Microbial and inflammatory regulation of intestinal epithelial gene transcription

肠上皮基因转录的微生物和炎症调节

基本信息

  • 批准号:
    10447745
  • 负责人:
  • 金额:
    $ 36.64万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-09-19 至 2024-06-30
  • 项目状态:
    已结题

项目摘要

ABSTRACT There exist fundamental gaps in our understanding of the transcriptional regulatory pathways through which microbiota and inflammation alter gene expression in the intestinal epithelium, and how those pathways promote and might predict intestinal homeostasis. Our long-term goal is to understand the evolutionarily-conserved mechanisms underlying host-microbe interactions in the intestine and how they contribute to human diseases. The overall objectives of this project are to identify conserved transcriptional regulatory pathways mediating intestinal epithelial cell (IEC) responses to microbiota and inflammation, and determine if their activity can be used as phenotypic indicators in human inflammatory bowel disease (IBD). Our preliminary studies in human, mouse, and zebrafish IECs have uncovered striking conservation of transcriptional signatures and regulatory mechanisms, predicting central conserved roles for transcription factors (TF) implicated in human IBD including HNF4A and ELF3. We recently made the key discovery that HNF4A is a novel mediator of IEC transcriptional responses to microbiota in zebrafish and mice. Mechanistic studies in zebrafish and mice revealed that HNF4A is a positive regulator of microbially-suppressed genes, and that microbiota broadly suppress HNF4A activity in IECs. Further, our results show that intestinal suppression of HNF4A target genes is a prevalent feature of human, mouse, and zebrafish models of IBD, and indicate that HNF4A constrains inflammatory responses to microbiota and suppresses a conserved IBD-like gene expression signature. Finally, we identified DNA enhancer elements in mouse IECs that are regulated by microbiota colonization, and leverage those results to implicate ELF3 as a potential integrator of inflammatory and microbial signals in IECs. We will test the central hypothesis that microbiota promote intestinal inflammation by coordinately suppressing anti-inflammatory HNF4A activity and activating ELF3 and other pro-inflammatory transcriptional pathways. In Specific Aim 1, we will identify host signaling mechanisms mediating microbial suppression of HNF4A activity in IECs. In Specific Aim 2, we will define the roles of ELF3 and broader transcriptional pathways in IEC responses to microbiota and inflammation, and test if IBD phenotypes are associated with distinct signatures of ELF3 and HNF4A activity. The expected outcomes will vertically advance the field in several ways. First, they will generate a foundational mechanistic understanding of how gut microbes regulate the activity of HNF4A and ELF3, conserved TFs with critical roles in intestinal inflammation. Second, they will provide much-needed insights into the transcriptional regulatory networks utilized by IECs to integrate microbial and inflammatory stimuli, and how those networks are deranged in human IBD. These outcomes are expected to have a significant impact because they will vertically advance our understanding of the IEC transcriptional programs that integrate responses to microbiota and inflammation, which can be expected to lead to new diagnostic, prognostic, and therapeutic approaches for human IBD.
抽象的 我们对转录监管途径的理解存在基本差距 微生物群和炎症改变了肠上皮中的基因表达,这些途径如何促进 并可能预测肠内稳态。我们的长期目标是了解进化保存的 肠相互作用的机制在肠道中及其对人类疾病的贡献。 该项目的总体目标是确定介导的保守转录调节途径 肠上皮细胞(IEC)对微生物群和炎症的反应,并确定它们的活性是否可以是 用作人类炎症性肠病(IBD)中的表型指标。我们在人类的初步研究, 鼠标和斑马鱼IEC具有转录特征和调节性的惊人保守性 机制,预测与人类IBD有关的转录因子(TF)的中心保守作用 HNF4A和ELF3。我们最近提出了一个关键发现,HNF4A是IEC转录的新调解人 斑马鱼和小鼠对菌群的反应。斑马鱼和小鼠的机械研究表明HNF4A 是微生物抑制基因的阳性调节剂,并且微生物群广泛抑制HNF4A活性 IEC。此外,我们的结果表明,HNF4A靶基因的肠道抑制是普遍的特征 IBD的人,小鼠和斑马鱼模型,并表明HNF4A限制了炎症反应 微生物群并抑制了保守的IBD样基因表达特征。最后,我们确定了DNA增强子 小鼠IEC中受微生物群定植调节的元素,并利用这些结果暗示 ELF3是IEC中炎症和微生物信号的潜在积分器。我们将检验中心假设 微生物群通过协调抑制抗炎HNF4A活性来促进肠道炎症 并激活ELF3和其他促炎性转录途径。在特定目标1中,我们将确定主机 信号传导机制介导了IEC中HNF4A活性的微生物抑制。在特定的目标2中,我们将 定义ELF3和更广泛的转录途径在IEC对微生物群和炎症的反应中的作用, 并测试IBD表型是否与ELF3和HNF4A活性的不同特征有关。预期 成果将以几种方式垂直地推进该领域。首先,它们将产生基础机械 了解肠道微生物如何调节HNF4A和ELF3的活性,保守的TF具有关键作用 在肠炎中。其次,他们将为转录调节提供急需的见解 IEC使用的网络来整合微生物和炎症刺激,以及这些网络如何破坏 在人类IBD中。预计这些结果将产生重大影响,因为它们将垂直进步 我们对整合对微生物群和炎症的响应的IEC转录程序的理解, 可以预期为人类IBD提供新的诊断,预后和治疗方法。

