MicroRNA-26a/GSK3β信号通路调控神经病理性疼痛的机制研究

Neuropathy pain(neuropathic pain，NP) is a clinical common disease. Hyperalgesia are closely related with the regeneration of damaged axon and myelin regeneration. Peripheral nerve injury can lead to the changes of MicroRNAs(miRNAs) which are very important to axon and myelin regeneration and signal transduction of pain. Glycogen synthase kinase 3beta (GSK3β) regulate the development of the nervous system, axon and myelin regeneration, neuropathic pain.Our preliminary work proved that GSK3β as a direct downstream target of miR-26a. In dorsal root ganglion (DRG) of peripheral nervous system, Inhibition of endogenous miR-26a markedly impaired axon regeneration in vivo and in vitro. The expression of miR-26a was reduced in DRG after neuropathic pain caused by sciatic nerve crush,We found that GSK3β inhibitor(BIO) alleviated neuropathic pain in vivo. While the mechanism of miR-26a/GSK3β signaling pathway in neuropathic pain is still unclear. This study aims to identify that miR-26a regulates the target gene GSK3β to affect the regeneration of damaged axons and myelin after peripheral nerve injury, then affect neuropathic pain. This project will provide solid evidence for determining a new epigenetic basis of neuropathic pain and reveal possible therapeutic approaches for the treatment of neuropathic pain.

神经病理性疼痛是临床常见病，痛觉过敏与受损神经的轴突和髓鞘再生密切相关。周围神经损伤可以导致miRNAs的改变，miRNAs对神经轴突和髓鞘的再生以及疼痛信号转导十分重要。GSK3β对神经系统的发育、轴突和髓鞘再生、神经病理性疼痛等过程进行调节。申请者前期工作证明神经细胞系miR-26a调控下游靶基因GSK3β，在周围神经系统DRG中，体内和体外抑制miR-26a能显著降低轴突的再生能力，小鼠坐骨神经卡压后引起的神经病理性疼痛模型中DRG内miR-26a表达降低，体内给予GSK3β抑制剂后疼痛症状明显缓解。但是miR-26a/GSK3β信号通路在神经病理性疼痛的作用及其机制目前尚不清楚。因此本研究旨在证明miR-26a通过调控下游靶基因GSK3β影响外周神经损伤后轴突和髓鞘的再生，进一步影响神经病理性疼痛，从表观遗传学方面为临床治疗神经病理性疼痛提供新的理论依据。

MicroRNAs 是调节轴突再生的重要表观遗传学因素。本研究中我们发现microRNA-26a (miR-26a)是影响哺乳动物体内轴突再生的生理调节因子。本研究在成年小鼠感觉神经元体外实验和体内实验中证明内源性miR-26a调控下游靶基因糖原合成酶激酶3β(GSK3β)。体外和体内实验中抑制感觉神经元中的miR-26a会阻碍轴突再生。并且miR-26a的调节作用是通过GSK3β介导的，因为下调GSK3β的表达能逆转抑制miR-26a后对神经轴突再生的影响。本研究证明miR-26a-GSK3β信号通路通过调控神经元胞体内的基因表达来调节轴突再生。miR-26a-GSK3β通过调控转录因子Smad1基因的表达影响轴突再生。在坐骨神经压迫引起的神经病理性疼痛模型中背根神经节内miR-26a表达降低。研究发现GSK3β抑制剂(BIO)可以缓解体内神经病理性疼痛。本研究结果为阐明miR-26a-GSK3β信号通路通过调控神经轴突的再生从而影响神经病理性疼痛提供新的途径，从表观遗传学方面为临床神经病理性疼痛的治疗提供新的实验依据。