Determinants of Asthma Following RSV Bronchiolitis in Early Life

早期 RSV 细支气管炎后哮喘的决定因素

• 批准号: 8119612
• 负责人: Leonard B Bacharier
• 金额: $ 74.26万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-13 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8119612
• 关键词: Acute; Age; Allergic; Asthma; Boston; Bronchiolitis; Candidate Disease Gene; Case-Control Studies; Characteristics; Child; Childhood; Collaborations; Data; Development; Diagnosis; Disease; Enrollment; Environmental Exposure; Epithelial Cells; Etiology; Extrinsic asthma; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Hypersensitivity; Immune response; Immune system; Immunologics; Incidence; Infant; Infection; Inflammation; Inflammatory Response; Life; Parents; Pediatric Hospitals; Phenotype; Population; Predictive Value; Predisposition; RANTES; Regulatory T-Lymphocyte; Reporting; Severities; Testing; Wheezing; airway hyperresponsiveness; atopy; cohort; experience; gene environment interaction; improved; indexing; prospective; public health relevance

DESCRIPTION (provided by applicant): We aim to prospectively define how specific genetic, biologic, and immunologic characteristics, along with environmental exposures, interact in children who experience severe RSV bronchiolitis early in life impact the subsequent development of asthma, airway hyperreactivity and allergy. Specifically, we will utilize a well- established cohort of children with severe RSV bronchiolitis that has been prospectively followed since 1998 (RSV Bronchiolitis in Early Life, RBEL-I, n=206), a retrospectively identified cohort of children with severe RSV bronchiolitis (Boston RSV Bronchiolitis cohort, n=200), and test our key findings from RBEL-I in a newly enrolled prospective cohort of infants with severe RSV bronchiolitis (RBEL-II, n=200). These cohorts will be the largest to date, with over 600 children with severe RSV bronchiolitis, and will enable us to test new hypotheses on the causation of asthma and allergic disorders early in life. We will be able to evaluate and confirm over 1500 polymorphisms in candidate genes associated with asthma, airway hyperreactivity, allergic sensitization and RSV susceptibility in three separate populations. We now propose to prospectively test the validity of the newly developed RSV-Asthma Predictive Index (RAPI) in this cohort as well as potentially modify this index to improve its predictive value. We will prospectively evaluate our findings of a dysregulated immune system associated with the development of asthma post-RSV bronchiolitis in RBEL-II. In concert with understanding the biologic and immunologic response of the host during and after severe RSV bronchiolitis, we are now proposing a powerful study of candidate genes associated with susceptibility to RSV and the development of asthma, airway hyperreactivity and allergic sensitization in the combined RBEL and Boston cohorts with over 600 children as well as their parent(s). Given the careful characterization of these children early in life, we will now be able to study potential gene-gene and gene-environment interactions leading to the development of different wheezing phenotypes in childhood. Our overall hypothesis is that children who experience severe RSV bronchiolitis in the context of the appropriate genetic predisposition, have a dysfunctional immune response that predisposes them to develop airway hyperreactivity and asthma. Accordingly, we propose to: Aim I: Evaluate prospectively the validity of a RSV-Asthma Predictive Index (RAPI) on the development of asthma and persistent wheezing following severe RSV bronchiolitis. Aim II: Evaluate prospectively the impact of a dysregulated immune system, specifically dendritic and regulatory T cells, on the development of asthma, persistent wheezing and allergic sensitization following severe RSV bronchiolitis. Aim III: Examine the relationships of ~1500 polymorphisms in genes associated with asthma, atopy, inflammation with the development of asthma, airway hyperreactivity, and allergic sensitization following severe RSV bronchiolitis. PUBLIC HEALTH RELEVANCE: We aim to prospectively define how specific genetic, biologic, and immunologic characteristics, along with environmental exposures, interact in children who experience severe RSV bronchiolitis early in life on the subsequent development of asthma, airway hyperreactivity and allergy. This study will be the largest to date, consisting of over 600 children with severe RSV bronchiolitis, and will enable us to test new hypotheses on the causation of asthma and allergic disorders early in life.

描述（由申请人提供）：我们的目的是前瞻性地定义特定的遗传，生物学和免疫学特征以及环境暴露，以及在生命早期经历严重RSV支气管炎的儿童中相互作用，影响了随后的哮喘，呼吸道高反应性和过敏性。 Specifically, we will utilize a well- established cohort of children with severe RSV bronchiolitis that has been prospectively followed since 1998 (RSV Bronchiolitis in Early Life, RBEL-I, n=206), a retrospectively identified cohort of children with severe RSV bronchiolitis (Boston RSV Bronchiolitis cohort, n=200), and test our key findings from RBEL-I in a新招收的患有严重RSV支气管炎的婴儿的前瞻性队列（RBEL-II，n = 200）。这些队列将是迄今为止最大的，有600多名患有严重的RSV细支气管炎的儿童，并将使我们能够在生命早期就哮喘和过敏性疾病的因果关系进行新的假设。我们将能够评估并确认与哮喘相关的候选基因，气道高反应性，过敏敏化和RSV敏感性相关的候选基因中的1500多种多态性。现在，我们建议在该队列中前瞻性地测试新开发的RSV-哮喘预测指数（RAPI）的有效性，并有可能修改该指数以提高其预测价值。我们将前瞻性地评估与RBEL-II中哮喘后RSV细支气管炎的发育相关的失调免疫系统的发现。为了了解宿主在严重的RSV细支气管炎期间和之后宿主的生物学和免疫反应，我们现在提出对与RSV易感性相关的候选基因以及哮喘的易感性，AIRWAM高反应性的发展，合并的RBEL和Boston Cohorts在与600多个父母及其父母及其父母及其父母（S）中的哮喘性高反应性和过敏性敏感性相关的研究。鉴于这些儿童在生命的早期的仔细表征，我们现在将能够研究潜在的基因基因和基因环境相互作用，从而导致童年时期不同喘息表型的发展。我们的总体假设是，在适当的遗传易感性的背景下经历了严重的RSV支气管炎的儿童具有功能失调的免疫反应，使他们倾向于发展气道高反应性和哮喘。因此，我们建议：目标I：在严重的RSV细支气管炎之后，RSV-哮喘预测指数（RAPI）对哮喘和持续性喘息的发展的前瞻性评估。 AIM II：前瞻性评估免疫系统失调的影响，特别是树突状和调节性T细胞对严重的RSV支气管炎后哮喘，持续性喘息和过敏敏化的发展。 AIM III：检查与哮喘，哮喘发育，气道高反应性和严重的RSV细支气管炎相关的基因，特应性，炎症，炎症，炎症，炎症，炎症，炎症，炎症，炎症。 公共卫生相关性：我们旨在前瞻性地定义特定的遗传，生物学和免疫学特征以及环境暴露，以及在随后的哮喘，气道高反应性和过敏性的儿童中经历严重的RSV支气管炎的儿童相互作用。这项研究将是迄今为止最大的一项，由600多名患有严重RSV细胞炎的儿童组成，并将使我们能够在生命早期就哮喘和过敏性疾病的因果关系进行新的假设。