The Role of Base Excision Repair in Regulating DNA-Mediated Inflammatory Signaling Pathways

碱基切除修复在调节 DNA 介导的炎症信号通路中的作用

基本信息

  • 批准号:
    10197494
  • 负责人:
  • 金额:
    $ 21.2万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-04-01 至 2023-03-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Defects in DNA repair underlie a number of human genetic diseases that affect a wide variety of physiological systems and cause adverse phenotypes such as accelerated aging and predisposition to cancer. Faithful DNA repair is necessary to maintain genomic integrity and prevent cancer. The base excision repair (BER) pathway is responsible for repairing at least 20,000 lesions per cell per day. If left unrepaired, the lesions can give rise to genomic instability and tumorigenesis. BER is also the major repair pathway for nonbulky damaged bases, abasic sites, and DNA single-strand breaks after treatment with different DNA- damaging agents. Several genes are involved in BER pathways, including DNA glycosylase, XRCC1, DNA polymerase beta (Polβ), DNA ligase III, flap endonuclease 1 (FEN1), and DNA ligase I. BER deficiency can lead to accumulated unrepaired DNA damage, generating cytosolic DNA that likely activates DNA-dependent innate immune pathways. Cyclic GMP-AMP synthase (cGAS) is a key cytosolic DNA sensor that produces the cyclic dinucleotide cGMP-AMP (cGAMP) upon activation, which triggers the activation of stimulator of interferon genes (STING), leading to type I Interferon production. However, how deficiency in BER promotes cGAS/STING-mediated inflammation is not yet fully understood. The goal of this exploratory R21 proposal is to uncover how spontaneous DNA damage and failed BER stimulate host inflammatory response. We recently developed a novel mouse model using a human genetic variant, which we will use to elucidate the molecular mechanism of inflammation. Using a Cre-flox targeting system, we constructed an L22P conditional knock-in mouse model that lacks dRP lyase function expressed at Rosa26a locus and cannot support BER. Our preliminary data revealed that BER deficiency in our mouse model markedly induces genomic instability and chronic inflammation. Thus, we hypothesize that BER deficiency accumulates cytosolic DNA that derives from spontaneous DNA damage, thereby triggering the innate immune response. In this study, we propose two Specific Aims: (1) Determine the molecular mechanisms through which aberrant BER induces inflammation. Using BER-deficient cells ( Polβ -/-; XRCC1; PARP1-/-; L22P (dRP lyase-deficient Polβ), we will study how BER deficiency triggers innate immune response-mediated inflammation. (2) Determine whether failed BER stimulates cGAS/STING-mediated inflammation in mice. Using in vitro and in vivo models (L22P mouse models), we will examine how cytosolic DNA-sensing pathways trigger inflammatory immune responses. The outcomes of this study will define a novel paradigm for how aberrant BER induces the innate immune system, and will have broad implications for the molecular mechanisms behind cGAS/STING function, as well as for future immune-directed cancer therapies.
项目总结 DNA修复缺陷是许多人类遗传病的基础,这些疾病影响到各种各样的 并导致不良表型,如加速衰老和易患癌症。 忠实的DNA修复对于保持基因组的完整性和预防癌症是必要的。根部切除修复 (BER)途径每天负责修复每个细胞至少20,000个病变。如果不进行修复, 损伤可导致基因组不稳定和肿瘤发生。BER也是糖尿病的主要修复途径 不同DNA处理后,未见大量碱基损伤、碱基位置和DNA单链断裂。 破坏性因素。误码率通路涉及几个基因,包括DNA糖基酶、XRCC1、DNA 聚合酶β、DNA连接酶III、FEN1和DNA连接酶I 导致累积的未修复的DNA损伤,产生胞浆DNA,可能激活DNA依赖 先天免疫途径。环状GMP-AMP合成酶(CGAS)是一种关键的胞质DNA传感器,它能产生 环二核苷酸cGMP-AMP(CGAMP)被激活时,它会触发 干扰素基因(STING),导致I型干扰素的产生。然而,误码率不足是如何促进 CGAS/STING介导的炎症机制尚不完全清楚。此探索性R21提案的目标是 揭示自发的DNA损伤和失败的BER如何刺激宿主炎症反应。我们最近 利用人类基因变体开发了一种新的小鼠模型,我们将用它来阐明分子 炎症机制。使用CRE-FLOX靶向系统,我们构建了L22P条件敲入 在Rosa26a基因座表达的缺乏DRP裂解酶功能的小鼠模型,不支持BER。我们的 初步数据显示,在我们的小鼠模型中,BER缺乏显著地诱导了基因组的不稳定和 慢性炎症。因此,我们假设BER缺乏症会积聚源于 自发的DNA损伤,从而触发先天免疫反应。 在这项研究中,我们提出了两个 具体目的:(1)确定BER异常引起炎症的分子机制。 使用误码率不足的小区( Polβ-/-;XRCC1;PARP1-/-;L22P(缺乏DRp裂解酶 POLβ),我们将研究如何 BER缺乏会触发先天免疫反应介导的炎症。(2)判断误码率是否出现故障 刺激cGAS/刺痛介导的小鼠炎症。使用体外和体内模型(L22P小鼠 模型),我们将研究胞浆DNA传感通路如何触发炎症免疫反应。这个 这项研究的结果将为BER异常如何诱导先天性免疫系统定义一个新的范式, 并将对cGAS/STING功能背后的分子机制以及 未来的免疫导向癌症疗法。

项目成果

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Dawit Kidane Mulat其他文献

Dawit Kidane Mulat的其他文献

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{{ truncateString('Dawit Kidane Mulat', 18)}}的其他基金

The Role of Base Excision Repair in Regulating DNA-Mediated Inflammatory Signaling Pathways
碱基切除修复在调节 DNA 介导的炎症信号通路中的作用
  • 批准号:
    10845149
  • 财政年份:
    2021
  • 资助金额:
    $ 21.2万
  • 项目类别:
DNA Polymerase Beta and Gastric Cancer
DNA 聚合酶 Beta 与胃癌
  • 批准号:
    8703630
  • 财政年份:
    2011
  • 资助金额:
    $ 21.2万
  • 项目类别:
DNA Polymerase Beta and Gastric Cancer
DNA 聚合酶 Beta 与胃癌
  • 批准号:
    8189716
  • 财政年份:
    2011
  • 资助金额:
    $ 21.2万
  • 项目类别:
DNA Polymerase Beta and Gastric Cancer
DNA 聚合酶 Beta 与胃癌
  • 批准号:
    8505411
  • 财政年份:
    2011
  • 资助金额:
    $ 21.2万
  • 项目类别:
DNA Polymerase Beta and Gastric Cancer
DNA 聚合酶 Beta 与胃癌
  • 批准号:
    8304905
  • 财政年份:
    2011
  • 资助金额:
    $ 21.2万
  • 项目类别:
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