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: 8851510
• 负责人: DIANE R GOLD
• 金额: $ 79.38万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-20 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8851510
• 关键词: Acetaminophen; Adolescence; Age; Allergic; Allergic Disease; Allergic rhinitis; Alveolar; Alveolar Macrophages; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Asthma; Biological Markers; Blood; C-reactive protein; Cells; Characteristics; Child; Childhood; Childhood Asthma; Chronic Disease; Clinical; DNA; DNA Methylation; Data; Development; Diet; Dietary intake; Disease; Emergency department visit; Environment; Environmental Exposure; Epigenetic Process; Equilibrium; Exhalation; Exposure to; Extrinsic asthma; Fetal Development; Gene Expression; Genetic; Genome; Growth; Health; Hospitalization; Hypersensitivity; Immune; Infant Development; Inflammation; Inflammatory; Inflammatory Response; Insulin-Like Growth Factor I; Interleukin-6; Leptin; Life; Link; Long-Term Effects; Lung; Lung diseases; Measures; Mediation; Mediator of activation protein; Methylation; Nitric Oxide; Nose; Obesity; Obstruction; Outcome; Overweight; Oxidative Stress; Oxidative Stress Pathway; Pathway interactions; Perinatal Exposure; Phenotype; Pollution; Pregnancy; Prevention strategy; Public Health; Pulmonary Inflammation; Reactive Oxygen Species; Rhinitis; Risk; Scanning; Source; Specimen; Symptoms; Testing; Time; Tumor Necrosis Factor Receptor; Umbilical Cord Blood; United States; Wheezing; Work; adiponectin; airway inflammation; bead chip; biobank; bronchial epithelium; cigarette smoking; cytokine; design; dietary antioxidant; disorder risk; early childhood; exposure pathway; fetal; follow-up; genome-wide; immune function; inflammatory marker; prenatal; prevent; primary outcome; programs; protective effect; respiratory; response; stressor; targeted treatment; trafficking

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。儿童哮喘以可变气流阻塞和气道炎症为特征，被认为起源于胎儿和婴儿的发育。在关键时间窗口内影响氧化平衡的环境暴露可能会对儿童气道和免疫功能、炎症的表观遗传编程以及随之而来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的增加与胎儿生命中接触氧化应激/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，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，可以评估这些胎儿暴露是否会产生长期的不利影响，或者对于抗氧化剂而言，是否会产生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，胎儿生命中接触膳食抗氧化剂的时间较短，而胎儿生命/幼儿期接触这些氧化应激/炎症来源的时间较长，将 (a) 增加过敏性鼻炎和活动性哮喘的风险； (b) 与 12 岁中年表型相关，包括鼻细胞 DNA 甲基化差异、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，而且与FeNO和活动性哮喘有关。最后，(3) 胎儿生命、母体膳食抗氧化剂和氧化应激/炎症来源与 12 岁时鼻腔和肺部结局的关系将通过脐带血中的以下生物标志物来捕获 (a) 先天和肥胖相关途径中的促炎和抗炎生物标志物 [可溶性 TNF-¿ 受体-II、IL-6 和 C 反应性 蛋白质;瘦素和类胰岛素生长因子 I 和 II] 和 (b) Illumina 450K BeadChip 进行的基因组规模扫描中脐带血的差异甲基化。我们将验证顶部鼻细胞甲基化标记对同一鼻细胞样本中基因表达的功能。除了进行外部复制外，我们还将在 Asthma BRIDGE 项目（一个包含来自血液、肺巨噬细胞和支气管上皮的甲基化和基因表达数据的生物存储库）中外部验证脐带血和鼻细胞中顶部甲基化标记对基因表达的功能。通过定义表观遗传、炎症和异质临床呼吸反应对影响氧化平衡的可改变暴露的纵向进展，这项研究将为哮喘和过敏性疾病的预防和靶向治疗策略的制定做出独特的贡献。