The Role of the Microenvironment in Barrett's Esophagus

微环境在巴雷特食管中的作用

• 批准号: 10607819
• 负责人: Julian Abrams
• 金额: $ 44.2万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10607819
• 关键词: 3-Dimensional; Ablation; Antibiotics; Barrett Esophagus; Bile Acids; Bile Reflux; Breath Tests; Cells; Chronic; Clinic; Clinical Research; Cross-Sectional Studies; Dana-Farber Cancer Institute; Development; Disease; Epithelial; Esophageal Adenocarcinoma; Genomics; Germ-Free; Goals; Housing; Human; Immune; Inflammation; Interleukin-6; Intervention; Knowledge; Lead; Malignant Neoplasms; Microbe; Microbiology; Modeling; Mutation; Myeloid Cells; Organoids; Patients; Pennsylvania; Porifera; Regulatory T-Lymphocyte; Research; Role; Saliva; Site; TP53 gene; Testing; Transgenic Organisms; Universities; biomarker signature; capsule; esophageal carcinogenesis; experimental study; genetic signature; immune activation; innovation; metabolomics; microbiome; microbiome research; microbiota; minimally invasive; mouse model; novel; novel marker; predictive marker; programs; response; screening; surveillance strategy; translational applications; translational research program; tumor microenvironment; tumorigenic

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.

项目摘要 巴雷特的食道是一种越来越普遍，由酸/胆汁反射X和 GE连接处的慢性炎症。订阅研究中心1代表翻译研究 哥伦比亚大学，宾夕法尼亚大学和梅奥诊所的计划。团队，有 高产性，一直集中在微生物群和肿瘤微环境中的作用上 巴雷特食管和食管腺癌的发展和进展。该小组还包括 MIT，Dana Farber癌症研究所和慕尼黑技术大学的其他协作站点，以及 在Penn-Chop上利用大量的微生物组和代谢组学核心。那团队包括广泛的 小鼠模型，基因组学，微生物学和临床研究方面的独特专业知识。我们的研究计划是建立的 围绕注射依赖性肿瘤微环境的假设，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。该提议利用了小说 转基因（L2-ILB）和创新的3D器官模型，以及对150个Barrett的横断面研究 非巴雷特的病人。项目1研究菌群和髓样细胞在L2-ilb小鼠模型中的作用 巴雷特的食道。该项目结合了无菌外壳，抗生素放射定位，定植与 定义的菌群，髓样细胞消融和相关的人类研究。项目2的重点是 BE中的微环境驱动器，包括CAFS和免疫细胞（MDSC/Tregs）的FACS/IHC分析 成为患者，以及培养物中的3D器官，并定义IL-6对上皮TP53的作用 突变和免疫细胞激活。最后，项目3旨在识别新颖的生物标志物和基因特征 与微生物组和微环境有关。该研究分析了胆汁酸，一种微生物的产物， 微创测试（例如唾液/呼气测试/束缚胶囊赞助商）分析微生物以发展 筛选/监视策略。总体而言，这些项目将推进微生物组的科学和 有望导致翻译应用的微环境。在扩展期间，我们建议 继续并完成与三个项目相关的实验和分析。

项目成果

Update on ablation for Barrett's esophagus.

巴雷特食管消融的最新进展。

• DOI: 10.1007/s11894-013-0368-7
• 发表时间: 2014
• 期刊: Current gastroenterology reports
• 作者: Falk,GaryW

Endoscopic evaluation and advanced imaging of Barrett's esophagus.

• DOI: 10.1016/j.giec.2010.09.013
• 发表时间: 2011-01
• 期刊: Gastrointestinal endoscopy clinics of North America
• 作者: Wang, Kenneth K;Okoro, Ngozi;Prasad, Ganapathy;WongKeeSong, Michel;Buttar, Navtej S;Tian, Jianmin
• 通讯作者: Tian, Jianmin

Barrett's esophagus: genetic and cell changes.

巴雷特食管：遗传和细胞变化。

• DOI: 10.1111/j.1749-6632.2011.06043.x
• 发表时间: 2011
• 期刊: Annals of the New York Academy of Sciences
• 影响因子: 5.2
• 作者: Souza,RhondaF;Freschi,Giancarlo;Taddei,Antonio;Ringressi,MariaNovella;Bechi,Paolo;Castiglione,Francesca;RossiDegl'Innocenti,Duccio;Triadafilopoulos,George;Wang,JeanS;Chang,AndrewC;Barr,Hugh;Bajpai,Manisha;Das,KironM;Schneid
• 通讯作者: Schneid

Emerging Insights into the Esophageal Microbiome.

• DOI: 10.1007/s11938-018-0171-5
• 发表时间: 2018-03
• 期刊: Current treatment options in gastroenterology
• 作者: May M;Abrams JA
• 通讯作者: Abrams JA

Goblet Cell Ratio in Combination with Differentiation and Stem Cell Markers in Barrett Esophagus Allow Distinction of Patients with and without Esophageal Adenocarcinoma.

• DOI: 10.1158/1940-6207.capr-16-0117
• 发表时间: 2017-01
• 期刊: Cancer prevention research (Philadelphia, Pa.)
• 作者: Schellnegger R;Quante A;Rospleszcz S;Schernhammer M;Höhl B;Tobiasch M;Pastula A;Brandtner A;Abrams JA;Strauch K;Schmid RM;Vieth M;Wang TC;Quante M
• 通讯作者: Quante M