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

1个项目摘要/摘要(约30行) 2毛细支气管炎是美国婴儿住院的头号原因，约有13万人次住院 每年3次。小规模队列研究(n&lt；210)表明，40%-50%的婴儿住院时患有 4毛细支气管炎随后会发展成哮喘。发展小学教育面临的最大挑战 针对这一大群儿童的预防策略是非常早地识别 6可改变的危险因素和哮喘的异质性。第35届多中心航道研究 7协作(MARC-35)研究(U01AI-87881；卡马戈，PI)是一个17中心的前瞻性队列 8项研究，2014年完成了921名毛细支气管炎住院婴儿的登记。在这 9个不同的队列(53%是非洲裔美国人或西班牙裔)，调查人员收集了生物标本， 包括鼻拭子在内的10名住院患者(中位年龄为3个月)。跟踪数据 11包括一年两次的家长访谈和5岁以下的医疗记录，&gt；90%的跟踪调查 12号约会。此次竞争性续签将延长这一最大、最全面的严重 世界上13个毛细支气管炎队列通过在6岁到 14诊断和表型哮喘，并通过检测鼻气道微RNA和NFκB信号 15名调解人/结果，在指数住院和6岁时。在目标1中，我们将 16确定预期与6岁时哮喘相关的鼻腔呼吸道微RNA。 17在目标2中，我们将确定呼吸道microRNA和炎症之间的相互关系 18反应(例如，核因子κB信号)及其对哮喘发病风险的综合贡献。 19个试点数据为我们的假设提供了令人信服的支持。最后，使用系统生物学 20方法，目标3将通过结合临床表型和分子来定义哮喘内型 21个数据(例如，呼吸道MicroRNA和NFκB信号)在6岁时。在这些患有 22严重毛细支气管炎--一个自然的实验--我们将有一个独特的机会来识别呼吸道 23个与肺发育重要时期哮喘发病相关的microRNAs 24这将为初级干预提供一个关键的窗口。此外，使用创新的 25种方法，我们将不仅调查毛细支气管炎与事件之间的潜在机制 26哮喘(例如，增强的NFκB信号)，但也识别哮喘的表型/内型 27个可能会对不同的干预措施做出不同的反应。这项研究将提供一个强有力的 28通过未来制定有针对性的干预措施提供初级预防的证据基础 29(例如，microRNA靶向治疗)。调查人员是由美国国立卫生研究院资助的研究人员 30该领域的国际专业知识。这项研究促进了对甲型肝炎一级预防的研究 31儿童哮喘，与2013年NIAID战略计划很好地匹配。

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.