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)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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University of Wisconsin Madison
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Ober, Carole; Sperling, Anne I; von Mutius, Erika et al. (2017) Immune development and environment: lessons from Amish and Hutterite children. Curr Opin Immunol 48:51-60
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
Hahn, Andrew D; Higano, Nara S; Walkup, Laura L et al. (2017) Pulmonary MRI of neonates in the intensive care unit using 3D ultrashort echo time and a small footprint MRI system. J Magn Reson Imaging 45:463-471
Griggs, Theodor F; Bochkov, Yury A; Basnet, Sarmila et al. (2017) Rhinovirus C targets ciliated airway epithelial cells. Respir Res 18:84
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
Liu, Y-P; Rajamanikham, V; Baron, M et al. (2017) Association of ORMDL3 with rhinovirus-induced endoplasmic reticulum stress and type I Interferon responses in human leucocytes. Clin Exp Allergy 47:371-382
Rubner, Frederick J; Jackson, Daniel J; Evans, Michael D et al. (2017) Early life rhinovirus wheezing, allergic sensitization, and asthma risk at adolescence. J Allergy Clin Immunol 139:501-507
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
Bjerregaard, Asger; Laing, Ingrid A; Poulsen, Nadia et al. (2017) Characteristics associated with clinical severity and inflammatory phenotype of naturally occurring virus-induced exacerbations of asthma in adults. Respir Med 123:34-41
Anderson, Halie M; Lemanske Jr, Robert F; Arron, Joseph R et al. (2017) Relationships among aeroallergen sensitization, peripheral blood eosinophils, and periostin in pediatric asthma development. J Allergy Clin Immunol 139:790-796

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