Stem Cells And The Origins of Barrett's Esophagus

干细胞和巴雷特食管的起源

• 批准号: 8731824
• 负责人: Anil K Rustgi
• 金额: $ 120.46万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8731824
• 关键词: Acids; Address; Adenocarcinoma; Animal Model; Animals; Attention; Barrett Esophagus; Basic Science; Bile Acids; Biological Markers; Cell model; Cells; Chemoprevention; Chronic; Clinic; Clinical; Clinical Investigator; Clinical Trials; Columnar Cell; Columnar Epithelium; Columnar Metaplasia; Cultured Cells; Cytoplasmic Granules; DNA Damage; Data Set; Development; Disease; Dysplasia; Electron Microscopy; Environment; Epidemiology; Esophageal; Esophageal Adenocarcinoma; Esophageal injury; Esophagus; Figs - dietary; Foundations; G-Protein-Coupled Receptors; Gastroesophageal reflux disease; Generations; Genes; Genetic; Goals; Human; Incidence; Inflammation; Inflammatory; Injury; Instruction; Interleukin-1; Intestinal Metaplasia; Intestines; Knock-out; Knowledge; Lesion; Link; Malignant Neoplasms; Malignant neoplasm of esophagus; Malignant neoplasm of gastrointestinal tract; Mediator of activation protein; Metaplasia; Metaplastic; Methylation; Modeling; Mucins; Mus; Mutation; Neoplasms; Operative Surgical Procedures; Outcome; Pathogenesis; Pathway interactions; Patients; Pennsylvania; Pre-Clinical Model; Preneoplastic Conditions; Preventive; Publishing; Radiofrequency Interstitial Ablation; Rattus; Reflux; Reporting; Research Personnel; Risk; Rodent; Role; Signal Pathway; Signal Transduction; Squamous Epithelium; Staging; Stem cells; Study models; Surgical Models; Testing; Time; Tissues; Transgenic Mice; Transgenic Organisms; Translational Research; Universities; Up-Regulation; Work; base; bench to bedside; burden of illness; carcinogenesis; cell type; cellular microvillus; clinical practice; cohort; cytokine; deoxycholate; drinking water; experience; improved; laser capture microdissection; model development; mortality; mouse model; multidisciplinary; notch protein; novel; outcome forecast; overexpression; patient population; progenitor; programs; response; stem; stomach cardia; tool

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.

描述（由申请人提供）：巴雷特食管是一种日益普遍的肿瘤前期疾病，主要由胃十二指肠酸和胆汁反流引起。申请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，提出了一项多学科、多中心、转化研究计划，以研究该疾病的起源和发病机制。该团队中的许多人过去曾合作过，他们将重点研究慢性炎症和胆汁酸在已建立的和新型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。该提案建立在广泛的基础科学发现、新型转基因 (L2-IL-1beta) 和 BE/食管腺癌手术模型的开发以及人类 BE 的初步分析的基础上 组织。这些小组将为该网络带来大量的 BE 患者群体、经验丰富的 Barrett 临床研究人员以及在干细胞和胃肠道癌症炎症模型方面拥有丰富经验的基础研究人员。提出了三个项目。项目 1 将重点研究 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谱系追踪在我们的模型和人类 BE 中上调的活性和静态祖细胞。此外，我们将使用在 BE 中表达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 的目标是识别 BE 中的新型生物标志物和基因特征，将动物和人类模型的数据集关联起来，阐明非杯状细胞柱状上皮和胃贲门变化的重要性。我们还将收集一组接受射频消融的患者，识别治疗反应的生物标志物，并使用成功消融的患者作为新的人体模型来研究 BE 的发展。总的来说，这些研究旨在阐明 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疗法。