Regulation of IL-6 and DNA and RNA methylation by PM-induced mitochondrial ROS
PM 诱导的线粒体 ROS 对 IL-6 以及 DNA 和 RNA 甲基化的调节
基本信息
- 批准号:8927841
- 负责人:
- 金额:$ 25.42万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-05-01 至 2017-04-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAir PollutionAlveolarAlveolar MacrophagesAnimalsAntioxidantsBiologicalBlood VesselsBreathingCardiovascular systemCell SeparationCessation of lifeChemical DynamicsChronicComplexCytosineDNADNA MethylationDNA Modification MethylasesDNA Modification ProcessDataDevelopmentDoseEngineeringEnvironmental HealthEnzymesEpigenetic ProcessEpithelial CellsEtiologyEventExposure toFlow CytometryGene ExpressionGene Expression ProfileGenerationsGenesGenetic TranscriptionGenomeHealthIn VitroIndividualInterleukin-6LabelLinkLongevityLungMeasurementMeasuresMessenger RNAMethodsMethylationMitochondriaModificationMolecularMusMyocardial InfarctionOxidantsOxidation-ReductionParticulate MatterPathway interactionsPhasePlayPopulationProductionRNARNA methylationRegulationRegulatory ElementReportingResolutionResourcesStrokeTestingThrombosisTissuesToxic effectTransgenic Miceair filterbaseenvironmental stressorgenome-wideglobal environmentin vivomRNA Expressionmacrophagemethylation patternmonocyteoxidationphase changeprematureprotein expressionpublic health relevanceresponsesealtooltranscription factor
项目摘要
DESCRIPTION (provided by applicant): Particulate matter (PM) air pollution is a global environmental health problem that causes 800K premature deaths per year worldwide largely due to increased acute thrombotic cardiovascular events. This team has discovered that PM induces a prothrombotic state and accelerates vascular thrombosis via mitochondrial ROS-dependent release of IL-6 from lung macrophages. While using a standard reductionist approach data was generated to show that mitochondrial ROS-induced release of IL-6 plays a key role in PM-induced toxicity. This data and that from other labs suggest that PM alters gene transcription through complex pathways, including epigenetic modifications. However, it is not known whether PM induces epigenetic changes via mitochondrial ROS. Dynamic chemical modifications of DNA by cytosine methylation (5mC) and hydroxymethylation (5hmC) represent a fundamental mechanism of biological regulation. In preliminary studies in alveolar macrophages, it was observed that PM causes loss of DNA methylation characterized by a reduction in 5mC and an increase in 5hmC, which could be reversed by an antioxidant. It was also found that PM increased Tet1 but decreased DNMT1 expression in alveolar macrophages. To specifically examine the links between mitochondrial ROS and DNA and RNA methylation in alveolar macrophages, a transgenic mouse was engineered that expresses a mitochondrial-targeted redox sensitive GFP (mito-roGFP), which allows one to isolate macrophages in which exposure to physiologically relevant concentrations of inhaled PM has increased the generation of mitochondrial ROS and compare them with unaffected macrophages. In the R21 phase, this tool will be exploited to test the hypothesis that PM-induced mitochondrial ROS alter IL-6 DNA and RNA methylation to regulate expression and determine whether PM-induced mitochondrial ROS regulate DNA/RNA methylation of the il-6 gene and its transcriptional regulators in alveolar macrophages (R21 Aim 1) in vitro and (R21 Aim 2) in vivo. The increased resources in the R33 phase will allow the analysis to be expanded to examine genome- and transcriptome-wide changes in DNA and RNA methylation patterns. To demonstrate causality, in the R33 phase, these changes will be measured in animals treated with mitochondrial-targeted antioxidants. To demonstrate the biologic importance of these findings, this approach will be used to determine whether the stochastic replacement of tissue-resident macrophages with monocyte-derived macrophages over the lifespan might explain why some individuals are more susceptible to PM-induced toxicity. Using a unique toolset to genetically label these different alveolar macrophage populations, the hypothesis that these distinct macrophage populations respond differentially to PM in their mito- ROS production, and DNA/RNA methylation profiles will be interrogated. In the R33 Aim 1, a determination of whether mitochondrial ROS are required for PM-induced changes in genome-wide DNA and transcriptome-wide RNA methylation in macrophages in vivo will be performed. In Aim 2, an examination as to how PM-induced mitochondrial ROS and changes in DNA/RNA methylation profiles differ in tissue-resident and monocyte-derived alveolar macrophages will be addressed.
描述(由申请人提供):颗粒物(PM)空气污染是一个全球性环境健康问题,每年在全球范围内导致80万人过早死亡,主要是由于急性血栓性心血管事件增加。该研究小组发现,PM通过肺巨噬细胞线粒体ROS依赖性释放IL-6诱导血栓前状态并加速血管血栓形成。虽然使用标准的还原论方法,但产生的数据表明线粒体ROS诱导的IL-6释放在PM诱导的毒性中起关键作用。这些数据和其他实验室的数据表明,PM通过复杂的途径改变基因转录,包括表观遗传修饰。然而,尚不清楚PM是否通过线粒体ROS诱导表观遗传变化。胞嘧啶甲基化(5 mC)和羟甲基化(5 hmC)对DNA的动态化学修饰代表了生物调节的基本机制。在肺泡巨噬细胞的初步研究中,观察到PM导致DNA甲基化的丧失,其特征在于5 mC的减少和5 hmC的增加,这可以通过抗氧化剂逆转。PM可增加肺泡巨噬细胞Tet 1的表达,但降低DNMT 1的表达。为了具体检查肺泡巨噬细胞中线粒体ROS与DNA和RNA甲基化之间的联系,对转基因小鼠进行工程改造,使其表达靶向细胞的氧化还原敏感性GFP(mito-roGFP),这允许分离其中暴露于生理相关浓度的吸入PM增加了线粒体ROS生成的巨噬细胞,并将其与未受影响的巨噬细胞进行比较。在R21阶段,该工具将被用来检验PM诱导的线粒体ROS改变IL-6 DNA和RNA甲基化以调节表达的假设,并确定PM诱导的线粒体ROS是否在体外(R21 Aim 1)和体内(R21 Aim 2)调节肺泡巨噬细胞中IL-6基因及其转录调节因子的DNA/RNA甲基化。R33阶段增加的资源将允许分析扩展到检查DNA和RNA甲基化模式的基因组和转录组范围内的变化。为了证明因果关系,在R33阶段,这些变化将在用脑靶向抗氧化剂治疗的动物中测量。为了证明这些发现的生物学重要性,这种方法将用于确定在整个生命周期内,单核细胞衍生的巨噬细胞是否会随机替换组织驻留的巨噬细胞,这可能解释为什么一些个体更容易受到PM诱导的毒性的影响。使用独特的工具集对这些不同的肺泡巨噬细胞群体进行遗传标记,将询问这些不同的巨噬细胞群体在其线粒体- ROS产生和DNA/RNA甲基化谱中对PM有差异反应的假设。在R33 Aim 1中,将确定体内巨噬细胞中PM诱导的全基因组DNA和全转录组RNA甲基化变化是否需要线粒体ROS。在目标2中,将研究PM诱导的线粒体活性氧和DNA/RNA甲基化谱变化在组织驻留和单核细胞衍生的肺泡巨噬细胞中的差异。
项目成果
期刊论文数量(0)
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CHUAN HE的其他文献
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