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， 敏感性、环境因素和对腔菌群的异常反应 内脏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，包括免疫和肠上皮细胞（IEC）和抗- TNF干预用作IBD治疗。尽管有临床意义， 已知体内因子控制TNF表达。在一条向前的斑马鱼中 遗传筛选我们发现，表观遗传调节因子Uhrf 1或Dnmt 1的缺失导致 肠上皮细胞中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 表观遗传调控的缺陷可以通过TNF的去抑制而触发IBD的发作。 我们将使用斑马鱼系统来定义转录和转录后 调节肠中TNFA表达和功能的机制以及这些机制是如何 受微生物群的影响。我们还将研究CD患者是否携带突变， DNMT 1或UHRF 1，可能导致启动子甲基化的丧失和去阻遏， 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。

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.