miR-34a/SIRT1/mGluR5/NF-κB信号通路在急性牙髓炎疼痛中枢调控过程中的功能及机制研究

Acute pulpitis can cause violent and unbearable spontaneous pain, severely disturbing patients’ mental and physical health, but the specific central mechanism remains unclear. miR-34a was one of the miRNAs screened by miRNAs differential expression chips from the medullary dorsal horn of rat acute pulpitis model. Our preliminary experiments reveal that rat acute pulpitis model was successfully developed with obvious pain behaviors, and significantly increased miR-34a, decreased SIRT1, and up-regulated NF-κB were detected in the medullary dorsal horn. Moreover, SIRT1, as a key target of miR-34a, could inhibit the expression of mGluR5 and NF-κB, and plays a pivotal role in the regulation of nociceptive information by miR-34a under acute pulpitis pain conditions. Furthermore, overexpression of mGluR5 could enhance the activity of NF-κB, while NF-κB activation could upregulate the expression of miR-34a. These results suggest that miR-34a/SIRT1//mGluR5 NF-κB pathway may participate in the regulation of nociceptive information under acute pulpitis pain conditions. In this study, by using experiment techniques in molecular biology, neuropharmacology, morphology and pain behavior, we plan to observe the dynamic changes of miR-34a, SIRT1, mGluR5 and NF-κB in medullary dorsal horn in acute pulpitis pain models and the neuron types involved in this process. Afterwards, we will aim at exploring the effects on acute pulpitis pain by interfering with the function of miR-34a, SIRT1, mGluR5 and NF-κB in the medullary dorsal horn. Furthermore, the molecular mechanism of miR-34a/SIRT1/mGluR5/NF-κB signal pathway in regulation of acute pulpitis pain will be studied. The results will provide new insight into the recognition of central regulation of acute pulpitis pain, and offer potential intervention targets for the development of new pulpitis pain analgesic medications.

急性牙髓炎能引起剧烈疼痛，严重影响患者身心健康，但其机制尚不清楚。miR-34a是我们利用芯片从急性牙髓炎模型中筛选得到的miRNA之一。预实验结果显示：急性牙髓炎大鼠延髓背角miR-34a 表达升高、SIRT1降低、NF-κB升高； SIRT1是受miR-34a调控的关键分子，可抑制mGluR5和NF-κB表达，在miR-34a调控急性牙髓炎疼痛中发挥了重要作用；过表达mGluR5可增强NF-κB活性、NF-κB活化上调miR-34a表达；以上结果提示miR-34a/SIRT1/mGluR5/NF-κB环路可能参与急性牙髓炎伤害性信息的处理。本课题拟应用分子生物学、形态学和行为学等方法，系统研究miR-34a/SIRT1/mGluR5/NF-κB环路在急性牙髓炎疼痛中枢调控中发挥的作用及其调控机制，为急性牙髓炎疼痛中枢调控机制研究提供新的认识，为临床治疗急性牙髓炎提供潜在的药物作用靶点。

急性牙髓炎能引起剧烈疼痛，严重影响患者身心健康，但其机制尚不清楚。miRNA在生物体内参与了细胞增殖与凋亡、生长发育、DNA修复等一系列生物学过程，与多种疾病和肿瘤的发生发展密切相关，但在急性牙髓炎症中尚未见报道。本项目通过以研究miR-34a/SIRT1/mGluR5/NF-κB环路为突破口，以大鼠牙髓暴露模拟急性牙髓炎性疼痛为模型，以分子、细胞、组织和整体等多种水平，利用免疫组织化学、细胞生物学、病毒定位注射等多项技术，系统探讨了miR-34a/SIRT1/mGluR5/NF-κB环路在急性牙髓炎疼痛中枢调控中发挥的作用及其调控机制。研究结果表明：（1）成功构建了大鼠急性牙髓炎症疼痛模型，在此基础上首次发现了miR-34a直接参与急性牙髓炎性痛的中枢调控；（2）急性炎症发生时，二级神经元中miR34a增加,抑制下游靶基因SIRT1表达；（3）抑制NF-κB以及mGluR5，促进其下游的TNF-α等炎症因子表达，进一步引发急性牙髓炎性痛的发生。该研究结果为急性牙髓炎疼痛中枢调控机制研究提供新的认识，为临床治疗急性牙髓炎提供潜在的药物作用靶点。.基于上述研究成果，共发表SCI论文4篇（均标准基金号）；发表中文核心期刊2篇，其中包括中华类杂志1篇。2019年和2021年分别以第三完成人和第四完成人获陕西省科技进步一等奖2项，参与获得中华口腔医学会科技奖三等奖一项。牵头获得陕西省线上线下一流课程一项，主编专著1部。参加各类学术会议并作大会发言10次，培养硕士研究生6人。

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