项目成果

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John F Rawls其他文献

John F Rawls的其他文献

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{{ truncateString('John F Rawls', 18)}}的其他基金

Genetic determinants of Bacteroides vulgatus colonization fitness and host inflammatory responses
普通拟杆菌定植适应性和宿主炎症反应的遗传决定因素
  • 批准号:
    10680228
  • 财政年份:
    2023
  • 资助金额:
    $ 36.64万
  • 项目类别:
Microbial regulation of intestinal lipid metabolism and its physiological consequences
肠道脂质代谢的微生物调控及其生理后果
  • 批准号:
    10533800
  • 财政年份:
    2021
  • 资助金额:
    $ 36.64万
  • 项目类别:
Microbial regulation of intestinal lipid metabolism and its physiological consequences
肠道脂质代谢的微生物调控及其生理后果
  • 批准号:
    10391368
  • 财政年份:
    2021
  • 资助金额:
    $ 36.64万
  • 项目类别:
A comprehensive research resource to define mechanisms underlying microbial regulation of host metabolism in pediatric obesity and obesity-targeted therapeutics
一个全面的研究资源,用于定义儿科肥胖和肥胖靶向治疗中宿主代谢的微生物调节机制
  • 批准号:
    10016253
  • 财政年份:
    2016
  • 资助金额:
    $ 36.64万
  • 项目类别:
A comprehensive research resource to define mechanisms underlying microbial regulation of host metabolism in pediatric obesity and obesity-targeted therapeutics
一个全面的研究资源,用于定义儿科肥胖和肥胖靶向治疗中宿主代谢的微生物调节机制
  • 批准号:
    9166349
  • 财政年份:
    2016
  • 资助金额:
    $ 36.64万
  • 项目类别:
Organotin influences on assembly and obesogenic activity of the gut microbiota
有机锡对肠道微生物群的组装和致肥活性的影响
  • 批准号:
    8605677
  • 财政年份:
    2014
  • 资助金额:
    $ 36.64万
  • 项目类别:
Microbial and inflammatory regulation of intestinal epithelial gene transcription
肠上皮基因转录的微生物和炎症调节
  • 批准号:
    10216243
  • 财政年份:
    2013
  • 资助金额:
    $ 36.64万
  • 项目类别:
Microbial and inflammatory regulation of intestinal epithelial gene transcription
肠上皮基因转录的微生物和炎症调节
  • 批准号:
    10642802
  • 财政年份:
    2013
  • 资助金额:
    $ 36.64万
  • 项目类别:
Mechanisms of Adipose Depot Morphogenesis in Zebrafish
斑马鱼脂肪库形态发生的机制
  • 批准号:
    8278718
  • 财政年份:
    2011
  • 资助金额:
    $ 36.64万
  • 项目类别:
Microbial regulation of host nutrient metabolism
微生物对宿主营养代谢的调节
  • 批准号:
    9766248
  • 财政年份:
    2008
  • 资助金额:
    $ 36.64万
  • 项目类别:

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嗜铬粒蛋白 A 是衰老的危险因素
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