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: 9215155
• 负责人: CARLOS A. CAMARGO
• 金额: $ 178.62万
• 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 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9215155
• 关键词: 5 year old; 6 year old; Adult; Affect; African American; Age; Asthma; Blood specimen; Bronchiolitis; Cells; ChIP-seq; Child; Childhood Asthma; Clinical; Cohort Studies; Collaborations; Complex; DNA Binding; Data; Development; Diagnosis; Disease; Early identification; Enrollment; Environment; Environmental Exposure; Epigenetic Process; Epithelial; 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; Preventive Intervention; 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; 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; novel; phenotypic data; prevent; 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个项目概要/摘要（约30行） 2细支气管炎是美国婴儿住院的头号原因，约有13万例住院 每年3次。小队列研究（n<210）表明，40-50%的婴儿住院与 4细支气管炎随后会发展为哮喘。发展小学面临的最大挑战 针对这一庞大儿童群体的5项预防战略是， 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协作（MARC-35）研究（U 01 AI-87881; Camargo，PI）是一项17中心前瞻性队列研究 8项研究于2014年完成了921例毛细支气管炎住院婴儿的入组。在这 9个不同的队列（53%的非洲裔美国人或西班牙裔），研究人员收集了生物标本， 10例，包括首次住院时的鼻拭子（中位年龄3个月）。随访数据 11项包括一年两次的父母访谈和5岁以下的医疗记录， 12日这一竞争性的更新将扩大这一最大的，最全面的严重 通过在6岁时进行现场检查， 通过检测鼻气道microRNA和NFκB信号， 15种介质/结局，在首次住院时和6岁时。在目标1中，我们 16确定与6岁时哮喘前瞻性相关的鼻气道microRNA。 17在目标2中，我们将确定气道microRNAs和炎症因子之间的相互关系。 18响应（例如，NFκB信号）及其对哮喘发病风险的综合贡献。 [19]试验数据为我们的假设提供了有力的支持。最后，使用系统生物学 20方法，目标3将通过整合临床表型和分子生物学特征来定义哮喘内型。 21个数据（例如，气道microRNA和NFκB信号）。在这些婴儿中， 22严重的细支气管炎-一个自然的实验-我们将有一个独特的机会，以确定气道 在肺发育的重要时期与哮喘事件相关的23种microRNA 24这将为初级干预提供一个关键窗口。此外，利用创新 25的方法，我们不仅将研究毛细支气管炎与事件之间的潜在机制， 26哮喘（例如，增强NFκB信号传导），而且还鉴定哮喘的表型/内型， 27人可能对不同的干预措施作出不同的反应。这项研究将提供一个强有力的 28通过今后制定有针对性的干预措施进行初级预防的证据基础 29（例如，microRNA靶向治疗）。研究人员是NIH资助的研究人员， 30名国际专家。这项研究推动了对一级预防的研究， 31儿童哮喘，并与2013年NIAID战略计划相匹配。