Allergic disorders are a major global health burden affecting up to 40% of the world population. Common biologic pathways underlie allergic diseases such as asthma, AD, FA and EE with the epithelium being a link. Indeed, epithelial cells are increasingly recognized as critical participants in the pathogenesis of allergic inflammation. As such, studies are needed to further elucidate the epithelial genes and pathways that contribute to allergic inflammation. This is underscored by the fact that there is currently no asthma therapy that specifically targets the epithelium. In the last cycle of funding, we utilized a novel unbiased strategy, which combined expression profiling of nasal epithelial cells from patients with asthma, population differences in asthma prevalence, and genetic association studies, to identify epithelial genes that contributed to childhood asthma. We identified several epithelial genes with previously unrecognized roles in asthma. Further analyses of these genes suggest that some of these genes are specific to one epithelial surface and are associated with one allergic disease, while others are common to multiple epithelial surfaces and allergic disorders. Collectively, our data suggest that depending on the target organ/mucosal surface, there are common and distinct epithelial genes and pathways that contribute to allergic inflammation. The Identification of the epithelial genes and pathways, which predispose individuals to specific or shared allergic disorders, will empower the search for novel therapeutics aimed specifically at the epithelial surface, and the development of treatment strategies that are optimized for allergic disorders alone and/or in combination. In the prior cycle, we studied children with asthma and/or AR. In this application, we propose to extend our genetic approach to test the hypothesis that allergy-driven epithelial genes Identified in the prior cycle of funding (SERPINB3/4, KIF3A, DNAH5, SPRR2B, ADCY2, PDE4B, PLAU, EGFR) will demonstrate unique and overlapping associations with asthma, atopic dermatitis, and/or food allergy in children and that the genetic contribution of these genes is modified by epistatic interactions with epithelial genes critical in maintaining the integrity of the mucosal barrier and/or promoting Th2 responses.
Allergic disorders are a major global health burden affecting up to 40% of the world population. Common biologic pathways underlie allergic diseases with the epithelium being a link. The proposed studies are highly significant because they will identify epithelial genes and pathways that promote allergic disease. This information will provide a basis for improved phenotyping and optimized treatment strategies for allergic disorders.
|Davis, Benjamin P; Stucke, Emily M; Khorki, M Eyad et al. (2016) Eosinophilic esophagitis-linked calpain 14 is an IL-13-induced protease that mediates esophageal epithelial barrier impairment. JCI Insight 1:e86355|
|Zhang, Zhonghua; Biagini Myers, Jocelyn M; Brandt, Eric B et al. (2016) Î²-Glucan exacerbates allergic asthma independent of fungal sensitization and promotes steroid-resistant TH2/TH17 responses. J Allergy Clin Immunol :|
|Ji, Hong; Biagini Myers, Jocelyn M; Brandt, Eric B et al. (2016) Air pollution, epigenetics, and asthma. Allergy Asthma Clin Immunol 12:51|
|Gupta, Jayanta; Johansson, Elisabet; Bernstein, Jonathan A et al. (2016) Resolving the etiology of atopic disorders by using genetic analysis of racial ancestry. J Allergy Clin Immunol 138:676-99|
|Davis, Benjamin P; Rothenberg, Marc E (2016) Mechanisms of Disease of Eosinophilic Esophagitis. Annu Rev Pathol 11:365-93|
|Molina-Infante, Javier; Bredenoord, Albert J; Cheng, Edaire et al. (2016) Proton pump inhibitor-responsive oesophageal eosinophilia: an entity challenging current diagnostic criteria for eosinophilic oesophagitis. Gut 65:524-31|
|Ulm, Ashley; Mayhew, Christopher N; Debley, Jason et al. (2016) Cultivate Primary Nasal Epithelial Cells from Children and Reprogram into Induced Pluripotent Stem Cells. J Vis Exp :|
|Davis, Benjamin P; Epstein, Tolly; Kottyan, Leah et al. (2016) Association of eosinophilic esophagitis and hypertrophic cardiomyopathy. J Allergy Clin Immunol 137:934-936.e5|
|Giridhar, Premkumar Vummidi; Bell, Sheila M; Sridharan, Anusha et al. (2016) Airway Epithelial KIF3A Regulates Th2 Responses to Aeroallergens. J Immunol 197:4228-4239|
|D'Mello, R J; Caldwell, J M; Azouz, N P et al. (2016) LRRC31 is induced by IL-13 and regulates kallikrein expression and barrier function in the esophageal epithelium. Mucosal Immunol 9:744-56|
Showing the most recent 10 out of 73 publications