The Role of the Microenvironment in Barrett's Esophagus

总体项目摘要 巴雷特食管是一种越来越普遍的肿瘤前疾病，由酸/胆汁反流引起， GE连接处的慢性炎症。本申请是对长期多中心， 来自哥伦比亚大学、宾夕法尼亚大学和马约诊所的转化研究项目。 该团队一直富有成效，现在将专注于微生物群和肿瘤的作用 Barrett食管和食管癌发生发展的微环境 腺癌该组织在麻省理工学院的达纳法伯癌症研究所增加了额外的合作网站 和慕尼黑技术大学，并将大量利用宾夕法尼亚大学新的微生物组和代谢组学核心， 快点因此，该团队在小鼠模型、基因组学、微生物学和 临床研究该应用程序是建立在炎症依赖性肿瘤 微环境，由GE连接微生物组调节，对食管癌的早期进展至关重要。 致癌作用该提案将利用新型转基因（L2-IL-1β）和创新的3D类器官 模型，以及对100名BE患者的横断面研究，沿着。项目1将研究微生物群的作用， 骨髓细胞在巴雷特食管的L2-IL-1β小鼠模型中的作用。该项目将采用无菌 圈养、抗生素根除、确定的植物群定植、骨髓细胞消融和相关人类 问题研究项目2的重点是BE中微环境驱动程序的特性，包括 BE患者中CAF和免疫细胞（MDSC/THEB）的FACS/IHC分析，沿着3D类器官， 文化将确定IL-6在响应上皮TP 53突变和免疫细胞活化中的作用。 最后，项目3将寻求确定与微生物组相关的新生物标志物和基因特征， 微环境这项研究将分析胆汁酸，一种微生物的产物， 作为唾液/呼吸测试/栓系胶囊海绵，用于分析微生物，以开展筛查/监测 战略布局总的来说，这些项目将推进BE中微生物组和微环境的科学， 将有望带来转化应用。

OVERALL PROJECT SUMMARY Barrett’s esophagus is an increasingly prevalent, preneoplastic disorder resulting from acid/bile reflux and chronic inflammation at the GE junction. This application is a renewal of a long-standing multicenter, translational research program from Columbia University, the University of Pennsylvania and the Mayo Clinic. The team, which has been highly productive, will now focus on the role of microbiota and the tumor microenvironment in the development and progression of Barrett’s esophagus and esophageal adenocarcinoma. The group has added additional collaborative sites at MIT, the Dana Farber Cancer Institute and Munich Technical University, and will utilize heavily a new Microbiome and Metabolomics Core at Penn- CHOP. Thus, the team comprises broad and unique expertise in mouse models, genomics, microbiology and clinical research. The application is built around the hypothesis that the inflammation-dependent tumor microenvironment, modulated by the GE junction microbiome, is critical for early progression of esophageal carcinogenesis. The proposal will utilize both the novel transgenic (L2-IL-1β) and innovative 3D organoid models, along with a cross-sectional study of 100 BE patients. Project 1 will study the role of microbiota and myeloid cells in the L2-IL-1β mouse model of Barrett’s esophagus. This project will incorporate germ-free housing, antibiotic eradication, colonization with defined flora, myeloid cell ablation and correlative human studies. Project 2 is focused on the characterization of microenvironment drivers in BE, and will include FACS/IHC analysis of CAFs and immune cells (MDSCs/Tregs) in BE patients, along with 3D organoids in culture. The role of IL-6 in response to epithelial TP53 mutations and immune cell activation will be defined. Finally, Project 3 will seek to identify novel biomarkers and gene signatures related to the microbiome and microenvironment. The study will analyze bile acids, a product of microbes, and minimally invasive tests such as saliva/breath test/tethered capsule sponge to analyze microbes to develop screening/surveillance strategies. Overall, these projects will advance the science of the microbiome and microenvironment in BE that will hopefully lead to translational applications.