我们拟利用大鼠疼痛模型在体内验证候选炎症因子对小胶质细胞的趋化聚集作用，并探讨腰段脊神经慢性压迫性疼痛产生过程中GCH1对小胶质细胞趋化聚集作用的分子机制。冀以进一步明确腰段脊神经慢性压迫性疼痛的机制，为临床脊神经疼痛靶向治疗提供新思路。

三磷酸鸟苷环化水解酶1（GTP cyclohydrolase 1, GCH1）通过调节相关炎症因子的表达介导神经性疼痛的发生，沉默GCH1基因表达后伴随疼痛缓解，同时神经元外周小胶质细胞聚集消失。GCH1是否通过活化小胶质细胞参与疼痛的产生尚不明确。本研究通过干预GCH1基因表达，检测小胶质细胞炎症因子的变化并筛选出对小胶质细胞具有活化作用的GCH1下游目标分子miR-133-3p。我们拟利用大鼠疼痛模型在体内验证miR-133-3p对小胶质细胞的活化作用。这些研究结果有利于明确GCH1和小胶质细胞在腰段脊神经慢性压迫性疼痛中的作用和分子机制，为临床脊神经疼痛靶向治疗提供新思路。另外，我们发现能够负向调节GCH1表达的microRNA：miR-124。高表达miR-124不仅能够抑制脂多糖（lipopolysaccharide, LPS）诱导的神经元凋亡，而且可以抑制神经元炎症因子BH4的表达和iNOS的活性。体内实验表明miR-124治疗能够显著促进脊髓损伤后大鼠运动功能的恢复。这些研究结果表明miR-124通过调节GCH1表达参与脊髓损伤中疼痛的产生，为临床脊髓损伤的治疗提供新思路。除此以外，我们还发现GCH1的上游调控蛋白: 核因子NF-kB。NF-kB不仅能够正向调节GCH1的表达，而且NF-kB通过调控GCH1表达参与LPS诱导的小胶质细胞炎症。最后，我们发现柳氮磺胺吡啶可以通过抑制星型胶质细胞激活和炎症因子释放从而缓解慢性压迫性神经损伤(chronic constriction injury, CCI)引起的神经病理性疼痛，提示柳氮磺胺吡啶可能在CCI中具有潜在的治疗作用，为后续的药物开发和制备新的疼痛治疗方案奠定基础。

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