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: 9057454
• 负责人: DIANE R GOLD
• 金额: $ 79.18万
• 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 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9057454
• 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; outcome prediction; 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（由适用提供）：美国最常见的童年慢性疾病是哮喘和过敏性鼻炎，是主要的公共卫生问题。以可变的气流异议和气道感染为特征，童年哮喘被认为起源于胎儿和婴儿发育。在关键时间窗口中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，生命的头两年中的喘息风险增加与胎儿生命的较高暴露有关氧化应激/炎症的来源（肥胖，香烟烟，交通污染和对乙酰氨基氨基酚）。相反，较高的产前抗氧化剂饮食摄入量降低了早期喘息风险。凭借12年的纵向数据，Viva项目具有最佳设计，可以评估这些胎儿暴露是持久的不利还是在抗氧化剂的情况下，对哮喘或气道炎症的保护作用会持续到青少年。我们假设以下情况：（1）在12岁时，胎儿寿命降低饮食抗氧化剂，胎儿寿命较高/儿童早期暴露于这些氧化应激/炎症来源（a）（a）增加过敏性鼻炎和活性哮喘的风险； （b）与中级12个表型相对，包括鼻细胞的差异DNA甲基化，分数耗尽的一氧化氮（Feno）和气流反对反对。 （2）鼻细胞的差异DNA甲基化不仅与过敏性鼻炎有关，还与Feno和活性哮喘有关。最终，（3）胎儿寿命饮食中饮食抗氧化剂以及氧化应激/炎症的来源与12岁时鼻和肺癌的氧化应激/炎症与鼻和肺癌的关系将被脐带血（a）促和抗炎的生物标志物中的以下生物标志物捕获。瘦素和胰岛素样生长因子I和II]和（b）Illumina 450k Beadchip中基因组尺度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品中基因表达的功能。除了进行外部复制外，我们还将在外部验证山脉血液和鼻细胞中顶部甲基化标记在哮喘桥项目中基因表达的功能 - 一种具有甲基化和基因表达数据的生物座，来自血液，肺巨噬细胞和支气中的上皮。通过定义表观遗传，炎症性和异质临床呼吸反应对可修改暴露的纵向进展，影响氧化平衡，这项研究将为预防和针对性治疗哮喘和过敏性疾病的策略做出独特的贡献。