Inflammation as a Mediator of Dynamic DNA Mutations
炎症作为动态 DNA 突变的中介
基本信息
- 批准号:7982878
- 负责人:
- 金额:$ 53.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-09-22 至 2015-05-31
- 项目状态:已结题
- 来源:
- 关键词:7,8-dihydro-8-oxoguanine8-hydroxyguanosineAdoptedAflatoxin B1AflatoxinsAreaBindingBiologicalBiological AssayCellsChemicalsChromatinChronicComplexDNADNA DamageDNA PackagingDNA Repair EnzymesDNA SequenceDataDiet ModificationDiseaseDisease ProgressionEnvironmental CarcinogensEnvironmental ExposureEpidemiologyEventExcisionFamilyGene MutationGenerationsGenesGenetic AnticipationGoalsHepatitis BHepatitis B VirusHot SpotHumanHuntington DiseaseIn VitroIndividualInfectious AgentInflammationInflammatoryInflammatory ResponseInterventionKnowledgeLaboratoriesLeadLengthLinkLocationMalignant NeoplasmsMalignant neoplasm of liverMediatingMediator of activation proteinMethodsModelingModificationMolecularMolecular ConformationMutationNeurodegenerative DisordersNitratesNitric OxideNucleosome Core ParticleOGG1 geneOligonucleotidesPathway interactionsPatientsPatternPeroxonitritePlayPolymerasePrimer ExtensionProcessProteinsReactionRelative (related person)Relative RisksResearchRiskRoleSourceStructureSuperoxidesTestingTissuesTraumaTrinucleotide RepeatsWorkbasecytokinedesignenvironmental agentexperiencehuman Huntingtin proteinhuman diseasemacrophagemouse modelnucleobaseoxidationoxidative DNA damageoxidative damagepreventpublic health relevancerepairedresearch studysynergismtherapy design
项目摘要
DESCRIPTION (provided by applicant): The goal of this work is to define the mechanism by which DNA damage resulting from an inflammatory response or other environmental sources of damage contribute to dynamic DNA mutations. Dynamic mutations are characterized by the expansion of a triplet repeat sequence such as (CAG)n/(CTG)n and are known to be the primary pathogenic signature of several neurodegenerative disorders. As one example, 5-35 repeats are present in the huntingtin gene of normal individuals but there are more than 40 repeats in Huntington's disease (HD) patients. Using a mouse model of HD, recent work from other laboratories has implicated the oxidative DNA damage product 7,8-dihydro-8-oxoguanine (8-oxoG) in dynamic mutations. Furthermore, the DNA repair enzyme OGG1, which is known to remove 8-oxoG from DNA duplexes, has also been linked to dynamic mutations. Our central hypothesis is based on our preliminary data that (CAG)n and (CTG)n sequences adopt non-B conformations that are hyper-susceptible to DNA damage relative to duplex, including the formation of 8-oxoG. In addition to containing hot spots for DNA damage we have also found that these non-B conformations are not efficiently repaired by OGG1. We postulate that formation of an OGG1- DNA misrepair complex stabilizes the non-B conformation and the DNA is then misreplicated and polymerase incorporates excess triplet repeats. This proposal outlines four specific aims to test our hypothesis. First, studies are proposed to identify the conformation of a family of repetitive CAG/CTG sequences that are prone to dynamic mutations. These experiments will be performed both with oligonucleotide substrates and also DNA in nucleosome core particles (NCP) which model the packaging of DNA in chromatin. Second, the patterns of damage in the triplet repeat DNA will be established using peroxynitrite as the damaging agent. Peroxynitrite is the reactive species produced during inflammation and is known to convert G to 8-oxoG. Third, the OGG1-mediated repair of 8-oxoG-containing DNA substrates, both oligonucleotide and NCP, will be characterized. The final aim of this proposal is to define the processing of damage-containing CAG/CTG sequences by the replication machinery and elucidate the role of OGG1 in modulating replication fidelity.
PUBLIC HEALTH RELEVANCE: The goal of this research is to define how the DNA damage derived from an inflammatory response or other environmental sources contribute to dynamic DNA mutations. In particular, this work will describe how the DNA damage product 7,8-dihydro-8-oxoguanine contributes to disease-initiating dynamic mutations. This knowledge is expected to provide the information needed to rationally design interventions to prevent or delay the onset of multiple diseases that are caused by dynamic mutations.
