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.