Rhinovirus (RV) lower respiratory infection in early childhood, such as RV bronchiolitis, is associated with a high risk of incident asthma. However, it remains unclear which infants with RV bronchiolitis will develop asthma and which will not; this knowledge gap has hindered primary prevention efforts. Our long-term goal is to develop primary prevention interventions for infants at high risk of asthma. The overall objective of this R21 application is, in the airway of 151 infants hospitalized with RV bronchiolitis, to discover modifiable factors that predict incident asthma. We will achieve this objective by using the biorepository from a 17-center, prospective cohort study called the 35th Multicenter Airway Research Collaboration (MARC-35) (U01 AI- 87881; Camargo, PI) that completed enrollment of 925 infants hospitalized with bronchiolitis. In this diverse U.S. cohort (~52% African-American or Hispanic), investigators have collected nasopharyngeal aspirate at the index hospitalization. Follow-up data include biannual parent interviews and annual review of medical records, which provide >90% follow-up to date. For timing reasons, the primary outcome of this R21 application is physician-diagnosed asthma by age 4 years. The central hypothesis is that, in the 151 infants with RV bronchiolitis, activated microRNA (e.g., miR-147b, miR-375) - thymic stromal lymphopoietin (TSLP) - T helper (TH)2 cytokine pathway signaling is a predictor of incident asthma. The hypothesis has been generated from strong preliminary data using the MARC-35 biorepository. The rationale for the proposed research is that identification of very early (infanc) markers of incident asthma will enable early prediction of asthma risk, thereby providing a new and potentially critical window for primary intervention. The central hypothesis will be tested by pursuing two specific aims: 1) To determine the relations of airway cytokines (TSLP, TH2 cytokines) in infants with RV bronchiolitis to risk of incident asthma; and 2) To use a transcriptomic approach to identify a global gene expression profile (i.e., mRNA and microRNA) in the airway of infants with RV bronchiolitis that predicts incident asthma. The approach is highly innovative because the proposed R21 will use specimens of infants during RV infection (median age, 3.7 months) and thereby focus on very early identification of increased asthma risk during a critical period of lung development; and because the study will support a new avenue for primary prevention through developing targeted interventions (e.g., anti-TSLP antibody, microRNA-targeting therapy). The study advances research on the primary prevention of asthma, and matches well with the goals indicated by the 2013 NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases.
Building on an ongoing, 17-center prospective cohort of infants hospitalized with bronchiolitis, the current R21 application will use specimens from the cohort biorepository to examine airway cytokines and transcriptome in the 151 infants with rhinovirus bronchiolitis, with the overall objective to identify novel biomarkers that predict incident asthma. The proposed research is significant because identification of biomarkers in infants will not only enable prediction of asthma risk during a critical period of lung development but it also provides potential targets for intervention. Thus, the proposed research is highly relevant to the NHLBI's objective to develop fundamental knowledge that will advance efforts on the primary prevention of asthma.
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