The Role of the Microenvironment in Barrett's Esophagus

整体项目总结 Barrett‘s食道是一种日益普遍的癌前疾病，由酸/胆汁反流和 GE交界处慢性炎症。这项申请是对一个历史悠久的多中心的更新， 哥伦比亚大学、宾夕法尼亚大学和梅奥诊所的翻译研究计划。 这个一直很有成效的团队现在将专注于微生物区系和肿瘤的作用 Barrett‘s食道和食道发育过程中的微环境 腺癌。该组织在麻省理工学院增加了更多的合作网站，即达纳·法伯癌症研究所 和慕尼黑工业大学，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- 砍吧。因此，该团队包括在老鼠模型、基因组学、微生物学和 临床研究。这项应用建立在一个假设之上，即炎症依赖型肿瘤 受GE连接微生物群调控的微环境是食道早期进展的关键 致癌。该提案将利用新型转基因(L2-IL-1β)和创新的3D有机化合物 模型，以及对100名BE患者的横断面研究。项目1将研究微生物区系的作用和 巴雷特食道L2-IL-1β小鼠模型中的髓系细胞该项目将包括无菌 住房、抗生素根除、有明确菌群的定居、髓细胞消融和相关的人类 学习。项目2的重点是BE中微环境驱动因素的特征，并将包括 BE患者CAF和免疫细胞(MDSCs/Tregs)以及3D有机物的FACS/IHC分析 文化。IL-6在上皮性TP53突变和免疫细胞激活反应中的作用将被确定。 最后，项目3将寻求确定与微生物组和 微环境。这项研究将分析微生物的产物胆汁酸，以及诸如 作为唾液/呼气测试/捆绑胶囊海绵分析微生物以开展筛查/监测 战略。总体而言，这些项目将推动微生物群和微环境科学的发展 将有望带来翻译应用程序。

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.