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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL070831-12
Application #
8743241
Study Section
Heart, Lung, and Blood Program Project Review Committee (HLBP)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
12
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
DUNS #
City
Madison
State
WI
Country
United States
Zip Code
53715
Higano, Nara S; Spielberg, David R; Fleck, Robert J et al. (2018) Neonatal Pulmonary Magnetic Resonance Imaging of Bronchopulmonary Dysplasia Predicts Short-Term Clinical Outcomes. Am J Respir Crit Care Med 198:1302-1311
Stein, Michelle M; Thompson, Emma E; Schoettler, Nathan et al. (2018) A decade of research on the 17q12-21 asthma locus: Piecing together the puzzle. J Allergy Clin Immunol 142:749-764.e3
Bønnelykke, Klaus; Coleman, Amaziah T; Evans, Michael D et al. (2018) Cadherin-related Family Member 3 Genetics and Rhinovirus C Respiratory Illnesses. Am J Respir Crit Care Med 197:589-594
Bashir, Hiba; Grindle, Kristine; Vrtis, Rose et al. (2018) Association of rhinovirus species with common cold and asthma symptoms and bacterial pathogens. J Allergy Clin Immunol 141:822-824.e9
Higano, Nara S; Bates, Alister J; Tkach, Jean A et al. (2018) Pre- and post-operative visualization of neonatal esophageal atresia/tracheoesophageal fistula via magnetic resonance imaging. J Pediatr Surg Case Rep 29:5-8
Jackson, Daniel J; Gern, James E; Lemanske Jr, Robert F (2017) Lessons learned from birth cohort studies conducted in diverse environments. J Allergy Clin Immunol 139:379-386
DeVries, Avery; Wlasiuk, Gabriela; Miller, Susan J et al. (2017) Epigenome-wide analysis links SMAD3 methylation at birth to asthma in children of asthmatic mothers. J Allergy Clin Immunol 140:534-542
Higano, Nara S; Hahn, Andrew D; Tkach, Jean A et al. (2017) Retrospective respiratory self-gating and removal of bulk motion in pulmonary UTE MRI of neonates and adults. Magn Reson Med 77:1284-1295
Barkal, Layla J; Procknow, Clare L; Álvarez-García, Yasmín R et al. (2017) Microbial volatile communication in human organotypic lung models. Nat Commun 8:1770
Higano, Nara S; Fleck, Robert J; Spielberg, David R et al. (2017) Quantification of neonatal lung parenchymal density via ultrashort echo time MRI with comparison to CT. J Magn Reson Imaging 46:992-1000

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