Molecular Mechanisms Underlying Barrett's Esophagus

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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.