The Fetal and Childhood Environment, Oxidative Balance, Inflammation and Asthma
胎儿和童年环境、氧化平衡、炎症和哮喘
基本信息
- 批准号:9057454
- 负责人:
- 金额:$ 79.18万
- 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:2013-06-20 至 2018-05-31
- 项目状态:已结题
- 来源:
- 关键词:AcetaminophenAdolescenceAgeAllergicAllergic DiseaseAllergic rhinitisAlveolarAlveolar MacrophagesAnti-Inflammatory AgentsAnti-inflammatoryAntioxidantsAsthmaBiological MarkersBloodC-reactive proteinCellsCharacteristicsChildChildhoodChildhood AsthmaChronic DiseaseClinicalDNADNA MethylationDataDevelopmentDietDietary intakeDiseaseEmergency department visitEnvironmentEnvironmental ExposureEpigenetic ProcessEquilibriumExhalationExposure toExtrinsic asthmaFetal DevelopmentGene ExpressionGeneticGenomeGrowthHealthHospitalizationHypersensitivityImmuneInfant DevelopmentInflammationInflammatoryInflammatory ResponseInsulin-Like Growth Factor IInterleukin-6LeptinLifeLinkLong-Term EffectsLungLung diseasesMeasuresMediationMediator of activation proteinMethylationNitric OxideNoseObesityObstructionOutcomeOverweightOxidative StressOxidative Stress PathwayPathway interactionsPerinatal ExposurePhenotypePollutionPregnancyPrevention strategyPublic HealthPulmonary InflammationReactive Oxygen SpeciesRhinitisRiskScanningSourceSpecimenSymptomsTestingTimeTumor Necrosis Factor ReceptorUmbilical Cord BloodUnited StatesWheezingWorkadiponectinairway inflammationbead chipbiobankbronchial epitheliumcigarette smokingcytokinedesigndietary antioxidantdisorder riskearly childhoodexposure pathwayfetalfollow-upgenome-wideimmune functioninflammatory markeroutcome predictionprenatalpreventprimary outcomeprogramsprotective effectrespiratoryresponsestressortargeted treatmenttrafficking
项目摘要
DESCRIPTION (provided by applicant): Asthma and allergic rhinitis, the most common chronic diseases of childhood in the United States, are major public health problems. Characterized by variable airflow obstruction and airway inflammation, childhood asthma is thought to have its origins in fetal and infant development. Environmental exposures influencing oxidative balance during critical time windows may have long-lasting effects on child airway and immune function, epigenetic programming of inflammation, and consequent risk of symptomatic asthma. In Project Viva, increased wheeze risk in the first two years of life was associated with higher fetal life exposures to sources of oxidative stress/inflammation (adiposity, cigarette smoke, traffic pollution, and acetaminophen). Conversely, higher prenatal maternal antioxidant dietary intake reduced early-life wheeze risk. With 12 years of longitudinal data, Project Viva has the best design to assess whether these fetal exposures have long-lasting adverse or, in the case of antioxidants, protective effects against asthma or airway inflammation that persist into adolescence. We hypothesize the following: (1) At age 12, lower fetal life exposure to dietary antioxidants and higher fetal life/early childhood exposure to these sources of oxidative stress/inflammation will (a) increase risk of allergic rhinitis and active asthma; and (b) be relatd to intermediate age 12 phenotypes including differential DNA methylation of nasal cells, fractional exhaled nitric oxide (FeNO), and airflow obstruction. (2) Differential DNA methylation of nasal cells will relate, not only to allergic rhinitis, but also to FeNO and active asthma. Finaly, (3) The relation of fetal life maternal dietary antioxidants and sources of oxidative stress/inflammation with nasal and pulmonary outcomes at age 12 will be captured by the following biomarkers in cord blood (a) Pro- and anti-inflammatory biomarkers in innate- and adiposity-related pathways [soluble TNF-¿ receptor-II, IL-6, and C-reactive protein; leptin and insulin-like growth factors I and II] and (b) Differential methylation of cord blood in genome-scal scans by the Illumina 450K BeadChip. We will validate the function of top nasal cell methylation marks on gene expression in the same nasal cell specimens. As well as performing external replication, we will externally validate the function of the top methylation marks in cord blood and nasal cells on gene expression in the Asthma BRIDGE project - a biorepository with methylation and gene expression data from blood, pulmonary macrophages and bronchial epithelium. By defining the longitudinal progression of epigenetic, inflammatory, and heterogeneous clinical respiratory responses to modifiable exposures influencing oxidative balance, this study will make a unique contribution to development of strategies for prevention and targeted treatment of asthma and allergic disease.
