Weight loss-induced Microbiome and Adipokine Changes in Barrett's Esophagus

描述(申请人提供)：Barrett‘s食道是一种日益普遍的癌前疾病，主要由胃十二指肠酸和胆汁反流引起。申请者小组包括来自哥伦比亚大学、宾夕法尼亚大学和梅奥诊所的资深研究人员，他们提出了一个多学科、多中心的翻译研究计划，以研究这种疾病的起源和发病机制。他们中的许多人过去曾合作过，他们将专注于慢性炎症和胆汁酸在已建立的和新的干细胞标记物上调中的作用，以及针对这些祖细胞的可能方法。该建议建立在广泛的基础科学发现、新型转基因(L2-IL-1β)和BE/食管腺癌手术模型的开发以及对人类BE的初步分析的基础上 纸巾。这些小组将为网络带来非常大的BE患者群体，经验丰富的巴雷特临床研究人员，以及在干细胞和G1癌症炎症模型方面拥有丰富经验的板凳研究人员。提出了三个项目。项目1将重点研究Notch信号在Barrett‘s食道模型中的作用，并将确定Notch抑制或Notch激活对进展为异型增生的影响。项目2将在我们的小鼠模型中寻找Barrett‘s食道起源细胞的特征。我们将使用构成的和可诱导的Cre表达的小鼠模型来追踪在我们的模型和人类BE中上调的活跃和静止的祖细胞。此外，我们将使用在BE上调的祖细胞上表达的G蛋白偶联受体的拮抗剂进行一项试点临床试验。最后，项目3将致力于在BE中识别新的生物标记物和基因签名，将来自动物和人类模型的数据集关联起来，澄清非杯状细胞柱状上皮和贲门变化的重要性。我们还将组织一组接受射频消融的患者，识别治疗反应的生物标志物，并将成功消融的患者作为新的人类模型来研究BE的发展。总体而言，这些研究旨在阐明有助于发病的早期阶段和细胞类型，以便更好地分层风险和开发预防性治疗。

DESCRIPTION (provided by applicant): Barrett's esophagus is an increasingly prevalent, preneoplastic disorder that results primarily from gastroduodenal reflux of acid and bile. The applicant group, which includes established investigators from Columbia University, the University of Pennsylvania, and the Mayo Clinic, propose a multidisciplinary, multicenter, translational research program to study the origins and pathogenesis of the disorder. The team, many of whom have collaborated in the past, will focus on the role of chronic inflammation and bile acids in the upregulation of established and novel stem cell markers, and possible ways to target these progenitor cells. The proposal builds on extensive basic science findings, the development of novel transgenic (L2-IL-1beta) and surgical models of BE/esophageal adenocarcinoma, and preliminary analyses of human BE tissues. The groups will bring to the network a very large BE patient population, experienced Barrett's clinical investigators, and bench researchers with extensive experience with stem cells and inflammatory models of Gl cancer. Three projects are proposed. Project 1 will focus on the role of Notch signaling in models of Barrett's esophagus, and will determine the effects of Notch inhibition or Notch activation on progression to dysplasia. Project 2 will seek to characterize the cell of origin in Barrett's esophagus in our mouse models. We will use constituitive and inducible mouse models of Cre expression to lineage trace active and quiescent progenitors that are upregulated in our model and in human BE. Additionally, we will carry out a pilot clinical trial using an antagonist of a G-protein coupled receptor expressed on progenitor cells upregulated in BE. Finally, Project 3 will aim to identify novel biomarkers and gene signatures in BE, correlating data sets from animal and human models, clarifying the importance of non-goblet cell columnar epithelium and changes in the gastric cardia. We will also assemble a cohort of patients undergoing radiofrequency ablation, identifying biomarkers of response to therapy and using successfully ablated patients as a novel human model to study the development of BE. Overall, these studies aim to elucidate the earliest stages and cell types that contribute to BE pathogenesis in order to better stratify risk and develop preventive therapies.