Transgenic Mouse Model for Barrett's Esophagus

描述（由申请人提供）：美国食管腺癌的发病率正在以惊人的速度增加。胃食管交界处或Barrett食管的肠型特化柱状化生被认为是食管发育不良和腺癌发展的主要危险因素。胃酸反流对食管鳞状上皮的损伤被认为导致鳞状上皮被腺上皮替代，随后出现胃型杯状细胞，其通常在胃或食管中不存在。导致Barrett食管的特定细胞事件，包括化生细胞的起源（鳞状细胞与腺细胞）和转化为肠表型的时间过程尚未得到很好的表征。本研究的主要目的是建立一种转基因小鼠Barrett食管的诱导性损伤模型，以研究Barrett食管的发病机制。我们分离了角蛋白15启动子，该启动子驱动小鼠食管和前胃鳞状上皮的转基因表达。通过使用该启动子表达K15/HSV-1胸苷激酶自杀基因，我们发现更昔洛韦给药后，与Barrett食管非常相似的肠上皮化生在鳞柱状连接处发生。在这份提案中，我们计划1.优化肠上皮化生发生的条件，并检测肠上皮化生的可逆性; 2.在分子水平上验证Barrett食管转基因小鼠模型; 3.评估p53突变在胃鳞状柱状连接处肠上皮化生、异型增生和腺癌发展中的作用; 4.研究化生转化过程中基因表达的变化。这将是第一个模仿巴雷特食管的转基因诱导损伤模型。对于那些有兴趣研究Barrett食管的发病机制，化学预防和治疗的人来说，这应该是一个有价值的资源。

DESCRIPTION (provided by applicant): 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.