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

• 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
• 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

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”是一种分子途径，假定为CRC的一个子集， 一些锯齿状的前驱病变此外，炎症是一个已知的危险因素， 《儿童权利公约》。然而，驱动锯齿状病变的分子致癌机制 转化，这是经常与慢性炎症，仍然是一个问题。 重要的知识差距。以前我们发现Notch/HES 1表达缺失， 大多数人类无蒂锯齿状腺瘤和右侧CRC，是一种普遍存在的标志物 IBD相关的锯齿状病变和CRC。此外，Notch/Hes 1-损失 结肠炎相关CRC动物模型的肠道病理学特征为锯齿状 病变在这个建议中，我们将使用一种方法的组合（类器官培养， 人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物动物模型 研究HES 1缺失破坏上皮稳态的机制， 定义该过程如何与促肿瘤细胞因子环境合作 以IL-1 β为代表的促癌作用。