The Role of the Microenvironment in Barrett's Esophagus

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。BETRNet研究中心1代表一个转化研究 哥伦比亚大学、宾夕法尼亚大学和马约诊所的项目。该小组，其中有 一直专注于微生物群和肿瘤微环境在肿瘤中的作用。 Barrett食管和食管腺癌的发展和进展。该小组还包括 麻省理工学院、达纳法伯癌症研究所和慕尼黑技术大学的其他合作网站，以及 利用了Penn-CHOP的微生物组和代谢组学核心。因此，该小组由广泛和 在小鼠模型、基因组学、微生物学和临床研究方面拥有独特的专业知识。我们的研究计划是建立在 炎症依赖的肿瘤微环境，由GE连接调节， 微生物组，对于食管癌发生的早期进展至关重要。该提案既利用了小说 转基因（L2-ILB）和创新的3D类器官模型，沿着150例Barrett's和 非巴雷特综合征患者项目1研究了微生物群和骨髓细胞在L2-ILB小鼠模型中的作用。 巴雷特食管。该项目包括无菌住房，抗生素根除，殖民化， 明确的植物群、骨髓细胞消融和相关的人体研究。项目2侧重于 微环境驱动因素，并包括CAF和免疫细胞（MDSC/THP）的FACS/IHC分析。 BE患者，沿着培养中的3D类器官，以及确定IL-6在响应上皮TP 53中的作用 突变和免疫细胞激活。最后，项目3旨在确定新的生物标志物和基因签名 与微生物组和微环境有关。这项研究分析了胆汁酸，一种微生物的产物， 微创测试，如唾液/呼吸测试/栓系胶囊海绵，以分析微生物， 筛查/监测策略。总的来说，这些项目将推进微生物组科学， 这将有望导致翻译应用。在延长期内，我们建议 继续并完成与这三个项目有关的实验和分析。

PROJECT SUMMARY Barrett’s esophagus is an increasingly prevalent, preneoplastic disorder resulting from acid/bile reflux and chronic inflammation at the GE junction. The BETRNet Research Center 1 represents a translational research program from Columbia University, the University of Pennsylvania and the Mayo Clinic. The team, which has been highly productive, has been focused on the role of microbiota and the tumor microenvironment in the development and progression of Barrett’s esophagus and esophageal adenocarcinoma. The group also includes additional collaborative sites at MIT, the Dana Farber Cancer Institute and Munich Technical University, and utilizes heavily a Microbiome and Metabolomics Core at Penn-CHOP. Thus, the team comprises broad and unique expertise in mouse models, genomics, microbiology and clinical research. Our research program 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 utilizes both the novel transgenic (L2-ILB) and innovative 3D organoid models, along with a cross-sectional study of 150 Barrett’s and non-Barrett’s patients. Project 1 studied the role of microbiota and myeloid cells in the L2-ILB mouse model of Barrett’s esophagus. This project incorporated germ-free housing, antibiotic eradication, colonization with defined flora, myeloid cell ablation and correlative human studies. Project 2 focused on the characterization of microenvironment drivers in BE, and included FACS/IHC analysis of CAFs and immune cells (MDSCs/Tregs) in BE patients, along with 3D organoids in culture, as well as defining the role of IL-6 in response to epithelial TP53 mutations and immune cell activation. Finally, Project 3 seeks to identify novel biomarkers and gene signatures related to the microbiome and microenvironment. The study analyzed 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. For the extension period, we propose to continue and complete experiments and analyses related to the three Projects.