PROJECT SUMMARY Childhood asthma is the most common chronic respiratory condition in the U.S. While epidemiological studies have identified risk factors (e.g., severe bronchiolitis) for childhood asthma, the underlying mechanisms of asthma development (and its different phenotypes) remain poorly understood. This major knowledge gap has hindered efforts to develop asthma prevention strategies. The 35th Multicenter Airway Research Collaboration (MARC-35) study (U01AI087881; Camargo, PI) is an ongoing 17-center cohort study that enrolled 921 hospitalized infants with bronchiolitis (median age, 3 months) during 2011-2014. In this racially/ethnically- and geographically-diverse cohort, investigators have collected high-quality biospecimens, including nasopharyngeal airway and blood samples at the index hospitalization. Follow-up data include biannual parent interviews, medical record reviews, and in-person exam at age 6 years, with ~80% follow-up to date. The present K01 project would extend this large well-characterized bronchiolitis cohort by integrating genome, metabolome, and microbiome (both 16S rRNA gene and metagenomic sequencing) data, which will not only elucidate the mechanisms of incident asthma but also identify its endotypes. In Aim 1, we will determine the integrated relationships of host genome and nasopharyngeal airway metabolome in infancy with asthma development by age 6 years. In Aim 2, we will determine the integrated relationships of host genome and nasopharyngeal airway microbiome (both structure and function) in infancy with the risk of developing asthma by age 6 years. Finally, in Aim 3, we will identify clinically- relevant endotypes of childhood asthma by integrating clinical, immunological (e.g., specific IgE, 25OHD, cytokines), and multi-omics data (i.e., host genome, serum metabolome, and airway microbiome) at age 6 years. Our pilot data provide compelling support to the proposed work. This K01 project will provide a unique opportunity to define the pathobiology of incident asthma through examining the integrative role of genome, metabolome, and microbiome. Furthermore, we will also define childhood asthma endotypes by leveraging multi-omics data in the comprehensively-phenotyped MARC-35 cohort. These findings will lead to the development of endotype-specific prevention strategies for asthma (e.g., through modulation of metabolism pathways and microbiome) during early childhood. The mentoring team consists of NIH-funded researchers with international expertise in all relevant fields. The study matches well with the 2017 NIAID Strategic Plan, which both ultimately aim to prevent allergic diseases, such as asthma.

PROJECT NARRATIVE Asthma is a major public health problem in American children, but effective strategies to prevent the development of childhood asthma are not yet available. In an ongoing, diverse cohort of U.S. children (53% African-American or Hispanic) with a history of severe bronchiolitis, the investigators will elucidate the mechanisms of developing asthma and define subtypes (endotypes) by integrating genome, metabolome, and microbiome data. This research aims to identify novel approaches for primary prevention of childhood asthma.