Molecular pathogenesis of intestinal serrated polyps

肠锯齿状息肉的分子发病机制

基本信息

批准号：
9104512
负责人：
SERGIO A. LIRA
金额：
$ 40.26万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9104512
关键词：
Aberrant DNA Methylation Accounting Adenomatous Polyps Affect Area Automobile Driving BRAF gene Bacteria Biochemical Biology Cancer Etiology Cancer Model Carcinoma Categories Colon Colon Carcinoma Colorectal Colorectal Cancer Communities Complex DNA DTR gene Data Development Diagnosis Disease Employee Strikes Environmental Risk Factor Epidermal Growth Factor Receptor Epithelial Epithelium Gene Expression Genes Genetic Germ-Free Goals Human Hyperplastic Polyp Individual Intestines Investigation KRAS2 gene Lasers Lead Left Lesion Libraries Ligands Location Malignant - descriptor Malignant Neoplasms Messenger RNA MicroRNAs Microbe Microsatellite Instability Modeling Molecular Molecular Analysis Mucins Mus Mutation Neoplasms Organism Outcome Study Pathogenesis Pathology Pathway interactions Play Polyps Prevention Preventive treatment Publishing Rectum Role Serrated Adenoma Testing Tissues Tumor Suppressor Proteins United States Work adenoma base commensal microbes epigenome germ free condition insight methylome microbial microbiome microbiota mortality mouse model neoplastic novel novel marker pathogen programs public health relevance receptor transcriptome tumor

项目摘要

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. For many years it was believed that colorectal cancers (CRC) evolved from advanced adenomatous polyps. In recent years, however, convincing evidence has emerged that a significant proportion of CRC develops within a small subset of serrated polyps, through a mechanism that is different from those responsible for the adenoma-carcinoma developmental progression. The two most common epithelial polyp in the colorectum are adenomas and serrated polyps. Serrated polyps are morphologically characterized by a "saw-toothed" unfolding of the crypt epithelium. Currently, serrated polyps are grouped in 4 major categories: hyperplastic polyps, sessile serrated adenomas, traditional serrated adenomas, and mixed serrated polyps. Serrated polyps have a striking subtype dependent location in the gut. Hyperplastic polyps are most frequently found in the left colon and rectum, while sessile serrated adenomas are usually found in the right colon. Historically, hyperplastic polyps have been considered to have little or no malignant potential. This view, however, has changed recently, as evidence has emerged that hyperplastic polyps display molecular features seen in neoplastic lesions, such as microsatellite instability (MSI), aberrant DNA methylation, and mutations in BRAF and KRAS genes. In addition to KRAS and BRAF mutations, our work suggests that activation of the EGFR receptor also promotes the development of serrated polyps. We have developed a novel model for serrated polyps in mice that represents a subset of human serrated polyps that arise independent of activating mutations in BRAF or KRAS, but rather occur due to increased activity of the EGFR receptor. This model presents morphological and biochemical similarities to serrated polyps in humans. Strikingly, similar to human serrated polyps, serrated polyps in HBUS mice develop in a specific location of the gut and are dependent on both genetic and environmental factors. In this proposal we will investigate how one such an environmental factor, namely the microbiota, affects the development of serrated polyps. Aim 1 is focused on the identification of the causative organism(s). Aim 2 is aimed at understanding how the microbiota affects the host and how this leads to the development of serrated polyps. A team of experts in microbiome (J. Faith, and J.C. Clemente, Sinai), microRNA biology (B. Brown, Sinai), methylome (Daniel Carvalho, Toronto) and pathology (Noam Harpaz, Sinai) will assist us in these studies.

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。多年来，人们认为结直肠癌（CRC）是由晚期腺瘤性息肉演变而来。然而，多年来，令人信服的证据表明，很大一部分结直肠癌是在一小部分锯齿状息肉中发生的，其机制不同于导致腺瘤-癌发展的两种最常见的机制。结直肠中的上皮性息肉是腺瘤和锯齿状息肉，其形态特征是隐窝上皮呈“锯齿状”展开。目前，锯齿状息肉分为 4 大类：增生性息肉、无蒂锯齿状腺瘤和传统锯齿状腺瘤。，和混合锯齿状息肉在锯齿状息肉中具有显着的亚型依赖性位置。增生性息肉最常见于左结肠和直肠，而无蒂锯齿状腺瘤通常发现于右结肠。历史上，增生性息肉被认为很少或没有恶性潜力，但最近这种观点发生了变化。，因为有证据表明，增生性息肉表现出肿瘤性病变中常见的分子特征，例如微卫星不稳定性 (MSI)、异常 DNA 甲基化以及 BRAF 和 KRAS 基因突变。除了 KRAS 和 BRAF 突变之外，我们的工作表明 EGFR 受体的激活也会促进锯齿状息肉的发展。我们开发了一种小鼠锯齿状息肉的新模型，该模型代表了人类锯齿状息肉的一个子集，其产生与激活突变无关。 BRAF 或 KRAS，而是由于 EGFR 受体活性增加而发生，该模型与人类锯齿状息肉具有惊人的相似性。锯齿状息肉，HBUS 小鼠的锯齿状息肉在肠道的特定位置发育，并且依赖于遗传和环境因素。在本提案中，我们将研究这样一种环境因素，即微生物群，如何影响锯齿状息肉的发育。目标 1 侧重于识别致病微生物，目标 2 旨在了解微生物群如何影响宿主以及如何导致锯齿状息肉的形成。微生物组（J. Faith 和 J.C. Clemente，西奈）、microRNA 生物学（B. Brown，西奈）、甲基化组（Daniel Carvalho，多伦多）和病理学（Noam Harpaz，西奈）将协助我们进行这些研究。