疏肝和胃方调控NMDA-MAPK-CREB-BDNF通路改善难治性胃食管反流病食管高敏感的机制研究

难治性胃食管反流病（rGERD）是临床消化科面临的一个棘手问题。食管内脏高敏感是引发rGERD的重要原因，但其参与发病的分子机制尚未阐明且无有效防治药物上市。申请人前期发现疏肝和胃方能明显改善rGERD患者的内脏高敏状态并下调脊髓致敏NMDA受体的表达。结合“肝主疏泄”、肝能调畅全身气机的中医理论及前期研究基础，提出如下假说：大脑及脊髓中枢NMDA-MAPK-CREB-BDNF通路参与了rGERD食管致敏过程，疏肝和胃方可通过下调神经中枢及外周NMDA通路相关蛋白的表达，“畅达全身气机”，进而改善rGERD食管高敏状态。为验证该假说，本研究拟通过构建食管内脏高敏感大鼠模型，利用免疫学、行为学及分子生物学等技术探究食管的致敏机制，揭示疏肝和胃方原方、拆方对外周和食管致敏相关蛋白表达及NMDA通路相关蛋白的调控作用，以期为疏肝和胃方的临床应用提供科学依据并为rGERD的治疗提供新靶点和新思路。

Refractory gastroesophageal reflux disease (rGERD) is a difficult problem in clinical digestive department. Esophageal visceral hypersensitivity is an important cause of rGERD. However，the molecular mechanism of its involvement in the pathogenesis has not been elucidated and there is no effective therapeutic drug on the market. The applicant has found that Soothing Liver and Harmonizing Stomach Decoction (SLHSD) can significantly improve the visceral hypersensitivity of patients with rGERD and down regulate the expression of NMDA receptor in sensitized spinal cord. Based on the classical theories of traditional Chinses medicine that liver dominates dispersion and liver can regulate Qi of the whole body and previous research foundation, the following hypothesis is proposed that NMDA-MAPK-CREB-BDNF signal path of brain and spinal cord may be involved in the process of esophageal sensitization and SLHSD can reduce the expression of protein related with NMDA pathway in centeral and peripheral nerve system, dispersing Qi of the whole body, to improve the esophageal hypersensitivity of rGERD. In order to verify the hypothesis, this research intends to establish a rat model of esophageal visceral hypersensitivity, explore the sensitization mechanism of esophagus and reveal the intervention effect of SLHSD (including its decomposed recipes) on the expression of gene protein related with NMDA pathway by experimental techniques of immunology, ethology and molecular biology, so as to provide scientific basis for the clinical application of SLHSD and provide a new target and a new idea for the treatment of rGERD.