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

描述（由申请人提供）：巴雷特食管是一种日益普遍的肿瘤前疾病，主要由胃十二指肠酸和胆汁反流引起。申请人小组，其中包括来自哥伦比亚大学，宾夕法尼亚大学和马约诊所的既定调查人员，提出了一个多学科，多中心，翻译研究计划，以研究疾病的起源和发病机制。该团队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上调已建立和新型干细胞标志物中的作用，以及靶向这些祖细胞的可能方法。该提案建立在广泛的基础科学发现、BE/食管腺癌的新型转基因（L2-IL-1 β）和手术模型的开发以及人类BE的初步分析基础上 组织中这些小组将为网络带来非常大的BE患者群体，经验丰富的Barrett临床研究人员，以及在干细胞和GI癌症炎症模型方面具有丰富经验的实验室研究人员。提出了三个项目。项目1将重点关注Notch信号在Barrett食管模型中的作用，并将确定Notch抑制或Notch激活对发育不良进展的影响。项目2将寻求在我们的小鼠模型中表征巴雷特食管中的起源细胞。我们将使用Cre表达的组成型和诱导型小鼠模型来追踪在我们的模型和人类BE中上调的活性和静止祖细胞。此外，我们将使用BE中上调的祖细胞上表达的G蛋白偶联受体的拮抗剂进行试点临床试验。最后，项目3将旨在确定BE中的新生物标志物和基因特征，将动物和人类模型的数据集相关联，阐明非杯状细胞柱状上皮和贲门变化的重要性。我们还将收集一组接受射频消融的患者，确定对治疗反应的生物标志物，并使用成功消融的患者作为一种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BE发病机制的最早阶段和细胞类型，以便更好地分层风险并开发预防性治疗。

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.