背根神经节神经元与卫星胶质细胞间作用涉及探究糖尿病神经病理痛机制和潜在治疗靶点的新途径

Diabetic neuropathic pain (DPN) is a very common complication, which causes considerable suffering and is difficult to treat. The studies in our lab have shown previously that satellite glial cells (SGCs) in dorsal root ganglia (DRG) are profoundly altered in diabetic rat models, and related to pain behaviors in animal models. Therefore satellite glial cells should be a therapeutic target. As virtually nothing is known on SGCs in DPN, the study will be to investigate the role of neuron - SGC interactions in DRG in DNP. Our aim is to learn how pathological neuron-SGC interactions contribute to DPN. Our main hypothesis is that in diabetes cellular interactions are enhanced, and cause augmented spread of excitation via calcium waves, which are mediated by purinergic P2 receptors and gap junctions. Our preliminary data shows that P2(P2X7、P2Y12) receptors and gap junctions are enhanced in a diabetes model. We will study subsequent changes in neurons and SGCs in DRG in type 2 diabetic rat models. We will focus on changes in responses to ATP via P2 receptors, and the augmented gap junctions. The study will search for monomer molecules from natural medicine that will block P2 receptors or gap junctions, and thus have a therapeutic potential. After the application of nano materials for drug / gene collaborative targeting drug delivery system, which combined the antagonists of P2 receptors or gap junction proteins or natural medicine monomers with small interfering RNA of P2 receptors or gap junction proteins, we will observe the synergies in the co-application of two or more drugs on diabetic neuropathic pain. The research will provide new ideas to explore the mechanism and effective therapeutic targets for the occurrence of DNP.

糖尿病神经痛(DNP)是常见并难治并发症。前期研究显示糖尿病大鼠背根神经节(DRG)中卫星胶质细胞(SGCs)出现异常变化，并与动物痛行为相关，SGCs可能成其防治新靶点。由于对DNP中SGCs作用的了解较少，本项目开展DNP的DRG神经元与SGCs间作用研究，了解神经元与SGC间异常相互作用对DNP发病的影响。假设糖尿病提高神经元与SGC间异常作用，嘌呤（P）2受体和缝隙连接参与经钙波增强的DRG兴奋传播。预实验显示糖尿病模型DRG中P2（P2X7、P2Y12）受体和缝隙连接异常。项目观察2型糖尿病模型大鼠DRG中P2受体异常反应及缝隙连接增大引起神经元和SGCs间的病变，及P2受体或缝隙连接拮抗剂和其小干扰RNA、天然药物单体、及以上药物/小干扰RNA整合的纳米材料性协同靶向给药对神经元与SGC间异常相互作用引发DNP的作用，从而为DNP发生机制及防治靶点研究提供新思路。

糖尿病神经痛(DNP)是常见并难治并发症。应用2型糖尿病神经病理痛模型，研究发现长非编码RNA NONRATT021972 小干扰核糖核酸（siRNA）抑制2型糖尿病大鼠背根神经节中P2X7受体介导的神经病理痛。长非编码RNA uc.48+ 的siRNA缓解2型糖尿病大鼠DRG中P2X3受体介导的神经病理痛痛。青藤碱减轻背根神经节P2X3受体介导糖尿病神经病理痛。纳米颗粒包裹大黄素降低背根神经节P2X3受体介导的糖尿病神经病理痛。背根神经节(DRG)卫星胶质细胞(SGC)P2Y12受体介导糖尿病神经病理痛，P2Y12短发夹RNA(shRNA)、纳米粒子包裹的姜黄素抑制背根神经节P2Y12受体介导的糖尿病神经性疼痛。蛇床子素抑制大鼠背根神经节P2X4受体介导的糖尿病神经病理痛。长链非编码RNA UC.360+短发夹核糖核酸（shRNA）缓解大鼠背根神经节P2X7受体介导的糖尿病神经病理痛。以上研究结果为糖尿病神经病理痛的发病机制研究及防治措施探索提供新的实验基础。