Project I of this Program Project Grant revised renewal application will address the following hypothesis: HRV wheezing illnesses, working through at least two independent mechanistic pathways, lead to the development of distinct asthma phenotypes that can be characterized immunologically and physiologically and be further modulated over time based on gender and developmental stage of the host. This project will continue prospective immunologic and physiologic asthma phenotyping while simultaneously interrogating two novel findings relating human rhinovirus (HRV) wheezing illnesses to the inception of asthma: preschool HRV wheezing illnesses significantly predict asthma risk at 11 years of age through at least two independent asthma risk pathways that we have termed 17q21 (human chromosomal region) and FceRI (high affinity receptor for IgE antibody) based on their relationships to genetic variation at these loci and to surface expression of FCERI on cord blood mononuclear cells. The mechanisms linking these asthma risk pathways to HRV wheezing and childhood asthma are unclear and of high importance for further study. Project I has been, and will continue to be, the central resource for all projects for the immunologic and physiologic phenotypic characterization in the COAST cohort. It has uncovered alterations in innate immune response patterns that are associated with the frequency and severity of viral respiratory illnesses and loss of lung function related to both HRV infections and gender. Project I will continue to longitudinally evaluate the expression of clinical phenotypes such as persistent wheezing, allergic sensitization, asthma (expression and remission), and atopic dermatitis, and developmentally assess cytokine immune response profiles (using cell culture and state-of-the-art flow cytometry assays) and a variety of physiological measurements including spirometry, impulse oscillometry, fractional exhaled nitric oxide, plethysmography, mannitol challenge and magnetic resonance imaging. The strength of the longitudinal study design and 80% retention rate are critical to understanding the impact of these immunologic and physiologic alterations on changes in asthma prevalence and severity based on age and gender as the cohort approaches puberty and early adulthood.

Public Health Relevance

Asthma is the most common chronic disease in children. As such, understanding mechanisms that lead to asthma inception initially, and exacerbations once the disease is established, is of major relevance in order to better inform the appropriate timing (age and gender) and nature of future prevention studies and to better understand why various therapies may or may not be of benefit to reduce ongoing morbidity and mortality.

National Institute of Health (NIH)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Program Project Review Committee (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Wisconsin Madison
United States
Zip Code
Nakagome, Kazuyuki; Bochkov, Yury A; Ashraf, Shamaila et al. (2014) Effects of rhinovirus species on viral replication and cytokine production. J Allergy Clin Immunol 134:332-41
Thomas, Amy O; Lemanske Jr, Robert F; Jackson, Daniel J (2014) Infections and their role in childhood asthma inception. Pediatr Allergy Immunol 25:122-8
Kloepfer, Kirsten M; Lee, Wai Ming; Pappas, Tressa E et al. (2014) Detection of pathogenic bacteria during rhinovirus infection is associated with increased respiratory symptoms and asthma exacerbations. J Allergy Clin Immunol 133:1301-7, 1307.e1-3
Brockman-Schneider, Rebecca A; Pickles, Raymond J; Gern, James E (2014) Effects of vitamin D on airway epithelial cell morphology and rhinovirus replication. PLoS One 9:e86755
Liggett, Stephen B; Bochkov, Yury A; Pappas, Tressa et al. (2014) Genome sequences of rhinovirus a isolates from wisconsin pediatric respiratory studies. Genome Announc 2:
Bousquet, Jean; Gern, James E; Martinez, Fernando D et al. (2014) Birth cohorts in asthma and allergic diseases: report of a NIAID/NHLBI/MeDALL joint workshop. J Allergy Clin Immunol 133:1535-46
Kruger, Stanley J; Fain, Sean B; Johnson, Kevin M et al. (2014) Oxygen-enhanced 3D radial ultrashort echo time magnetic resonance imaging in the healthy human lung. NMR Biomed 27:1535-41
Guilbert, Theresa W; Bacharier, Leonard B; Fitzpatrick, Anne M (2014) Severe asthma in children. J Allergy Clin Immunol Pract 2:489-500
Campbell, Catarina D; Mohajeri, Kiana; Malig, Maika et al. (2014) Whole-genome sequencing of individuals from a founder population identifies candidate genes for asthma. PLoS One 9:e104396
Basta, Holly A; Ashraf, Shamaila; Sgro, Jean-Yves et al. (2014) Modeling of the human rhinovirus C capsid suggests possible causes for antiviral drug resistance. Virology 448:82-90

Showing the most recent 10 out of 79 publications