Molecular Mechanisms Underlying Barrett's Esophagus

巴雷特食管的分子机制

• 批准号: 6666818
• 负责人: DEBRA G. SILBERG
• 金额: $ 15.85万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6666818
• 关键词: Barretts esophagus; biopsy; cell adhesion molecules; cell growth regulation; clinical research; differential display technique; endoscopy; functional /structural genomics; gastrointestinal epithelium; human subject; immunocytochemistry; microarray technology; molecular oncology; neoplasm /cancer genetics; neoplastic transformation; oncogenes; patient oriented research; preneoplastic state; tissue /cell culture; transfection

DESCRIPTION (provided by applicant): Barrett's esophagus is the transformation of the squamous epithelium of the esophagus to an intestinal type. The metaplastic tissue is preneoplastic and progresses to adenocarcinoma through a stepwise transition with a dysplastic intermediate stage. Esophageal adenocarcinoma is increasing in incidence yet little is known about the molecular mechanisms underlying the development of Barrett's esophagus, the earliest lesion. To understand the transformation to metaplasia it is necessary to investigate the genes that are involved at the initiation of the events. The research outlined in this proposal focuses on the identification and characterization of genes induced in Barrett's esophagus. It is our hypothesis that the elucidation of these genes is fundamental to the understanding of the molecular pathogenesis of Barrett's esophagus as well as its predilection to adenocarcinoma. The following interrelated specific aims will be pursued: Aim 1: To determine the genes that are induced in Barrett's esophagus through microarray analysis by comparing squamous epithelium to Barrett's esophagus. The genes selected for further evaluation will be those that may be important in cellular differentiation and proliferation. Preliminary studies have identified sixteen genes that meet these criteria. Further analysis of these genes and others identified will include: quantitative PCR for validation of the array results and localization of gene expression in tissue by either immunohistochemistry or in situ hybridization. Aim 2: To determine the functional significance of the genes identified in Specific Aim 1. Esophageal organotypic cultures will be propagated that are infected with retroviruses expressing the genes of interest. The cultures will be analyzed for changes in morphology and gene expression. It is anticipated that the results of these studies will lay the foundation for our understanding of the molecular mechanisms, which underlie the development of Barrett's esophagus. With this knowledge it will be possible to further study the genes in transgenic mice to better elucidate the significance of the genes in an in vivo system. The understanding of the fundamental properties of Barrett's esophagus, specifically the initiating molecular events, will allow for the development of better diagnostic, treatment and chemoprevention strategies to target the metaplasia to cancer process at an early stage.

描述（由申请人提供）：巴雷特食管是食管鳞状上皮向肠型的转变。化生组织是癌前组织，并通过发育不良中间阶段逐步转变为腺癌。食管腺癌的发病率正在增加，但人们对最早病变巴雷特食管发展的分子机制知之甚少。为了了解化生的转变，有必要研究参与事件启动的基因。该提案中概述的研究重点是巴雷特食管中诱导基因的识别和表征。我们的假设是，阐明这些基因对于理解巴雷特食管的分子发病机制及其对腺癌的倾向至关重要。 将追求以下相互关联的具体目标： 目标 1：通过比较鳞状上皮和巴雷特食管，通过微阵列分析确定巴雷特食管中诱导的基因。选择用于进一步评估的基因将是那些在细胞分化和增殖中可能重要的基因。初步研究已经确定了 16 个符合这些标准的基因。对这些基因和其他已识别基因的进一步分析将包括：用于验证阵列结果的定量 PCR 以及通过免疫组织化学或原位杂交定位组织中的基因表达。目标 2：确定特定目标 1 中鉴定的基因的功能意义。将繁殖被表达感兴趣基因的逆转录病毒感染的食管器官型培养物。将分析培养物的形态和基因表达的变化。预计这些研究结果将为我们理解巴雷特食管发育的分子机制奠定基础。有了这些知识，就有可能进一步研究转基因小鼠的基因，以更好地阐明基因在体内系统中的重要性。了解巴雷特食管的基本特性，特别是起始分子事件，将有助于开发更好的诊断、治疗和化学预防策略，以在早期阶段针对化生到癌症过程。