Epithelial cells are the first cells that encounter environmental exposures and they are responsible for initiating the response to environmental triggers of disease, including common allergens. They are increasingly recognized as active participants in the development of atopic disorders. Over the past few years, several genes and mediators associated with increased susceptibility to atopy have been identified;many of these are expressed in the mucosa and epidermis, further supporting that events at epithelial-cell surfaces might be driving disease processes. The long-term objective of these studies is to elucidate the mechanisms by which epithelial cells contribute to the pathogenesis of allergic disorders. The focus of this Center proposal is to dissect the role of allergy-driven epithelial genes in allergic disorders of childhood. Specifically, this Center proposal includes 3 projects, each focusing on epithelial-derived genes and gene products. Project by Rothenberg will define the genetics of epithelial genes in childhood asthma. Project by Khurana will dissect the role of epithelial-derived eotaxin 3 in the pathogenesis of eosinophilic esophagitis. Project by Wills-Karp will focus on the biology of allergy-driven epithelial genes, specifically chitinases, in allergy and asthma. Each project will utilize a well-characterized cohort of children with allergic disorders (asthma, allergic rhinitis, food allergy, eosinophilic esophagitis) who live in the Greater Cincinnati Ohio Metropolitan Region. The genetic, phenotypic, and health outcome data generated in each project will be integrated by a central core and analyzed independently and in conjunction with each of the other projects to identify potential genetic, biologic, and environmental interactions. The public health impact of this study will be significant. Through the results of this study, we will be able to provide information regarding: 1. mechanisms by which epithelial cells drive the development of allergic disease; 2. the relevant epithelial genes with regard to allergic disorders of childhood; 3. genotypes to identify children that are at greater risk for severe asthma; 4. genetic biomarkers of childhood asthma;and 5. novel targets for therapeutic intervention for allergic disorders.
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