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(由申请人提供):哮喘和过敏性鼻炎是美国儿童最常见的慢性疾病,是主要的公共卫生问题。儿童哮喘的特征是可变的气流阻塞和气道炎症,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对儿童气道和免疫功能、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Viva项目中,生命头两年喘息风险增加与胎儿暴露于氧化应激/炎症来源(肥胖、吸烟、交通污染和对乙酰氨基酚)的风险较高相关。相反,产前母亲抗氧化剂饮食摄入量较高可降低早期喘息风险。凭借12年的纵向数据,Project Viva拥有最佳设计,以评估这些胎儿暴露是否具有长期的不良影响,或者在抗氧化剂的情况下,对持续到青春期的哮喘或气道炎症的保护作用。我们假设如下:(1)在12岁时,较低的胎儿暴露于膳食抗氧化剂和较高的胎儿/幼儿暴露于这些氧化应激/炎症来源将(a)增加过敏性鼻炎和活动性哮喘的风险;和(B)与12岁中期的表型有关,包括鼻细胞的差异DNA甲基化、呼出一氧化氮(FeNO)分数和气流阻塞。(2)鼻细胞的差异DNA甲基化不仅与过敏性鼻炎有关,还与FeNO和活动性哮喘有关。最后,(3)胎儿期母体膳食抗氧化剂和氧化应激/炎症来源与12岁时鼻和肺结果的关系将通过脐带血中的以下生物标志物来捕获:(a)先天性和肥胖相关途径中的促炎和抗炎生物标志物[可溶性TNF-α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]和(B)通过Illumina 450 K BeadChip进行的基因组规模扫描中脐带血的差异甲基化。我们将在相同的鼻细胞标本中验证顶部鼻细胞甲基化标记对基因表达的作用。除了进行外部复制外,我们还将在哮喘桥项目中外部验证脐带血和鼻细胞中最高甲基化标记对基因表达的作用-这是一个生物储存库,具有来自血液,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变暴露的表观遗传、炎症和异质性临床呼吸反应的纵向进展,本研究将为制定预防和靶向治疗哮喘和过敏性疾病的策略做出独特贡献。
项目成果
期刊论文数量(0)
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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
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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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