The Fetal and Childhood Environment, Oxidative Balance, Inflammation and Asthma

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，是重大的公共卫生问题。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。在关键时间窗期间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之而来的症状性哮喘风险产生长期影响。在Viva项目中，出生头两年的喘息风险增加与胎儿暴露于氧化应激/炎症源（肥胖、香烟烟雾、交通污染和对乙酰氨基酚）的风险增加有关。相反，孕妇产前摄入更多抗氧化剂可降低早期喘息的风险。有了12年的纵向数据，Viva项目有最好的设计来评估这些胎儿暴露是否有长期的不利影响，或者在抗氧化剂的情况下，对哮喘或气道炎症的保护作用持续到青春期。我们的假设如下：(1)在12岁时，较低的胎儿寿命暴露于膳食抗氧化剂和较高的胎儿寿命/儿童早期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；(b)与中等年龄12岁的表型有关，包括鼻细胞的差异DNA甲基化，分数呼出一氧化氮（FeNO）和气流阻塞。(2)鼻腔细胞DNA甲基化的差异不仅与变应性鼻炎有关，还与FeNO和活动性哮喘有关。最后，(3)脐带血中的以下生物标志物将捕获12岁时胎儿寿命、母亲膳食抗氧化剂和氧化应激/炎症来源与鼻腔和肺部结局的关系(a)先天和肥胖相关途径中的促炎性和抗炎性生物标志物[可溶性TNF-¿受体- ii、IL-6和c反应蛋白；(b) Illumina 450K BeadChip在基因组尺度扫描中脐带血的差异甲基化。我们将在相同的鼻细胞样本中验证鼻尖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Asthma BRIDGE项目中从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。Asthma BRIDGE项目是一个来自血液、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。通过定义表观遗传、炎症和异质性临床呼吸反应对影响氧化平衡的可变暴露的纵向进展，本研究将为哮喘和过敏性疾病的预防和靶向治疗策略的发展做出独特的贡献。

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.