Barrett食管是一种癌前病变，其分子机制尚不清楚。我们前期研究显示Notch信号通路可能通过其下游靶基因ATOH1与Barrett化生关键基因CDX2直接结合并启动后者表达，从而调控胃食管反流诱导的Barrett化生过程。本研究一方面将利用体外实验验证Notch1/Hes1/ATOH1/CDX2通路在胃食管反流诱导食管Barrett化生中的调控机制。采用染色质免疫共沉淀及荧光素酶报告基因方法明确ATOH1能否与CDX2直接结合并启动其表达，促进Barrett食管化生。另一方面，将创新性地利用目前已启动的纳入食管切除胃食管吻合术后患者的观察队列，作为理想的胃食管反流人体模型，前瞻性验证正常食管鳞状上皮在胃食管反流的作用下向Barrett化生过程中Notch1/Hes1/ATOH1/CDX2的表达变化及作用。为进一步阐明食管Barrett化生的分子机制及反流性食管损伤的防治奠定基础。

The underling pathogenesis of Barrett’s esophagus, a precancerous leision caused by long-term gastroesophageal reflux, is still unclear. According to our previous research, Notch signaling plays an important role in the development of esophagal mucosal damage induced by gastroesophageal reflux, and Barrett metaplasia might be regulated by the Notch downstream target gene ATOH1, which could bind to CDX2 promotor and induce its expression. In the current study, in vitro experiments will be conducted to confirm the role of Notch1/Hes1/ATOH1/CDX2 pathway in the pathogenesis of Barrett’s metaplasia induced by gastroesophageal reflux. Chromatin Immunoprecipaitation and Promoter Dual-Luciferase Detection will be used to test if ATOH1 could bind to CDX2 promoter and modulate its expression. Besides, an observational cohort of the patients after esophagectomy and gastroesophageal anastomosis will be used as an ideal gastroesophageal reflux model to prospectively evaluate the role of Notch1/Hes1/ATOH1/CDX2 signaling during the process of Barrett metaplasia in human. Our study will help to clarify the molecular pathogenesis of Barrett esophagus, and benefit the prevention and treatment for the esophageal mucosa damage caused by gastroesophageal reflux.