描述(申请人提供):哮喘和过敏性鼻炎是美国最常见的儿童慢性病,是主要的公共卫生问题。以可变气流阻塞和呼吸道炎症为特征的儿童哮喘被认为起源于胎儿和婴儿的发育。在关键时间窗内影响氧化平衡的环境暴露可能会对儿童的呼吸道和免疫功能、炎症的表观遗传编程以及随后的症状性哮喘风险产生长期影响。在Project Viva中,出生后头两年喘息风险的增加与胎儿一生中接触氧化应激/炎症来源(肥胖、香烟烟雾、交通污染和对乙酰氨基酚)的增加有关。相反,较高的产前母体抗氧化剂饮食摄入量可降低早期喘息风险。凭借12年的纵向数据,Project Viva拥有最佳的设计,可以评估这些胎儿暴露在环境中是否具有长期的不良影响,或者对于抗氧化剂,是否具有预防哮喘或持续到青春期的呼吸道炎症的保护作用。我们假设:(1)在12岁时,胎儿一生中较低的饮食抗氧化剂暴露和较高的胎儿生活/儿童早期氧化应激/炎症源暴露将(A)增加变应性鼻炎和活动性哮喘的风险;以及(B)与中年12岁的表型有关,包括鼻细胞的不同DNA甲基化、部分呼出的一氧化氮(FeNO)和气流阻塞。(2)鼻细胞DNA甲基化的差异不仅与变应性鼻炎有关,而且与FeNO和活动性哮喘有关。最后,(3)胎儿生命、母亲饮食抗氧化剂、氧化应激/炎症来源与12岁时鼻部和肺部结果的关系将被脐带血中的下列生物标记物捕捉到:(A)天然和肥胖相关途径中的促炎和抗炎生物标记物[可溶性肿瘤坏死因子受体II、IL-6和C反应蛋白;瘦素和胰岛素样生长因子I和II];以及(B)Illumina 450K BeadChip在基因组扫描中对脐带血的差异甲基化。我们将验证顶级鼻细胞甲基化标记对同一鼻细胞样本中基因表达的作用。除了进行外部复制,我们还将在哮喘桥项目中外部验证脐带血和鼻腔细胞中最高甲基化标记对基因表达的作用-这是一个生物信息库,包含来自血液、肺巨噬细胞和支气管上皮的甲基化和基因表达数据。通过定义影响氧化平衡的可改变暴露的表观遗传学、炎症性和异质性临床呼吸道反应的纵向进展,这项研究将为制定哮喘和过敏性疾病的预防和靶向治疗策略做出独特的贡献。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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{{ truncateString('DIANE R GOLD', 18)}}的其他基金
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在受控人体暴露中对 CAP 微生物成分的心血管反应
- 批准号:
8805972 - 财政年份:2015
- 资助金额:
$ 79.18万 - 项目类别:
Cardiovascular Response to CAP Microbial Components in Controlled Human Exposures
在受控人体暴露中对 CAP 微生物成分的心血管反应
- 批准号:
8995662 - 财政年份:2015
- 资助金额:
$ 79.18万 - 项目类别:
The Fetal and Childhood Environment, Oxidative Balance, Inflammation and Asthma
胎儿和童年环境、氧化平衡、炎症和哮喘
- 批准号:
9278076 - 财政年份:2013
- 资助金额:
$ 79.18万 - 项目类别:
The Fetal and Childhood Environment, Oxidative Balance, Inflammation and Asthma
胎儿和童年环境、氧化平衡、炎症和哮喘
- 批准号:
8584430 - 财政年份:2013
- 资助金额:
$ 79.18万 - 项目类别:
The Fetal and Childhood Environment, Oxidative Balance, Inflammation and Asthma
胎儿和童年环境、氧化平衡、炎症和哮喘
- 批准号:
8685884 - 财政年份:2013
- 资助金额:
$ 79.18万 - 项目类别:
The Fetal and Childhood Environment, Oxidative Balance, Inflammation and Asthma
胎儿和童年环境、氧化平衡、炎症和哮喘
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8851510 - 财政年份:2013
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