Epithelial cells are the first line of defense as they interface with the environment and initiate the response to environmental triggers. Thus, dysregulation at the level of the epithelial cell may profoundly affect subsequent development of allergic inflammation and disease. Defining the key epithelial cell derived drivers of persistent immune dysregulation that lead to persistence and progression of allergic inflammation is the focus of this application. Eczema or atopic dermatitis (AD) has been highlighted as the first step in the ?atopic march?, whereby AD typically predates the development of other allergic disorders later in life. It has been estimated that one-third to half of patients with AD will develop asthma, however the mechanisms that promote disease progression remain unclear. KIF3A (kinesin family member 3A) has recently emerged as an asthma and AD susceptibility gene. Our published and unpublished data demonstrate that (1) genetic variants in KIF3A locus are associated with childhood asthma, and this is specifically evident among children with current or previous AD; (2) 28% of KIF3A SNPs create or destroy a CpG site in the KIF3A gene, and the prevalence of these CpG- SNPs is further enriched among asthma-associated KIF3A SNPs (p<0.001); (3) KIF3A expression is significantly decreased in airway epithelial cells from children with severe acute asthma and in the lesional skin of children with AD; and (4) homozygous or heterozygous deletion of Kif3a exon 2 in airway epithelial cells results in increased susceptibility and severity of allergen-induced asthma in mice confirming a direct role for KIF3A. Collectively, these data strongly suggest that KIF3A promotes the development of lung disease in children with atopic dermatitis and may be a key mechanistic link in promoting crosstalk between the skin and airway epithelium. Our central hypothesis is that there are distinct endotypes of AD that are predictive of asthma development, that KIF3A contributes to the progression of atopic dermatitis to asthma by driving persistent immune dysregulation and propagation of allergic inflammation, and that the contribution of KIF3A to asthma in mediated in part by CpG-SNPs that alter gene methylation. This application will have significant public health impact. Through the proposed aims, we will (1) delineate immunologic, clinical, physiologic, genetic, genomic, epigenetic, and environmental factors that promote disease progression from AD to asthma; (3) elucidate the mechanistic role of KIF3A in the progression of AD to asthma; and (4) provide the foundation for development of new algorithms to accurately predict the development of asthma among children who have early life AD.
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