Molecular Mechanisms Underlying Barrett's Esophagus

描述（由申请方提供）：Barrett食管是食管鳞状上皮向肠型的转化。化生组织是癌前病变，并通过发育异常的中间阶段逐步转变为腺癌。食管腺癌的发病率正在增加，但很少有人知道的分子机制的发展巴雷特食管，最早的病变。为了了解转化为化生，有必要研究在事件开始时涉及的基因。该提案中概述的研究重点是鉴定和表征Barrett食管中诱导的基因。我们的假设是，这些基因的阐明是了解巴雷特食管的分子发病机制，以及它的好发腺癌的基础。 目的1：通过比较鳞状上皮与巴雷特食管，通过微阵列分析确定巴雷特食管中诱导的基因。选择用于进一步评价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。这些基因和其他确定的进一步分析将包括：用于验证阵列结果的定量PCR和通过免疫组织化学或原位杂交定位组织中的基因表达。目的2：确定特定目的1中鉴定的基因的功能意义。食管器官型培养物将被表达目的基因的逆转录病毒感染。将分析培养物的形态学和基因表达变化。预计这些研究的结果将为我们理解Barrett食管发展的分子机制奠定基础。有了这些知识，将有可能进一步研究转基因小鼠中的基因，以更好地阐明基因在体内系统中的意义。了解巴雷特食管的基本特性，特别是起始分子事件，将允许开发更好的诊断，治疗和化学预防策略，以在早期阶段靶向化生到癌症过程。

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.