Stem Cells And The Origins of Barrett's Esophagus

干细胞和巴雷特食管的起源

• 批准号: 9325648
• 负责人: Anil K Rustgi
• 金额: $ 23.7万
• 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 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9325648
• 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; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Pennsylvania; Pre-Clinical Model; Preneoplastic Conditions; Preventive therapy; 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; genetic signature; improved; laser capture microdissection; model development; mortality; mouse model; multidisciplinary; notch protein; novel; novel marker; outcome forecast; overexpression; patient population; progenitor; programs; response; response biomarker; stem; stomach cardia; tool; 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; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Pennsylvania; Pre-Clinical Model; Preneoplastic Conditions; Preventive therapy; 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; genetic signature; improved; laser capture microdissection; model development; mortality; mouse model; multidisciplinary; notch protein; novel; novel marker; outcome forecast; overexpression; patient population; progenitor; programs; response; response biomarker; 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）：Barrett的食道是一种日益普遍的肿瘤性疾病，主要由酸和胆汁的胃十二指肠回流产生。申请人组包括哥伦比亚大学，宾夕法尼亚大学和梅奥诊所的既定研究人员，提出了一个多学科的多中心，转化研究计划，以研究该疾病的起源和发病机理。该团队过去曾在过去合作，将重点关注慢性炎症和胆汁酸在已建立和新型干细胞标记的上调中的作用，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，新的转基因（L2-IL-1BETA）和BE/食管腺癌的外科模型以及人类BE的初步分析的基础上。 组织。这些小组将带来非常大的患者人群，经验丰富的Barrett的临床研究人员，以及具有在干细胞和GL癌的炎症模型方面经验丰富的替补研究人员。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激活对发展不良增生的影响。项目2将寻求在我们的小鼠模型中的Barrett食管中表征原始细胞。我们将使用CRE表达的构成和诱导的小鼠模型，以在我们的模型和人类中上调的谱系痕量痕迹和静止的祖细胞。此外，我们将使用在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验临床试验。最后，项目3将旨在确定BE中的新型生物标志物和基因特征，从而将数据集与动物和人类模型相关联，从而阐明非go脚细胞柱状上皮的重要性以及胃Cardia的变化。我们还将组装一批接受射频消融的患者，鉴定对治疗的反应生物标志物，并使用成功消融的患者作为研究BE发展的新型人类模型。总体而言，这些研究旨在阐明有助于发病机理的最早阶段和细胞类型，以更好地分层风险并发展预防疗法。