PARP1 and PARylation as novel effectors of gut inflammation

PARP1 和 PARylation 作为肠道炎症的新型效应物

基本信息

  • 批准号:
    10679646
  • 负责人:
  • 金额:
    $ 61.55万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-06-01 至 2027-03-31
  • 项目状态:
    未结题

项目摘要

Despite recent advances in the understanding host-microbiome interactions in the pathogenesis of Inflammatory Bowel Diseases (IBD), the complexity of the host’s response to changing gut microbiota is daunting and still incompletely understood. In this proposal, we show that poly-ADP-ribosylation (PARylation), a post-translational modification that involves the enzymatic transfer of ADP-ribose (ADPr) from NAD+ to specific amino acids of target proteins, plays key roles as a mediator of inflammatory response in the gut. For the first time, we provide evidence that PARP1 is the primary PAR writer in the colon, where it serves as a powerful transcriptional modulator. Commensal bacteria are necessary for mucosal PARP1 activity and PARylation and, reciprocally, PARP1 controls the microbial composition and metabolic activity, modulates colonic epithelial barrier function, and restricts the mucosal Treg compartment. Importantly, human and murine colitis is associated with mucosal hyperPARylation, which can be transferred to germ-free mice with complex microbial community from IBD patients. Total or epithelial-specific knockout of PARP1 (or pharmacological inhibition) protect from and promote recovery from mucosal injury. Based on these novel preliminary observations, we hypothesized that hyperPARylation is a significant contributor to mucosal inflammation and impaired mucosal restitution via both extrinsic (interaction with gut microbiota) and intrinsic effects in the colonic mucosa. We will address this hypothesis in the following three well-integrated, but not mutually contingent specific aims, which will: (1) Define the role of NAD+ depletion vs. hyperPARylation as putative culprits in the pathogenesis of experimental colitis (2) Define the role of PARP1 and PARylation in colitis mediated by human IBD microbiota; and (3) Mechanistically define the roles of PARP1 in the highly interactive relationship between gut microbiota and epithelial barrier function and mucosal restitution.in the inflamed colon. This novel research plan will greatly advance the field of fundamental mucosal biology and will offer targeting of PARP1 activity as a potential IBD therapy.
尽管最近在了解炎症性肠病 (IBD) 发病机制中宿主与微生物组相互作用方面取得了进展,但宿主对肠道微生物群变化的反应的复杂性令人望而生畏,而且仍未完全了解。在本提案中,我们表明,聚 ADP 核糖基化 (PARylation) 是一种翻译后修饰,涉及 ADP 核糖 (ADPr) 从 NAD+ 酶促转移到目标蛋白的特定氨基酸,它作为肠道炎症反应的介质发挥着关键作用。我们首次提供证据表明 PARP1 是结肠中主要的 PAR 写入器,在结肠中它充当强大的转录调节剂。共生细菌对于粘膜 PARP1 活性和 PARylation 是必需的,反过来,PARP1 控制微生物组成和代谢活性,调节结肠上皮屏障功能,并限制粘膜 Treg 区室。重要的是,人类和小鼠结肠炎与粘膜过度PARylation有关,这种过度PARylation可以从IBD患者身上转移到具有复杂微生物群落的无菌小鼠身上。 PARP1 的完全敲除或上皮特异性敲除(或药物抑制)可以防止粘膜损伤并促进其恢复。基于这些新颖的初步观察,我们假设过度PARylation是通过结肠粘膜的外在(与肠道微生物群相互作用)和内在作用导致粘膜炎症和粘膜恢复受损的重要因素。我们将通过以下三个整合良好但不是相互关联的具体目标来解决这一假设,这些目标将:(1)定义 NAD+ 耗竭与过度 PARylation 的作用,作为实验性结肠炎发病机制中假定的罪魁祸首(2)定义 PARP1 和 PARylation 在人类 IBD 微生物群介导的结肠炎中的作用; (3) 从机制上定义 PARP1 在发炎结肠中肠道微生物群与上皮屏障功能和粘膜恢复之间的高度交互关系中的作用。这项新颖的研究计划将极大地推进基础粘膜生物学领域的发展,并将以 PARP1 活性为目标,作为一种潜在的 IBD 疗法。

项目成果

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Fayez Khalaf Ghishan其他文献

Fayez Khalaf Ghishan的其他文献

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{{ truncateString('Fayez Khalaf Ghishan', 18)}}的其他基金

Novel Roles of Sodium Hydrogen Exchanger 8 (NHE8) in Mucosal Homeostasis
钠氢交换器 8 (NHE8) 在粘膜稳态中的新作用
  • 批准号:
    9402244
  • 财政年份:
    2017
  • 资助金额:
    $ 61.55万
  • 项目类别:
Novel Roles of Sodium Hydrogen Exchanger 8 (NHE8) in Mucosal Homeostasis
钠氢交换器 8 (NHE8) 在粘膜稳态中的新作用
  • 批准号:
    9980395
  • 财政年份:
    2017
  • 资助金额:
    $ 61.55万
  • 项目类别:
Modulation of dendritic cell function in the pathogenesis of Inflammatory Bowel Diseases
炎症性肠病发病机制中树突状细胞功能的调节
  • 批准号:
    9349503
  • 财政年份:
    2016
  • 资助金额:
    $ 61.55万
  • 项目类别:
Modulation of dendritic cell function in the pathogenesis of Inflammatory Bowel Diseases
炎症性肠病发病机制中树突状细胞功能的调节
  • 批准号:
    9754114
  • 财政年份:
    2016
  • 资助金额:
    $ 61.55万
  • 项目类别:
Summers in Children's Research for Diverse High School Students
不同高中生的儿童研究暑期活动
  • 批准号:
    10610857
  • 财政年份:
    2013
  • 资助金额:
    $ 61.55万
  • 项目类别:
Summers in Children's Research for Diverse High School Students
不同高中生的儿童研究暑期活动
  • 批准号:
    10383164
  • 财政年份:
    2013
  • 资助金额:
    $ 61.55万
  • 项目类别:
Regulation of a Novel Intestinal NHE Isoform (NHE8)
新型肠道 NHE 亚型 (NHE8) 的调节
  • 批准号:
    8332260
  • 财政年份:
    2006
  • 资助金额:
    $ 61.55万
  • 项目类别:
Regulation of a Novel Intestinal NHE Isoform (NHE8)
新型肠道 NHE 亚型 (NHE8) 的调节
  • 批准号:
    8913142
  • 财政年份:
    2006
  • 资助金额:
    $ 61.55万
  • 项目类别:
Regulation of a Novel Intestinal NHE Isoform (NHE8)
新型肠道 NHE 亚型 (NHE8) 的调节
  • 批准号:
    7657335
  • 财政年份:
    2006
  • 资助金额:
    $ 61.55万
  • 项目类别:
Regulation of a Novel Intestinal NHE Isoform (NHE8)
新型肠道 NHE 亚型 (NHE8) 的调节
  • 批准号:
    7268715
  • 财政年份:
    2006
  • 资助金额:
    $ 61.55万
  • 项目类别:
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