Genetic and Epigenetic Regulation of Intestinal Inflammation

炎症性肠病(IBD)的发病，包括克罗恩病(CD) 和溃疡性结肠炎，知之甚少，但似乎涉及宿主的组合 易感性、环境因素和对管腔微生物区系的异常反应 我的直觉。炎症性肠病的特征之一是促炎细胞因子的上调 多种细胞类型的肿瘤坏死因子，包括免疫和肠上皮细胞(IECS)和抗- 肿瘤坏死因子干预被用作IBD的治疗。尽管它与临床相关，但几乎没有 了解体内控制肿瘤坏死因子表达的因素。在前进的斑马鱼中 基因筛查我们发现表观遗传调控因子uhrf1或dnmt1的缺失会导致 肠上皮细胞中TNFa基因的表达下调与微生物依赖性肠炎 这就像人类的CD。我们提出的研究解决了中心假说 表观遗传调控缺陷可通过抑制肿瘤坏死因子的表达而触发IBD的发病。 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 受微生物区系的影响。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抑制 肿瘤坏死因子基因座。这些研究有望对IBD有新的机制认识。 这可能会促进IBD诊断和治疗的新方法。

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.