长非编码RNA-US在颈部交感神经节P2X4受体介导糖尿病心交感神经病理损伤中的作用及机理研究

Changes of expression and regulating factor in long non coding RNAs (lncRNAs) (more than 200 nucleotides in length) are related with nevous diseases, but its mechanism is unknown. Diabetic cardiac sympathetic neuropathy is a very common complication. On the groundwork of previous studies, our studies select an lncRNA (preliminary name as lncRNA-US) of the upregulated expression in the cervical sympathetic ganglia (superior cervical ganglia and stellate ganglia) of type 2 diabetic rat model. Project presumes that the inflammatory state of hyperglycemia will activate the P2X4 receptor in the neurons of the cervical sympathetic ganglia, which induce that P2X4-NLRP1 or NLRP3 inflammasome signal pathway will mediate IL-1β release, and then drive pyroptosis-apoptosis in the cervical sympathetic nerves. The pyroptosis-apoptosis in the cervical sympathetic nerves results in the cardiac autonomic nerve remoding and the cardiac functional damage. Pre experiment showed that lncRNA-US interacted with the P2X4 receptor, and this project futher assumes that lncRNA-US may play a positive regulatory role in P2X4 receptor mediated-pathological changes of cardiac sympathetic damage. By application of diabetic rat model and cell model treated with high sugar, our studies will observe the effects of lncRNA-US and its shRNA on the pathological changes of cardiac dysfunction mediated by the P2X4 receptor in the cervical sympathetic ganglia and its mechanism. The research will provide new ideas to explore the pathological mechanism and the effective preventive and therapeutic measures against the occurrence of diabetic cardiac sympathetic neuropathy.

长度大于200个核苷酸的长非编码RNA(lncRNA)的表达变化与神经疾病有关，但机制不清楚。心交感神经病变是糖尿病最常见的并发症之一。项目选择2型糖尿病模型大鼠颈部交感神经节（颈上和星状神经节）表达增加的lncRNA-US进行研究。项目假设高糖炎性状态下可激活颈部交感神经节神经元P2X4受体，通过P2X4-NLRP1、NLRP3炎性小体依赖的信号通路诱发IL-1β释放介导颈部交感神经节神经细胞焦亡/凋亡，引起心交感神经重构导致心功能损害。预实验提示lncRNA-US与P2X4受体存在相互作用，进一步推测lncRNA-US可能正性调控P2X4受体介导的效应，加重心交感神经损伤。实验用2型糖尿病动物模型、高糖培养细胞损伤模型，观察lncRNA-US及其shRNA对颈部交感神经节P2X4受体介导心交感功能病理变化的作用及可能机制，为糖尿病心交感神经损伤的机制及防治研究提供新的实验基础。

心交感神经病变是糖尿病(DM)的常见并发症。项目观察嘌呤受体介导DM交感神经病变及敲低长非编码RNA(lncRNA) uc.360+或48+及嘌呤受体的影响。研究发现lncRNA-uc.360+短发夹核糖核酸(shRNA)缓解星状神经节(SG)P2X4受体介导糖尿病大鼠心交感功能损伤。P2X4受体shRNA减轻大鼠背根神经节涉及心肌缺血后心脏功能异常。P2Y12 shRNA改善2型糖尿病大鼠腹腔神经节、肝葡萄糖激酶的炎症性功能异常。lncRNA uc.48+小干扰RNA(siRNA)影响肝葡萄糖激酶(GK)降低2型糖尿病模型大鼠的高血糖。敲低GK可减轻SG中GK与P2X3受体协同介导的2型糖尿病大鼠心交感神经病变。P2Y12受体shRNA减轻2型糖尿病小鼠慢性瘙痒。lncRNA uc.48+的shRNA抑制颈上神经节P2Y12受体介导心肌缺血大鼠的异常交感兴奋性反射。lncRNA-uc.360+ shRNA 减轻NLRP3 炎症小体诱导大鼠SG细胞焦亡介导糖尿病心交感神经损伤。CpG寡核苷酸1826改善大鼠SG中P2Y12受体介导的糖尿病心脏自主神经病变。以上研究结果为糖尿病交感神经病变的机制研究及防治探索提供新的实验基础。