Transgenic Mouse Model for Barrett's Esophagus

描述(申请人提供)：美国食管腺癌的发病率正在以惊人的速度增长。胃食道交界处的特殊肠型柱状化生，或Barrett‘s食道，被认为是食管异型增生和食管腺癌的主要危险因素。胃酸反流对食道鳞状上皮的损伤被认为是导致腺上皮取代鳞状上皮，随后出现肠型杯状细胞，这在胃或食道中通常是不存在的。导致Barrett‘s食道的特殊细胞事件，包括化生细胞的起源(鳞状细胞和腺状细胞)以及转化为肠道表型的时间过程尚未得到很好的描述。该方案的总体目标是开发和利用转基因小鼠Barrett‘s食道的可诱导损伤模型，以便我们可以研究这种疾病的发病机制。我们分离了角蛋白15启动子，它驱动转基因表达到小鼠的食道和前胃的鳞状上皮。利用该启动子表达K15/HSV-1胸苷激酶自杀基因，我们发现更昔洛韦治疗后，与Barrett‘s食道相似的肠上皮化生在鳞状结肠交界处发育。在这个方案中，我们计划1.优化肠化生的发展条件，并测试肠化生的可逆性；2.在分子水平上验证Barrett‘s食道的转基因小鼠模型；3.评估P53突变在胃鳞腔交界处肠化生、异型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道的转基因可诱导损伤模型。对于那些对Barrett‘s食道的发病机制、化学预防和治疗感兴趣的人来说，它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.