胃食管反流病（GERD）是一种严重影响生活质量的慢性疾病，传统的抑酸药仅能缓解部分患者的症状。通过抑制一过性食管下括约肌松弛（TLESRs）及改善负性情绪有望提高GERD的治疗疗效，而代谢型谷氨酸受体5（mGluR5）可能在两个环节中都发挥重要作用，但具体机制尚不清楚。我们前期开展了大量mGluR5的基础研究，发现GERD模型孤束核（NTS）和杏仁核（AMY）脑区内mGluR5表达升高，且mGluR5抑制剂可以有效缓解焦虑样症状。本课题拟在前期工作基础上，通过高尔基染色和免疫电镜等方法明确GERD模型NTS-AMY环路结构可塑性变化; 利用micro-PET-CT、光遗传学技术、行为药理学实验、靶向定量蛋白组学技术以及食管测压等方法揭示NTS-AMY环路内mGluR5参与抑制TLESRs及改善负性情绪的作用和分子机制。该研究有助于为开发GERD更加有效的靶向治疗策略提供新思路。

Gastroesophageal reflux disease (GERD) is a chronic condition that seriously affects the quality of life. Traditional antacids only alleviate the symptoms of some patients. The therapeutic efficacy of GERD is expected to be improved by inhibiting transient esophageal sphincter relaxation (TLESRs) and improving negative emotions. Metabotropic glutamate receptor type 5 (mGluR5) may play an important role in both phases, whereas the specific mechanism is unclear. We conducted a large number of basic researches in mGluR5 and found that the expression of mGluR5 was elevated in the brain regions of the nucleus tractus solitarii (NTS) and amygdala (AMY) of the GERD model. And mGluR5 inhibitors could effectively relieve the anxiety symptoms. Based on the previous work, this project aims to clarify the plasticity of NTS-AMY circuit structure in GERD model by Golgi staining and immune-electron microscopy. Using micro-PET-CT, optogenetics, behavioral pharmacology and targeted quantitative proteomics techniques and esophageal manometry reveal the role and molecular mechanisms of mGluR5 in the NTS-AMY circuit involved in the inhibition of TLESRs and improving negative emotions. This research may help to provide new ideas for developing more effective targeted therapy strategies for GERD.