The role of nuclear receptor co-repressor NCoR1 in ulcerative colitis

核受体共阻遏物NCoR1在溃疡性结肠炎中的作用

• 批准号: 9600568
• 负责人: Shujuan Chen
• 金额: $ 23.25万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-14 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9600568
• 关键词: ASCL2 gene; Adult; Affect; Animal Model; Apoptosis; Asia; Bacteria; Basic Science; Biological Assay; Body Weight decreased; Bromodeoxyuridine; CA-15-3 Antigen; Cell Differentiation process; Cell Maturation; Cell Proliferation; Cells; Chemicals; Clinical; Colitis; Colon; Colorectal Cancer; Coupled; Developed Countries; Development; Discipline; Disease; Drops; Enterocytes; Environmental Risk Factor; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Event; Exhibits; Family member; Functional disorder; Gastrointestinal Diseases; Gene Expression; Gene Family; Genes; Genetic Markers; Genetic Transcription; Genetically Modified Animals; Genomics; Goblet Cells; High-Throughput Nucleotide Sequencing; Incidence; Industrialization; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interleukin-1 beta; Interleukin-18; Intestines; LGR5 gene; Laboratories; Lead; Life Style; Link; Mitotic; Mucins; Mucous body substance; Mus; NCOR1 gene; Natural regeneration; Neonatal; North America; Northern Europe; Nuclear Receptors; Organoids; Pathologic; Pathway interactions; Penetration; Play; Predisposition; Prevalence; Proctitis; Production; Quality of life; Regulation; Risk; Role; Scheme; Secretory Cell; Severity of illness; Signal Transduction; Sodium Dextran Sulfate; Stem cells; Symptoms; T-Lymphocyte; TNF gene; TdT-Mediated dUTP Nick End Labeling Assay; Technology; Thick; Tissues; Transcription Factor AP-1; Ulcerative Colitis; Water; Wild Type Mouse; angiogenin; antimicrobial peptide; cell motility; colonic crypt; crypt cell; cytokine; gene environment interaction; intestinal homeostasis; islet; macrophage; migration; mouse model; novel; nuclear receptor co-repressor; transcription factor; transcriptome sequencing

Project Summary Ulcerative colitis (UC) is a serious condition with the highest incidence and prevalence in Northern Europe and North America. Following industrialization and cultural implementation of a Westernized life style, a significant rise in UC has also been observed in Asia. UC is a long-term condition that results in colon and rectum inflammation, impacting the quality of life and potentially leading to colorectal cancer. The cause of UC is unknown. Basic research in genetically modified animal models coupled with high throughput sequencing technology to examine altered regulatory events because of disease has been of significant value in elucidating the pathophysiological factors involved in UC. Nuclear receptor corepressor 1 (NCoR1) interacts with a host of transcriptional factors that repress and transrepress families of genes that are closely associated with inflammatory events. The importance of intrinsic NCoR1 in intestinal homeostasis was first discovered in our laboratory when we generated intestinal epithelial cell (IEC) specific NCoR1 deletion mice (NCoR1IEC) and identified the role of NCoR1 in regulating IEC proliferation and enterocyte maturation during neonatal development. When adult wild-type mice are treated with dextran sulfate sodium (DSS), an important experimental agent used in this discipline, the mice develop UC. In comparison to wild-type mice, NCoR1IEC mice treated with DSS exhibit increased susceptibility to weight loss and colitis, heightened by a significant decrease in proliferative Ki67+ cells accentuated by a dramatic drop in mitotic Lgr5 gene expression. Furthermore, we discovered that IEC-NCoR1 deletion in naïve (water exposure only) NCoR1IEC mice leads to accelerated cell proliferation along with transcriptional inhibition of various antimicrobial peptides (AMPs), including Reg4, Ang4, and Itln1. In colon tissue, AMPs are produced by Paneth-like deep crypt secretory (DCS) cells, which are intimately coupled with mucin-producing goblet cells to form the first line of innate defense in protecting IECs and the intestinal stem cells (ISC) that reside at the bottom of the crypts. Therefore, we hypothesis that “intestinal NCoR1 protects crypt cells through regulating the function of colonic secretory cells”. By utilizing both naïve and DSS-treated NCoR1F/F and NCoR1IEC mice, we will examine ISC proliferation, migration and apoptosis. We will also determine the impact on mucus thickness, goblet cell maturation, and regulation of DSC secretory markers. These studies will help us determine if altered AMPs and mucins in NCoR1IEC mice lead to bacteria penetration and crypt cell apoptosis. In addition, global genomic studies will be initiated to identify molecules and pathways that are associated with the differentiation and maturation of goblet and DCS cells. Included in these pathways will be examination of the role played by IL-18, an important epithelial- derived cytokine involved in regulating goblet cell maturation which is repressed in IECs by NCoR1. We will determine the possibility that NCoR1 maintains intestinal homeostasis through regulating cytokine IL-18 signaling.

项目摘要 溃疡性结肠炎（UC）是一种严重的疾病，在北方欧洲的发病率和患病率最高 和北美随着工业化和西方化生活方式的文化实施， 在亚洲也观察到UC显著上升。UC是一种导致结肠和直肠 炎症，影响生活质量并可能导致结直肠癌。UC的病因是 未知转基因动物模型基础研究与高通量测序相结合 检查由于疾病而改变的调节事件的技术在阐明 UC的病理生理因素。核受体辅阻遏物1（NCoR1）与宿主细胞相互作用， 转录因子抑制和反式抑制基因家族，这些基因家族与 炎症事件。内源性NCoR1在肠道内稳态中的重要性首先在我们的研究中发现。 当我们产生肠上皮细胞（IEC）特异性NCoR1缺失小鼠（NCoR1缺失IEC）时， 确定了NCoR1在新生儿期调节IEC增殖和肠上皮细胞成熟中的作用， 发展当成年野生型小鼠用葡聚糖硫酸钠（DSS）治疗时， 在本学科中使用的实验剂中，小鼠发展UC。与野生型小鼠相比， 用DSS治疗的小鼠表现出对体重减轻和结肠炎的敏感性增加， 增殖性Ki 67+细胞的减少，由有丝分裂Lgr 5基因表达的急剧下降加重。 此外，我们发现，在未经处理（仅接触水）的NCoR1-IEC小鼠中，IEC-NCoR1缺失导致 加速细胞增殖沿着各种抗微生物肽（AMP）的转录抑制， 包括Reg4、Ang4和Itln 1。在结肠组织中，AMP是由Paneth样深隐窝分泌（DCS） 细胞，与产生粘蛋白的杯状细胞紧密结合，形成先天性防御的第一道防线， 保护位于隐窝底部的IEC和肠干细胞（ISC）。所以我们 假设"肠NCoR1通过调节结肠分泌功能保护隐窝细胞， 细胞"。通过使用未经处理的和DSS处理的NCoR1F/F和NCoR1HIEC小鼠，我们将检查ISC增殖， 迁移和凋亡。我们还将确定对粘液厚度、杯状细胞成熟和 DSC分泌标志物的调节。这些研究将帮助我们确定是否改变AMP和粘蛋白， NCoR1介导的肠上皮细胞凋亡导致细菌穿透和隐窝细胞凋亡。此外，全球基因组研究将 开始鉴定与杯状细胞分化和成熟相关的分子和途径， DCS细胞这些途径包括检查IL-18所起的作用，IL-18是一种重要的上皮细胞因子， 参与调节杯状细胞成熟的衍生细胞因子，其在IEC中被NCoR1抑制。我们将 确定NCoR1通过调节细胞因子IL-18维持肠道稳态的可能性 信号