miR-31参与去甲肾上腺素介导慢性内脏痛敏的表观调控机制研究

项目名称： miR-31参与去甲肾上腺素介导慢性内脏痛敏的表观调控机制研究

项目编号： No.81500952

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 胡淑芬

作者单位： 苏州大学

项目金额： 17.5万元

中文摘要： IBS的病理机制尚不清楚，治疗手段也非常短缺。我们前期的研究结果显示新生期母爱剥夺(NMD)导致成年大鼠内脏痛高敏，近期研究发现NMD大鼠成年期进行成年应激（AS）会加剧内脏痛反应、升高血浆NE水平、增强肠DRG神经元ATP电流及P2X3R的表达，并下调miR-31的表达；另外给予NE受体拮抗剂可翻转内脏高敏反应，NE孵育肠DRG神经元可下调miR-31的表达。由此我们拟提出以下研究假设:复合应激（NMD+AS）通过激活肾上腺素能信号系统下调miR-31的表达，介导P2X3R表达上调且功能增强，诱导慢性内脏痛。从而确立了以下研究内容：1）初步阐明NE在IBS慢性内脏痛敏中的作用；2）探讨NE对P2X3R的功能和表达的调控作用；3) 探讨miR-31参与内脏痛模型中NE对P2X3R的调控作用。预期通过本研究将进一步阐明IBS慢性内脏痛的病因和病理机制，并有望为临床治疗IBS提供新的治疗靶点。

中文关键词： 慢性内脏痛；背根神经节；去甲肾上腺素；；P2X3受体；表观调控

英文摘要： The pathogenesis of irritable bowel syndrome（IBS）remains largely unknown and treatment options are very limited. Recent studies in our laboratory indicate that Neonatal Maternal Deprivation (NMD) results in visceral hypersensitivity in adult rats, and further studies show that adverse environmental stress at adult age imposed on NMD rats significantly exacerbated visceral pain responses. We also detected a higher norepinephrine (NE) level in blood plasma in NMD+AS rats than that in CON+AS rats. NE inhibitor treatment significantly reversed visceral hypersensitivity of NMD+AS rats; P2X3R expression and ATP-evoked currents in colon specific dorsal root ganglion (DRG) were significantly enhanced after NMD+AS treatment. More interestingly, we also found that after NMD+AS treatment, the expression of microRNA-31 (miR-31) was downregulated in colon DRGs; incubation of NE on colon specific DRG neurons decreased the expression of miR-31. Based on these exciting results, we propose the following experiment hypothesis: NMD+AS activates the NE signaling pathways to downregulate miR-31 expression, thus sensitizing P2X3R, and eventually produces chronic visceral hyperalgesia. Inhibitors of NE receptor and miR-31 Lentiviral over expression strategies will be employed to investigate the following specific aims: (1) To define the function of NE in visceral pain model; (2) To determine the roles of NE in sensitization of P2X3R; (3) To explore the mechanisms of miR-31 involved in NE-P2X3R signaling pathway in visceral pain model. We hope that our study will further explain pathological mechanisms of stress-induced chronic visceral pain and that this signaling pathway would be a novel potential target for treatment of chronic visceral pain in patients with IBS.

英文关键词： visceral hyperalgesia;dorsal root ganglion;norepinephrine;P2X3 receptors;epigenetic regulation