Molecular pathogenesis of intestinal serrated polyps

描述(申请人提供)：结肠癌是美国第三种最常见的癌症，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小部分内，这与CpG岛甲基化表型(CIMP)有关。许多遗传损害与锯齿状息肉有关，但导致锯齿状腺瘤和癌症形成的机制尚不清楚。我们已经建立了第一个锯齿状息肉的小鼠模型。在HB28小鼠中，HB-EGF和激活的GPCR(US28)在肠道上皮细胞中的联合表达导致了与人类锯齿状息肉在形态和生化上有许多相似之处的病变的发展。值得注意的是，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US28的联合活性通过上调RAS/RAF信号来诱导疾病的发展，这在人类锯齿状腺瘤中可以看到。我们将通过比较和对比HB28小鼠和在肠道上皮中表达活化的BRAF和Kras的新产生的转基因小鼠来直接检验这一假设。最后，我们将确定锯齿状息肉的形成是否需要微生物等环境因素。总之，这项提案中概述的研究应该有助于确定锯齿状息肉发生的分子机制。

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.