Transgenic Mouse Model for Barrett's Esophagus

描述（申请人提供）：美国食道腺癌的发病率正以惊人的速度增长。胃食管连接处（Barrett食管）肠型特化柱状化生被认为是发展为食管发育不良和腺癌的主要危险因素。胃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取代，随后出现肠型杯状细胞，这在胃或食管中通常是不存在的。导致巴雷特食管的特定细胞事件，包括化生细胞（鳞状或腺状）的起源以及转化为肠道表型的时间过程尚未得到很好的表征。本研究的总体目标是建立和利用转基因小鼠Barrett食管的诱导损伤模型，以便我们研究该疾病的发病机制。我们分离了角蛋白15启动子，该启动子驱动转基因在小鼠食管和前胃鳞状上皮的表达。通过表达使用该启动子的K15/单纯疱疹病毒-1胸苷激酶自杀，我们发现在给药更昔洛韦后，在鳞状柱状交界处出现了与巴雷特食管相似的肠化生。在这个提案中，我们计划1。优化肠化生发育条件，检验肠化生的可逆性；2. 在分子水平上验证该Barrett食管转基因小鼠模型；3. 评估p53突变在胃鳞柱交界处肠化生、异常增生和腺癌发生中的作用；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。对于那些对巴雷特食管的发病机制、化学预防和治疗感兴趣的人来说，这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.