Ubiquitination, Intestinal Homeostasis and Cancer

泛素化、肠道稳态和癌症

• 批准号: 10522777
• 负责人: AVERIL I MA
• 金额: $ 44.86万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522777
• 关键词: Adoptive Cell Transfers; Adult; Bar Codes; Binding; Biochemical; Cell Differentiation process; Cell physiology; Cells; Chronic; Colon Carcinoma; Colonic Polyps; Data; Enterocolitis; Enzymes; Epithelial; Epithelial Cells; Genetic Epistasis; Homeostasis; Human; Immune; Inflammation; Inflammation Mediators; Interferons; Interleukin-17; Interleukins; Intestinal Cancer; Intestinal Neoplasms; Intestines; Knock-in Mouse; Lead; Length; Life; Light; Lymphocyte; Malignant - descriptor; Malignant Neoplasms; Mediating; Molecular; Mus; Population; Predisposition; Process; Proliferating; Proteomics; Radiation Chimera; Risk; Role; Small Intestinal Polyp; T-Lymphocyte; Testing; Tissue Preservation; Tissues; Ubiquitin; Ubiquitination; cell transformation; colitis associated cancer; colon cancer prevention; colorectal cancer risk; cytokine; gut inflammation; in vivo; intercellular communication; interleukin-22; intestinal epithelium; intestinal homeostasis; mouse model; novel; paracrine; preservation; single-cell RNA sequencing; transcriptomics

Abstract Adult intestinal tissues are maintained in a normal functional state despite rapidly proliferating and differentiating intestinal epithelial cell populations that replenish the epithelium layer every 6-7 days. Intestinal epithelial cells reside in close association with both adaptive and innate immune cells of the gut. A reciprocal and dynamic dialogue among these components maintains intestinal homeostasis and is mediated in part by paracrine cytokine and interleukin networks. Intestinal inflammation predisposes intestinal epithelial cells (IEC) to malignant transformation via incompletely understood mechanisms. We have generated a novel knock-in mouse line that spontaneously develops perturbed IEC differentiation, gut elongation, and have a high susceptibility to colon cancer. These mice provide us with a unique opportunity to discover the key inflammatory mediators that regulate intestinal homeostasis and drive IEC transformation. Using transcriptomic, proteomic, genetic epistasis and cellular approaches, our preliminary data implicate selected immune cytokines in these processes.

摘要 成人肠组织维持在正常的功能状态，尽管快速增殖， 分化肠上皮细胞群，其每6-7天补充上皮层。肠 上皮细胞与肠道的适应性和先天性免疫细胞密切相关。对等 这些成分之间的动态对话维持肠道内稳态，并部分由 旁分泌细胞因子和白细胞介素网络。肠道炎症倾向于肠上皮细胞（IEC） 通过不完全理解的机制导致恶性转化。我们创造了一种新的敲门方式 小鼠系，自发发展干扰IEC分化，肠伸长，并具有高的 易患结肠癌。这些老鼠为我们提供了一个独特的机会来发现 炎症介质调节肠内稳态和驱动IEC转化。使用 转录组学、蛋白质组学、遗传上位性和细胞方法，我们的初步数据表明， 免疫细胞因子在这些过程中。