Hes1-loss promotes dysregulation of epithelial homeostasis and inflammation in a serrated adenocarcinoma model

Hes1缺失促进锯齿状腺癌模型上皮稳态和炎症的失调

基本信息

批准号：
10206048
负责人：
Lan Zhou
金额：
$ 41.52万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10206048
关键词：
Adenocarcinoma Animal Model Automobile Driving BRAF gene Benign Biological Markers Cancer Etiology Cancer Model Carcinogens Carcinoma Cells Cessation of life Characteristics Chronic Colitis Colitis associated colorectal cancer Colon Colon Carcinoma Colorectal Cancer CpG Island Methylator Phenotype CpG Islands Development Dysplasia ES01 Epithelial Fucose Functional disorder Gastroenterology Genes Genetic Transcription Goblet Cells Hematopoietic High grade dysplasia High-Frequency Microsatellite Instability Homeostasis Homologous Gene Human Hyperplasia Hyperplastic Polyp IBD-associated colorectal cancer IL1R1 gene Immune Immune response Immune signaling Immunologic Markers Immunotherapy Inflammation Inflammation Mediators Inflammatory Interleukin-1 Interleukin-1 beta Interleukin-17 Intervention Intestinal permeability Intestines Knowledge Lesion Ligands Malignant - descriptor Malignant Neoplasms Mediating Mediator of activation protein Methylation Microsatellite Instability Modeling Molecular Mus Mutation Myeloid-derived suppressor cells Organoids Pathology Pathway Analysis Pathway interactions Patients Phenotype Polyps Process Reporting Risk Risk Factors Role Secretory Cell Serrated Adenoma Side Signal Pathway Signal Transduction Specimen Tissues Transactivation Transgenic Mice adenoma carcinogenesis carcinogenicity cohort colorectal cancer prevention cytokine cytotoxic gut dysbiosis immunoregulation improved inflammatory milieu intestinal barrier macrophage microbiome mouse model notch protein novel pathobiont premalignant prevent progenitor protein expression recruit stem cell homeostasis stem cell proliferation stem cells transcriptome tumor-immune system interactions tumorigenic

项目摘要

Distinct from the conventional adenoma–carcinoma pathway, the “serrated pathway” is a molecular pathway postulated for a subset of CRCs that develop from some serrated precursor lesions. In addition, inflammation is a known risk factor for CRC. However, molecular carcinogenic mechanism driving serrated lesion transformation, which is frequently associated with chronic inflammation, remains an important knowledge gap. Previously we found that Notch/HES1 expression is lost in most human sessile serrated adenoma and right-sided CRC, and is a ubiquitous marker for IBD-associated serrated lesions and CRC. In addition, Notch/Hes1-loss underlies the gut pathology of an animal model of colitis-associated CRC featuring serrated-like lesions. In this proposal, we will use a combination of approaches (organoid culture, molecular and cellular signaling network analysis of human SSA and serrated CRC, and microbiome deep gene sequencing, etc) and our unique carcinogen-free animal models to study the mechanism by which HES1-loss disrupts epithelial homeostasis, and defining how this process cooperates with a pro-tumorigenic cytokine milieu represented by IL1β to promote carcinogenesis.

不同于常规腺瘤 - 卡诺马瘤途径，“锯齿状” 途径”是针对由CRC的子集发布的分子途径一些锯齿状的前体病变。此外，炎症是已知的危险因素 CRC。但是，分子致癌机制驱动锯齿病变经常与慢性感染相关的转化仍然是重要的知识差距。以前我们发现Notch/Hes1表达在大多数人类无链锯齿状腺瘤和右侧CRC，是无处不在的标记用于IBD相关的锯齿病变和CRC。此外，Notch/HES1损失基础结肠炎相关的CRC动物模型的肠道病理学，具有锯齿状样病变。在此提案中，我们将使用多种方法（器官培养，人类SSA和锯齿状CRC的分子和细胞信号网络分析，以及微生物组深基因测序等）和我们独特的无致癌动物模型研究HES1-LOSS破坏上皮稳态的机制，并定义该过程如何与亲肿瘤的细胞因子环境合作由IL1β表示，以促进致癌作用。