Genetic and Epigenetic Regulation of Intestinal Inflammation

肠道炎症的遗传和表观遗传调控

基本信息

批准号：
9900787
负责人：
Michel Bagnat
金额：
$ 41.99万
依托单位：
DUKE 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：
2018-04-02 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9900787
关键词：
3&apos Untranslated Regions Address Affect American Americas Ascending colon Basic Science Biological Assay Biopsy Cells Chronic Clinical Code Complex Crohn&apos s disease DNA DNA Methylation DNA Methylation Regulation Defect Disease Disease model Elements Environmental Risk Factor Epigenetic Process Epithelial Cells Foundations Gene Expression Profile Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genetic Screening Genetic Transcription Gnotobiotic Human Immune Impairment Incidence Inflammation Inflammatory Inflammatory Bowel Diseases Intervention Intestines Lead Link Measures Mediating Methylation Microbe Modeling Mutation Neutrophil Infiltration Onset of illness Pathway interactions Patients Pattern Phenotype Play Post-Transcriptional Regulation Predisposition Production Quality of life Regulation Repression Research Role Signal Transduction Stimulus System TNF gene Testing Therapeutic Tissues Transgenic Organisms Translating Ulcerative Colitis Up-Regulation Work Zebrafish cell type clinically relevant colorectal cancer risk cytokine diagnostic assay disease diagnosis epigenetic regulation genome wide association study gut microbiota host microbiota ileum improved in vivo inflammatory disease of the intestine insight intestinal barrier intestinal epithelium knock-down large bowel Crohn&apos s disease microbial microbiota microbiota transplantation mutant novel novel diagnostics novel strategies novel therapeutic intervention prognostic promoter public health relevance response transcriptome sequencing

项目摘要

The onset of inflammatory bowel diseases (IBD), which includes Crohn's disease (CD) and ulcerative colitis, is poorly understood, but appears to involve a combination of host susceptibility, environmental factors and aberrant response to the luminal microbiota of the gut. One of the hallmarks of IBD is the upregulation of the pro-inflammatory cytokine TNF in various cell types, including immune and intestinal epithelial cells (IECs) and anti- TNF interventions are used as IBD therapy. In spite of its clinical relevance, little is known about the in vivo factors controlling TNF expression. In a forward zebrafish genetic screen we found that loss of the epigenetic regulators Uhrf1 or Dnmt1 leads to de-repression of the tnfa locus in IECs and microbe-dependent intestinal inflammation that resembles human CD. Our proposed research addresses the central hypothesis that defects in epigenetic regulation can trigger IBD onset in via de-repression of TNF. We will use the zebrafish system to define transcriptional and post-transcriptional mechanisms regulating tnfa expression and function in the intestine and how these are influenced by microbiota. We will also investigate whether CD patients carry mutations in DNMT1 or UHRF1 that may lead to loss of promoter methylation and de-repression of the TNF locus. These studies are expected to yield new mechanistic insights into IBD onset and may facilitate new approaches for IBD diagnosis and therapy.

炎症性肠病 (IBD) 的发作，包括克罗恩病 (CD) 和溃疡性结肠炎，人们知之甚少，但似乎涉及宿主的组合易感性、环境因素和对腔内微生物群的异常反应肠道。 IBD 的标志之一是促炎细胞因子的上调各种细胞类型中的 TNF，包括免疫细胞和肠上皮细胞 (IEC) 以及抗 TNF 干预措施被用作 IBD 治疗。尽管它具有临床相关性，但很少有已知控制 TNF 表达的体内因素。在向前的斑马鱼中遗传筛选我们发现表观遗传调节因子 Uhrf1 或 Dnmt1 的缺失会导致 IEC 中 tnfa 位点的去抑制和微生物依赖性肠道炎症类似于人类CD。我们提出的研究解决了中心假设表观遗传调控缺陷可通过 TNF 的去抑制引发 IBD 发作。我们将使用斑马鱼系统来定义转录和转录后肠道中 TNFA 表达和功能的调节机制及其作用机制受微生物群的影响。我们还将调查 CD 患者是否携带突变 DNMT1 或 UHRF1 可能导致启动子甲基化缺失和去抑制 TNF 基因座。这些研究有望对 IBD 产生新的机制见解发病并可能促进 IBD 诊断和治疗的新方法。