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：
10433908
负责人：
Lan Zhou
金额：
--
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 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10433908
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 IL1R1 gene Immune Immune response Immune signaling Immunologic Markers Immunotherapy Inflammation Inflammation Mediators Inflammatory Inflammatory Bowel Diseases 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 marker inflammatory milieu intestinal barrier macrophage microbiome murine colitis 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.

与传统的腺瘤-癌途径不同，“锯齿状”途径途径”是为 CRC 的子集假设的分子途径，其发展自此外，炎症是已知的危险因素。然而，CRC 的分子致癌机制驱动锯齿状病变。通常与慢性炎症相关的转化仍然是一种之前我们发现Notch/HES1表达丢失。大多数人类无蒂锯齿状腺瘤和右侧结直肠癌，是一种普遍存在的标记此外，Notch/Hes1 缺失也是 IBD 相关锯齿状病变和 CRC 的基础。结肠炎相关结直肠癌动物模型的肠道病理学特征为锯齿状在本提案中，我们将使用多种方法的组合（类器官培养、人类 SSA 和锯齿状 CRC 的分子和细胞信号网络分析，以及微生物组深度基因测序等）和我们独特的无致癌动物模型研究 HES1 缺失破坏上皮稳态的机制，以及定义该过程如何与促肿瘤细胞因子环境合作以IL1β为代表，促进癌变。