描述(由申请人提供):这项工作的目标是定义由炎症反应或其他环境损伤源导致的DNA损伤导致动态DNA突变的机制。动态突变的特征在于三联体重复序列如(CAG)n/(CTG)n的扩增,并且已知是几种神经退行性疾病的主要致病特征。作为一个实例,正常个体的亨廷顿基因中存在5-35个重复,但在亨廷顿病(HD)患者中存在超过40个重复。使用HD的小鼠模型,最近来自其他实验室的工作已经暗示了动态突变中的氧化DNA损伤产物7,8-二氢-8-氧代鸟嘌呤(8-oxoG)。此外,DNA修复酶OGG 1(已知可从DNA双链体中去除8-oxoG)也与动态突变有关。我们的中心假设是基于我们的初步数据,即(CAG)n和(CTG)n序列采用相对于双链体对DNA损伤(包括形成8-oxoG)高度敏感的非B构象。除了含有DNA损伤的热点外,我们还发现这些非B构象不能被OGG 1有效修复。我们假设OGG 1- DNA错修复复合物的形成稳定了非B构象,然后DNA被错误复制,聚合酶掺入过量的三联体重复。这一提议概述了四个具体目标来检验我们的假设。首先,研究提出,以确定一个家庭的重复CAG/CTG序列的构象,易于动态突变。这些实验将使用寡核苷酸底物以及核小体核心颗粒(NCP)中的DNA进行,核小体核心颗粒(NCP)模拟DNA在染色质中的包装。第二,将使用过氧亚硝酸盐作为损伤剂来建立三联体重复DNA中的损伤模式。过氧亚硝酸盐是炎症过程中产生的反应性物质,已知可将G转化为8-oxoG。第三,将表征OGG 1介导的含8-oxoG的DNA底物(寡核苷酸和NCP)的修复。本提案的最终目的是定义由复制机制加工的含损伤的CAG/CTG序列,并阐明OGG 1在调节复制保真度中的作用。
公共卫生相关性:这项研究的目的是确定来自炎症反应或其他环境来源的DNA损伤如何导致动态DNA突变。特别是,这项工作将描述如何DNA损伤产物7,8-二氢-8-氧代鸟嘌呤有助于引发疾病的动态突变。这些知识有望提供合理设计干预措施所需的信息,以预防或延迟由动态突变引起的多种疾病的发作。
项目成果
期刊论文数量(0)
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Sarah Delaney其他文献
Sarah Delaney的其他文献
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{{ truncateString('Sarah Delaney', 18)}}的其他基金
NIH resubmission Deyu Li - Etheno adductome and repair pathways
NIH 重新提交 Deyu Li - 乙烯加合组和修复途径
- 批准号:
10659931 - 财政年份:2023
- 资助金额:
$ 53.13万 - 项目类别:
Inflammation as a Mediator of Dynamic DNA Mutations
炎症作为动态 DNA 突变的中介
- 批准号:
8412815 - 财政年份:2010
- 资助金额:
$ 53.13万 - 项目类别:
Inflammation as a Mediator of Dynamic DNA Mutations
炎症作为动态 DNA 突变的中介
- 批准号:
8466972 - 财政年份:2010
- 资助金额:
$ 53.13万 - 项目类别:
Inflammation as a Mediator of Dynamic DNA Mutations
炎症作为动态 DNA 突变的中介
- 批准号:
8682820 - 财政年份:2010
- 资助金额:
$ 53.13万 - 项目类别:
Inflammation as a Mediator of Dynamic DNA Mutations
炎症作为动态 DNA 突变的中介
- 批准号:
8272599 - 财政年份:2010
- 资助金额:
$ 53.13万 - 项目类别:
Inflammation as a Mediator of Dynamic DNA Mutations
炎症作为动态 DNA 突变的中介
- 批准号:
8146923 - 财政年份:2010
- 资助金额:
$ 53.13万 - 项目类别:
GENETIC PROPERTIES OF DNA DAMAGE INDUCED BY PEROXYNITRITE
过氧亚硝酸盐引起的 DNA 损伤的遗传特性
- 批准号:
7960147 - 财政年份:2009
- 资助金额:
$ 53.13万 - 项目类别:
MUTAGENESIS AND TOXICITY OF PEROXYNITRITE-INDUCED DNA LESIONS IN HUMAN CELLS
过氧亚硝酸盐引起的人类细胞 DNA 损伤的诱变和毒性
- 批准号:
7725168 - 财政年份:2008
- 资助金额:
$ 53.13万 - 项目类别: