The incidence of adenocarcinoma of the esophagus in the United States is increasing at an alarming rate. Specialized columnar metaplasia of the intestinal type at the gastroesophageal junction, or Barrett's esophagus, is recognized as a major risk factor for the development of dysplasia and adenocarcinoma of the esophagus. Injury of the esophageal squamous epithelium by acid reflux from the stomach is thought to lead to the replacement of the squamous epithelium by glandular epithelium, followed by the appearance of intestinal-type goblet cells, which are not normally found in the stomach or esophagus. The specific cellular events leading to Barrett's esophagus, including the origin of the metaplastic cells (squamous vs. glandular) and the time course for the conversion to an intestinal phenotype are not well characterized. The overall goals of this proposal are to develop and utilize an inducible injury model for Barrett's esophagus in transgenic mice so that we may study the pathogenesis of this disorder. We isolated the keratin 15 promoter that drives expression of transgenes to the squamous epithelium of the esophagus and forestomach in mice. By expressing the K15/HSV-1 thymidine kinase suicide gone using this promoter, we discovered that intestinal metaplasia that closely mimics Barrett's esophagus develops at the squamocolumnar junction after administration of ganciclovir. In this proposal, we plan to 1. optimize the conditions for developing intestinal metaplasia, and test the reversibility of the metaplasia; 2. validate this transgenic mouse model for Barrett's esophagus at the molecular level; 3. assess the role of p53 mutations on development of intestinal metaplasia, dysplasia and adenocarcinoma at the squamocolumnar junction in the stomach; 4. study changes in gene expression during the metaplastic transformation. This would be the first transgenic inducible injury model that mimics Barrett's esophagus. It should be a valuable resource for those interested in studying the pathogenesis, chemoprevention and treatment of Barrett's esophagus.
