Asthma is a heterogeneous disorder that has its onset in many patients within early childhood. One clinical feature of childhood asthma, loss of lung function, has been of particular concern because it appears to occur in the majority of patients within the first 5-6 years of life and is not reversible over time despite appropriate treatment. Regarding this loss of lung function, two contributing factors have received the most widespread support based on experimental evidence in both animal models and human data generated from prospective birth cohort studies: atopy (related to some form of immune dysregulation) and viral respiratory illnesses in early life. Data generated from rodent models indicate that respiratory viral infection in weanling animals, but not adult animals, initiates long-term structural changes that are associated in later life with chronic and recurrent airway obstruction. Furthermore, these responses are specific to an atopic rodent strain and appear to be regulated through altered cytokine secretion patterns, particularly interferons induced by the viral infection. Most importantly, our research group now has correlative data from a childhood birth cohort asthma study demonstrating that similar alterations in immune response in the context of viral infections in early life can lead to long-term alterations in lung function. These results in both animal and human models lead us now to propose the hypothesis that viral respiratory infections in early life alter long-term lung function by disrupting the normal program of lung development, and genetic factors such as low interferon responses, a key biomarker of atopy in infancy, intensify the impact of these infections. To evaluate this hypothesis, this application proposes to gather a multidisciplinary team of investigators with expertise in lung development, immunology, virology, pulmonary physiology and biostatistics. Cross-species experiments in rodent models and human birth cohorts will test the hypothesis on multiple molecular and genetic levels. Ultimately, the results of the proposed experiments will significantly advance our ability to predict, prevent, and treat recurrent wheezing and childhood asthma.

Public Health Relevance

For many children, the progression from wheezing during infancy to childhood asthma is associated with loss of lung function. This adverse clinical outcome may be initiated by an aberrant immune response to respiratory viral infections during critical periods of lung growth and development in early life. This grant proposal will use animal and human models to investigate interactive effects of respiratory virus infections and host genetic factors on the developing lung, with the goal of increasing our ability to predict, prevent and treat recurrent wheezing and childhood asthma.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL097134-02
Application #
7918230
Study Section
Special Emphasis Panel (ZHL1-CSR-H (M2))
Program Officer
Noel, Patricia
Project Start
2009-09-01
Project End
2014-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
2
Fiscal Year
2010
Total Cost
$506,949
Indirect Cost
Name
University of Wisconsin Madison
Department
Pediatrics
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Li, Rongbo; Bernau, Ksenija; Sandbo, Nathan et al. (2018) Pdgfra marks a cellular lineage with distinct contributions to myofibroblasts in lung maturation and injury response. Elife 7:
Nantie, Leah B; Young, Randee E; Paltzer, Wyatt G et al. (2018) Lats1/2 inactivation reveals Hippo function in alveolar type I cell differentiation during lung transition to air breathing. Development 145:
Verheyden, Jamie M; Sun, Xin (2017) Embryology meets molecular biology: Deciphering the apical ectodermal ridge. Dev Biol 429:387-390
Li, Rongbo; Herriges, John C; Chen, Lin et al. (2017) FGF receptors control alveolar elastogenesis. Development 144:4563-4572
Branchfield, Kelsey; Li, Rongbo; Lungova, Vlasta et al. (2016) A three-dimensional study of alveologenesis in mouse lung. Dev Biol 409:429-41
Branchfield, Kelsey; Nantie, Leah; Verheyden, Jamie M et al. (2016) Pulmonary neuroendocrine cells function as airway sensors to control lung immune response. Science 351:707-10
Zhang, Yan; Yokoyama, Shigetoshi; Herriges, John C et al. (2016) E3 ubiquitin ligase RFWD2 controls lung branching through protein-level regulation of ETV transcription factors. Proc Natl Acad Sci U S A 113:7557-62
McCulley, David; Wienhold, Mark; Sun, Xin (2015) The pulmonary mesenchyme directs lung development. Curr Opin Genet Dev 32:98-105
Darveaux, Jared I; Lemanske Jr, Robert F (2014) Infection-related asthma. J Allergy Clin Immunol Pract 2:658-63
Hines, Elizabeth A; Szakaly, Renee J; Leng, Ning et al. (2014) Comparison of temporal transcriptomic profiles from immature lungs of two rat strains reveals a viral response signature associated with chronic lung dysfunction. PLoS One 9:e112997

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