Nrf2通路调控食管上皮屏障功能及用于治疗胃食管反流病的机制研究

Gastroesophageal reflux disease (GERD) is the most commonly seen gastrointestinal disorder. Its incidence has been increasing in the recent years in China. Current treatment mainly relies on antacid medicine which controls acid injury due to reflux. Previous studies have clearly shown that esophageal epithelial barrier function is dramatically impaired in GERD patients. Therefore, strengthening esophageal epithelial barrier function can be potentially therapeutic for GERD. Our previous work have shown that Nrf2 regulates expression of a major tight junction protein in esophageal epithelial cells, claudin 4 (Cldn4), and thus esophageal barrier fucntion. Nrf2 deficiency impairs esophageal barrier function in mice, particually in the presence of surgically induced gastroesophageal reflux. In this study, we plan to further study the role of Nrf2-Cldn4 pathway in esophageal barrier function in vitro and in vivo. Chemical activators of Nrf2 will be studied to understand their potential of strengthening esophageal barrier function and blocking epithelial injury due to gastroesophageal reflux. Using pharmaceutical agents, genetically modified mice, cell culture and surgically induced reflux models, we aim to further understand the regulatory mechanism of esophageal barrier function by Nrf2 in order to develop novel and effective therapy for GERD, particularly for those patients who do not respond well to antacid therapy.

胃食管反流病（GERD）是一种常见的消化道疾病，近年来在我国的发病率逐年增高。目前治疗以抑酸剂为主，主要控制损害性因素，但部分患者的治疗效果不明显。既往研究表明，GERD患者的食管上皮屏障功能大幅度降低，因此增强食管上皮的屏障功能必然对GERD有治疗作用。深入研究食管上皮屏障功能的调控机制，有利于探寻GERD治疗的新的药物作用靶点。我们前期研究发现，敲除Nrf2后，小鼠的食管上皮屏障功能明显下降，特别是在手术诱导反流的情况下。本项目拟采用基因修饰及药物学策略，通过细胞实验和动物实验，结合手术反流小鼠模型，进一步深入研究Nrf2通路在食管上皮屏障功能中的调控作用及机制，观察Nrf2激活剂能否通过Nrf2-Cldn4通路增强食管上皮屏障功能，拮抗胃食管反流对上皮屏障功能的损伤。目的是发展新的有效的GERD治疗策略，用于抑酸剂疗效不佳的GERD患者。

胃食管反流病（GERD）是一种常见的消化道疾病，近年来在我国的发病率逐年增高。目前治疗以抑酸剂为主，主要控制损害性因素，但部分患者的治疗效果不明显。既往研究表明，GERD患者的食管上皮屏障功能大幅度降低，因此增强食管上皮的屏障功能必然对GERD有治疗作用。深入研究食管上皮屏障功能的调控机制，有利于探寻GERD治疗的新的药物作用靶点。我们研究发现，敲除Nrf2后，小鼠的食管上皮屏障功能明显下降，特别是在手术诱导反流的情况下。采用基因修饰及药物学策略，通过细胞实验和动物实验，结合手术反流小鼠模型，进一步深入研究了Nrf2通路在食管上皮屏障功能中的调控作用及机制，观察了Nrf2激活剂能否通过Nrf2-Cldn4通路增强食管上皮屏障功能，拮抗胃食管反流对上皮屏障功能的损伤，结果显示Nrf2激活剂可以增强食管上皮屏障功能。