Nasal microRNA during bronchiolitis and age 6y asthma phenotypes: MARC-35 cohort

细支气管炎和 6 岁哮喘表型期间的鼻 microRNA：MARC-35 队列

• 批准号: 10062795
• 负责人: CARLOS A. CAMARGO
• 金额: $ 123.54万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-06 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10062795
• 关键词: 5 year old; 6 year old; Adult; Affect; African American; Age; Asthma; Blood specimen; Bronchiolitis; Cells; Cellular Structures; ChIP-seq; Child; Childhood Asthma; Clinical; Cohort Studies; Collaborations; Complex; DNA Binding; Data; Development; Diagnosis; Disease; Early identification; Enrollment; Environment; Environmental Exposure; Epigenetic Process; Funding; Future; Gene Expression; Genetic Predisposition to Disease; Heterogeneity; Hispanics; Hospitalization; Immune; Immune response; Immunologics; Infant; Infection; Inflammatory; Influenza; International; Intervention; Interview; Knowledge; Link; Literature; Measures; Mediator of activation protein; Medical Records; Messenger RNA; Methods; MicroRNAs; Molecular; National Institute of Allergy and Infectious Disease; Natural experiment; Nose; Outcome; Parents; Participant; Pathogenesis; Pathologic; Persons; Phenotype; Positioning Attribute; Prevention strategy; Primary Prevention; Prospective cohort; Prospective cohort study; Proteins; Recurrence; Research; Research Personnel; Rhinovirus; Risk; Risk Factors; Sampling; Signal Transduction; Strategic Planning; Structural Protein; Sum; Swab; System; Systems Biology; Technology; Testing; Time; United States National Institutes of Health; Viral; Viral Respiratory Tract Infection; Virus; Wheezing; airway epithelium; asthma prevention; asthmatic; base; biobank; chemokine; clinical phenotype; cohort; critical period; cytokine; differential expression; evidence base; follow-up; high risk; high risk population; indexing; infancy; inhibitor/antagonist; innovation; lung development; modifiable risk; nano-string; nasal swab; novel; phenotypic data; prevent; preventive intervention; prospective; response; sex; targeted treatment; therapeutic target

1 PROJECT SUMMARY / ABSTRACT (~30 lines) 2 Bronchiolitis is the #1 cause of hospitalization in US infants, with ~130,000 hospitalizations 3 annually. Small cohort studies (n<210) suggest that 40-50% of infants hospitalized with 4 bronchiolitis will subsequently develop asthma. The greatest challenges for developing primary 5 prevention strategies for this large group of children are the very early identification of 6 modifiable risk factors and the heterogeneity of asthma. The 35th Multicenter Airway Research 7 Collaboration (MARC-35) study (U01AI-87881; Camargo, PI) is a 17-center prospective cohort 8 study that completed enrollment of 921 hospitalized infants with bronchiolitis in 2014. In this 9 diverse cohort (53% African-American or Hispanic), investigators have collected biospecimens, 10 including nasal swabs at the index hospitalization (median age 3 months). Follow-up data 11 include biannual parent interviews and medical records to age 5 years, with >90% follow-up to 12 date. This competitive renewal would extend this largest, most comprehensive severe 13 bronchiolitis cohort in the world by conducting an in-person examination at age 6 years to 14 diagnose and phenotype asthma and by examining nasal airway microRNA and NFκB signaling 15 mediators/outcomes, at both the index hospitalization and at age 6 years. In Aim 1, we will 16 identify nasal airway microRNAs that are prospectively associated with asthma at age 6 years. 17 In Aim 2, we will determine the inter-relations among airway microRNAs and inflammatory 18 response (e.g., NFκB signaling) and their integrated contributions to risk of incident asthma. 19 Pilot data provide compelling support for our hypotheses. Lastly, using a systems biology 20 approach, Aim 3 will define asthma endotypes by integrating clinical phenotype and molecular 21 data (e.g., airway microRNAs and NFκB signaling) at age 6 years. Among these infants with 22 severe bronchiolitis – a natural experiment – we will have a unique opportunity to identify airway 23 microRNAs associated with incident asthma during an important period of lung development 24 that would provide a critical window for primary intervention. Furthermore, using innovative 25 approaches, we will not only investigate underlying mechanisms linking bronchiolitis to incident 26 asthma (e.g., enhanced NFκB signaling) but also identify phenotypes/endotypes of asthma that 27 are likely to respond differently to different interventions. The study will provide a strong 28 evidence base for primary prevention through the future development of targeted interventions 29 (e.g., microRNA-targeting therapy). The investigators are NIH-funded researchers with 30 international expertise in the field. The study advances research on the primary prevention of 31 childhood asthma, and matches well with the 2013 NIAID Strategic Plan.

1 个项目摘要/摘要（约 30 行） 2 细支气管炎是美国婴儿住院的第一大原因，约有 130,000 名婴儿住院 每年 3 次。小队列研究 (n<210) 表明 40-50% 的婴儿因以下原因住院 4.细支气管炎随后会发展为哮喘。发展初级教育面临的最大挑战 针对这一大群儿童的 5 项预防策略是及早识别 6 个可改变的危险因素和哮喘的异质性。第35届多中心气道研究 7 合作 (MARC-35) 研究（U01AI-87881；Camargo，PI）是一项 17 个中心的前瞻性队列 8 研究于 2014 年完成了 921 名患有细支气管炎住院婴儿的入组。 9 个不同的队列（53% 为非裔美国人或西班牙裔），研究人员收集了生物样本， 10 包括首次住院时的鼻拭子（中位年龄 3 个月）。后续数据 11 包括每年两次的家长访谈和 5 岁之前的医疗记录，其中超过 90% 的随访 12 日期。此次竞争性更新将延续这一规模最大、最全面的严厉措施 通过在 6 岁时进行现场检查，对世界上 13 个细支气管炎队列进行了研究 14 通过检查鼻气道 microRNA 和 NFκB 信号来诊断和表型哮喘 15 个中介/结果，分别在住院指数和 6 岁时。在目标 1 中，我们将 16 发现鼻气道 microRNA 可能与 6 岁时的哮喘相关。 17 在目标 2 中，我们将确定气道 microRNA 与炎症之间的相互关系 18 反应（例如 NFκB 信号传导）及其对哮喘事件风险的综合贡献。 19 试点数据为我们的假设提供了令人信服的支持。最后，利用系统生物学 20 方法，目标 3 将通过整合临床表型和分子水平来定义哮喘内型 6 岁时的 21 个数据（例如气道 microRNA 和 NFκB 信号传导）。在这些婴儿中 22 严重细支气管炎 – 自然实验 – 我们将有一个独特的机会来识别气道 23 个 microRNA 与肺部发育重要时期的哮喘发作相关 24 这将为初级干预提供一个关键窗口。此外，利用创新 25 种方法，我们不仅会研究细支气管炎与事件之间联系的潜在机制 26 哮喘（例如，增强的 NFκB 信号传导），还可以识别哮喘的表型/内型 27 可能对不同的干预措施有不同的反应。该研究将提供强有力的 28 通过未来制定有针对性的干预措施进行一级预防的证据基础 29（例如，microRNA 靶向治疗）。研究人员是 NIH 资助的研究人员 30 位该领域的国际专家。该研究推进了一级预防的研究 31 儿童哮喘，与 2013 年 NIAID 战略计划非常吻合。