我国Barrett食管的发病率明显上升，其发病机制不明。课题组前期研究明确了，Notch信号的抑制在反流诱导的食管Barrett化生中发挥着重要的作用，但它通过何种生物学过程调控食管Barrett化生，其直接作用靶基因及分子机制尚需探究。课题组后续在组织样本中证实了自噬水平在Barrett食管中明显升高，体外细胞实验表明Notch信号可负向调控细胞自噬，是Notch信号在Barrett食管中的新功能、新机制。进一步的蛋白互作筛选，课题组原创性地发现了Notch1可与自噬关键蛋白ULK1直接相互作用，并影响ULK1磷酸化及下游自噬。在此基础上，本项目将在细胞、动物及人体模型多个层面系统研究Notch1-ULK1-自噬调控轴在Barrett食管中的功能作用和分子机制，深刻揭示Notch1靶向性作用ULK1的具体位点、功能修饰及其调控自噬的分子效应途径，为下一步的临床转化研究提供科学理论依据。

The incidence of Barrett esophagus has risen significantly in China. However, the molecular pathogenesis of Barrett esophagus is still unclear. Our preliminary study has indicated that the inhibition of Notch signaling has an important role in the development of Barrett esophagus, though how it regulates Barrett esophagus and its direct target genes are largely unknown. Our further investigation showed that cell autophagy level was increased significantly in Barrett esophagus as compared with normal esophagus. Autophagy might be involved in the development of Barrett esophagus via direct interaction between Notch1 and ULK1, and the phosphorylation of ULK1 was regulated by Notch1. The current study will explore the detailed function modification and molecular pathogenesis of Notch1-ULK1-autophagy axis in the pathogenesis of Barrett esophagus via in vivo and in vitro studies. Also, an ideal gastroesophageal reflux human model will be followed up in the long-term basis to investigate the potential clinical value of Notch1-ULK1 based autophagy regulation axis for the early diagnosis and treatment of Barrett esophagus.