Childhood asthma is particularly problematic to study because of the frequent presence of wheezing disorders which can be mistaken for asthma, the difficulty in obtaining relevant biologic specimens for analyses, and the evolving nature of immune system and lung development that needs to be evaluated in the context of both genetic and environmental interactions which contribute to this complex disorder. To address these important issues, the investigators constituting this Program Project Grant (PPG) application have implemented integrated approaches in conducting immunological, microbiological, epidemiological, physiological, molecular, and genetic evaluations that involve in vitro and in vivo models in humans and rodents, and a large birth cohort at high risk of developing both allergic diseases and asthma. Based on our early findings, we hypothesize that cytokine dysregulation is a pivotal component in childhood asthma inception, wheezing phenotype expression, and symptom exacerbation, all of which may be further influenced by viral respiratory tract infections. The airway physiologic abnormalities that characterize childhood asthmatic phenotypes are associated with cytokine dysregulation and are significantly influenced by gene-environment interactions that begin in utero and continue throughout infancy and early childhood. The components of this PPG application include 4 projects and 3 cores. Project I will utilize an established cohort of children at high risk of developing allergies and/or asthma to evaluate the contributions of cytokine dysregulation (Th1/Th2 imbalance), viral infections, and developmental phenotypes. Project II will evaluate molecular mechanisms involved with virus-epithelial cell interactions that enhance cytokine/chemokine synthesis and subsequent airway inflammation, and how these processes may be dysregulated in asthma resulting in symptomatic exacerbations. Project III will study mechanisms of airway closure in an animal model comprising many relevant features of childhood asthma including developmentally- dependent cytokine dysregulation and virus-induced airway dysfunction. Project IV will utilize phenotypic, epidemiologic, and mechanistic data generated in Project I-III to identify maternal-fetal, gene-gene, and gene-environment interactions during the prenatal period and in early childhood for their contributions to asthma inception, exacerbation and disease risk. The 3 Cores (Virology, Biostatistics, and Administrative) will provide integrated support to all 4 of the Projects. As opposed to new information that would be generated by each project if individually funded, we strongly feel that the diverse yet integrated interactions that will result from the formation of this PPG will provide the most powerful mechanism to advance the science in this very important area: the pathogenesis of childhood asthma.
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