Nav1.5在慢性内脏痛敏中的作用及其稳态表达失常机制的研究

慢性内脏痛是困扰患者最常见的临床症状之一，揭示该疾病机制的关键问题是明确慢性内脏痛发生发展过程中，内脏相关神经元敏化这一核心机制是如何形成的。人类遗传学研究表明Nav1.5可能与慢性内脏痛相关；我们前期的研究证实，结肠背根神经节（DRG）神经元Nav1.5表达失衡在调控新生期结肠炎症（NCI）诱导的慢性内脏痛以及结肠DRG神经元兴奋性中发挥重要的作用；进一步，我们研究发现慢性内脏痛条件下Nav1.5的稳态表达失衡与其基因启动子区域的低甲基化修饰以及特异性蛋白1(SP1) 转录因子密切相关。基于前期的工作基础，我们提出：甲基化修饰和SP1介导的Nav1.5的稳态表达失常通过调节结肠初级感觉神经元敏化参与慢性内脏痛的调控。本项目综合利用神经电生理记录、慢病毒工具以及一系列分子生物学实验技术，从整体、细胞和分子水平系统的对以上假设进行验证，以期为临床治疗慢性内脏痛提供新的理论基础和新的药物靶点。

Chronic visceral pain is one of the most common clinical symptoms that affect the patient. The main challenge of revealing the mechanism underlying such disease is to identify how visceral-related neuron sensitization, the core mechanism, is formed during the development and maintenance of chronic visceral pain. Human genetic studies indicated that Nav1.5 may be related to chronic visceral pain; our preliminary data confirmed that the imbalance of Nav1.5 expression in colonic DRG neurons plays an important role in the regulation of chronic visceral pain and the excitability of colonic dorsal root ganglia (DRG) neurons induced by neonatal colonic inflammation (NCI); Further, we found that the imbalance of Nav1.5 expression homeostasis is closely related to the hypomethylation of promoter region of SCN5A gene and transcription factor specific protein 1 (SP1) under the chronic visceral pain condition. Based on our preliminary work, we hypothesize that methylation- and SP1- mediated the imbalance of Nav1.5 expression homeostasis was involved in the modulation of chronic visceral pain through regulating the sensitization of colonic primary sensory neurons. Here, utilizing electrophysiological recording, viral tools and a series of molecular biological experiments, we will systematically investigate the above hypothesis in three levels: systemic level, cellular level and molecular level. We expect our research will provide new theoretical basis and novel drug targets for treatment of chronic visceral pain.