Molecular pathogenesis of intestinal serrated polyps

描述（由申请人提供）：结肠癌是美国第三大常见癌症，也是癌症相关死亡的第三大原因。大约10%的结直肠癌发生在锯齿状息肉的一个小子集内，这与CpG岛甲基化表型（CIMP）有关。许多遗传病变与锯齿状息肉有关，但导致锯齿状腺瘤和癌形成的机制知之甚少。我们开发了第一个锯齿状息肉的小鼠模型。在HB 28小鼠中，肠上皮中HB-EGF和活化的GPCR（US 28）的组合表达导致与人类锯齿状息肉具有许多形态学和生化相似性的病变的发展。引人注目的是，锯齿状病变的发展似乎取决于遗传和环境因素。我们假设HB-EGF和US 28的联合活性通过上调RAS/RAF信号传导诱导疾病发展，这在人类锯齿状腺瘤中可见。我们将通过比较和对比HB 28小鼠与在肠上皮中表达激活的Braf和Kras的新产生的转基因小鼠来直接测试这一假设。最后，我们将确定环境因素，如微生物，是否需要锯齿状息肉的发展。这项建议中概述的研究应该有助于确定锯齿状息肉发展的分子机制。

DESCRIPTION (provided by applicant): Colon cancer is the third most common cancer and the third leading cause of cancer-related mortality in the United States. Approximately 10% of colorectal cancer develops within a small subset of serrated polyps, which is associated with the CpG Island Methylator Phenotype (CIMP). A number of genetic lesions have been associated with the serrated polyps, but the mechanisms that cause serrated adenomas and carcinomas to form are poorly understood. We have developed the first mouse model for serrated polyps. In HB28 mice, the combined expression of HB-EGF and an activated GPCR (US28) in the intestinal epithelium leads to development of lesions that share many morphological and biochemical similarities to the serrated polyps in humans. Strikingly, development of the serrated lesions appears to be dependent on both genetic and environmental factors. We hypothesize that the combined activity of HB-EGF and US28 induces disease development by up-regulating RAS/RAF signaling, which is seen in human serrated adenomas. We will directly test this hypothesis by comparing and contrasting HB28 mice with newly generated transgenic mice expressing activated Braf and Kras in the intestinal epithelium. Finally, we will determine if environmental factors such as microbes are required for development of serrated polyps. Together the studies outlined in this proposal should help define the molecular mechanisms accounting for development of serrated polyps.