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: 7915723
• 负责人: Leonard B Bacharier
• 金额: $ 75.17万
• 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/7915723
• 关键词: Acute; Age; Allergic; Asthma; Boston; Bronchiolitis; Candidate Disease Gene; Case-Control Studies; Characteristics; Child; Childhood; 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（由申请方提供）：我们的目的是前瞻性地确定特定的遗传、生物学和免疫学特征以及沿着环境暴露如何在生命早期经历重度RSV细支气管炎的儿童中相互作用，从而影响随后哮喘、气道高反应性和过敏的发生。具体来说，我们将利用一个自1998年以来前瞻性随访的已建立的严重RSV毛细支气管炎儿童队列（早期RSV毛细支气管炎，RBEL-I，n=206），一项回顾性确定的重度RSV毛细支气管炎儿童队列（波士顿RSV毛细支气管炎队列，n=200），并在一个新入组的严重RSV毛细支气管炎婴儿前瞻性队列（RBEL-II，n=200）中检验我们从RBEL-I中获得的关键发现。这些队列将是迄今为止最大的，有超过600名患有严重RSV细支气管炎的儿童，并将使我们能够测试关于哮喘和过敏性疾病早期病因的新假设。我们将能够在三个不同的人群中评估和确认与哮喘、气道高反应性、过敏性致敏和RSV易感性相关的候选基因中的1500多个多态性。我们现在建议前瞻性地测试新开发的RSV-哮喘预测指数（RAPI）在该队列中的有效性，并可能修改该指数以提高其预测价值。我们将前瞻性地评估我们在RBEL-II中发现的与RSV毛细支气管炎后哮喘发展相关的免疫系统失调。为了了解宿主在严重RSV细支气管炎期间和之后的生物学和免疫学反应，我们现在提议在超过600名儿童及其父母的RBEL和波士顿联合队列中对与RSV易感性和哮喘、气道高反应性和过敏致敏性发展相关的候选基因进行强有力的研究。鉴于这些儿童在生命早期的仔细表征，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，导致儿童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背景下经历严重RSV细支气管炎的儿童具有功能失调的免疫应答，使其易于发生气道高反应性和哮喘。因此，我们提议：目标一：前瞻性评价RSV哮喘预测指数（RAPI）对重度RSV毛细支气管炎后哮喘和持续喘息发展的有效性。目标二：前瞻性评价免疫系统失调，特别是树突状细胞和调节性T细胞对重度RSV细支气管炎后哮喘、持续性喘息和过敏性致敏的影响。目标三：研究哮喘、特应性、炎症相关基因中约1500个多态性与严重RSV细支气管炎后哮喘、气道高反应性和过敏性致敏的关系。 公共卫生关系：我们的目的是前瞻性地确定特定的遗传、生物学和免疫学特征，沿着环境暴露，如何在生命早期经历严重RSV细支气管炎的儿童中对随后的哮喘、气道高反应性和过敏的发展相互作用。这项研究将是迄今为止规模最大的研究，包括600多名患有严重RSV细支气管炎的儿童，并将使我们能够测试有关哮喘和过敏性疾病早期病因的新假设。