miR-183家族在运动训练改善坐骨神经慢性压迫所致神经病理性痛的作用机制

Sciatica has an increasing incidence in young people, and increasing trend year by year. Exercise training has been implicated to be one of the non-pharmaceutical strategies for treatment of sciatica. However, the mechanism of exercise training is unclear in sciatica. Our preliminary researches have showed exercise training relieved the pain intensity and improved lumbar strength in patients with Sciatica. In addition, we found exercise training regulated the miR-183 cluster scales, and miR-183 cluster scales regulated sodium and calcium channels, anti-inflammatory and neuropeptides to relieve pain in neuropathic pain in rats with chronic constriction injury of the sciatic nerve (CCI). On the basis of these preliminary results, the CCI rats with overexpression and knock-down and of miR-183 cluster will be conducted to exercise training. First, the present proposal will elucidate the molecular mechanism of miR-183 cluster regulating neuropathic pain. Then, we will confirm the effects of exercise training on the expressions of miR-183 cluster and their target genes, as well as related pathway of therapeutic effect. Finally, we will clarify the molecular mechanisms of exercise training for regulating the expression of miR-183 cluster in dorsal root ganglion and spinal cord from the perspective of DNA methylation regulating miR-183 cluster gene promoter and transcription factor. This project not only reveals the molecular mechanism of exercise training in sciatica, but also provides a new theoretical explanation for the effects of exercise training in sciatica.

坐骨神经痛呈现年轻化和逐年增多的趋势，运动训练作为一种非药物干预措施是治疗坐骨神经痛的热点，但其机制尚不明确。我们前期临床研究结果发现：运动训练能减轻坐骨神经痛患者的疼痛程度。同时我们在坐骨神经慢性压迫（CCI）所致神经病理性痛大鼠模型中也发现，运动训练通过调控miR-183家族，进而调节钠和钙离子通道等而改善疼痛。在此基础上，我们将采用过表达和敲低miR-183家族的CCI大鼠进行运动训练，首先进一步研究miR-183家族对疼痛影响的分子机制；然后研究miR-183家族在运动训练改善CCI大鼠治疗作用的相关通路；最后从DNA甲基化调控miR-183家族基因启动子以及转录因子的角度，研究运动训练调节背根神经节和脊髓miR-183家族表达的分子机制。本研究成果将有助于阐明运动训练改善坐骨神经痛的分子机制，并为运动训练作为一种非药物干预措施治疗坐骨神经痛提供理论依据。

坐骨神经痛（sciatica）是成年人普遍存在的健康问题，是全球神经病理性疼痛（Neuropathic Pain，NP）患病率的主要组成部分。本研究通过系统实验阐明 miR-183 家族及其相关靶基因在运动训练改善NP的作用，结合miR-183敲除动物模型，研究运动训练调节背根神经节和脊髓 miR-183 家族表达的分子机制。结果发现，CCI大鼠和SNI小鼠中miR-183家族表达均显著下降、CaV亚基α2δ-1（Cacna2d1）和α2δ-2（Cacna2d2）mRNA和蛋白表达水平均显著上升。运动训练可改善周围神经损伤所致神经病理性疼痛大/小鼠机械性刺激痛觉超敏，同时逆转了神经损伤导致的miR-183家族的表达抑制与Cacna2d1/2的表达上调。miR-183 KO可诱发小鼠机械性刺激痛觉超敏，并导致Cacna2d1和Cacna2d2的表达上调。运动训练仅在一定程度上缓解miR-183 KO小鼠机械性刺激痛觉超敏，并降低Cacna2d1的表达而非Canca2d2。提示miR-183可通过靶向抑制Cacna2d2参与运动改善机械性刺激痛觉超敏的疗效机制。