Allergic disorders are a major global health concern affecting 150 million people worldwide. Recently, epithelial cells have emerged as central participants in the pathogenesis of allergic inflammation: (1) they interface with the environment and initiate the response to environmental triggers;(2) the mucosal epithelium in the lung, skin, and gut functions as a physical barrier against pathogens and environmental exposures including allergens;and (3) epithelial cells have been directly implicated in Th2 responses, serving as a critical interface between innate immune responses and Th2 immunity. The overall objective of these studies is to elucidate the mechanisms by which epithelial cells contribute to the pathogenesis of allergic disorders. The overarching hypothesis of this Center proposal is that epithelial cell genes play a central role in the pathogenesis of allergic disorders. This hypothesis will be tested by three integrated projects that use the Center for coordination and synergistic extension of the projects beyond the scopes and capabilities of the individual projects. This Center will provide important insights into the genes and pathways that may be Important in epithelial driven allergic inflammation and provide a basis for the design of novel therapeutic strategies aimed at the epithelial surface, i.e. lung (asthma), skin (atopic dermatitis), or gut (food allergy or eosinophilic esophagitis). Furthermore, integration of data across projects will provide novel insights into a key question in allergy - What are the mechanisms underlying tissue specific disease manifestations of allergic inflammation? Each project in the Center is focused on distinct epithelial cell genes and their roles in allergic disorders. Project 1 will examine the association of epithelial genes with allergic diseases that target distinct mucosal surfaces. Project 2 will dissect the role of epithelial desmoglein-1 in the pathogenesis of the allergic disorder eosinophilic esophagitis. Project 3 will focus on delineating the mechanisms by which epithelial-derived IL-33 is regulated by trefoil factor 2 (TFF2) during the early innate immune events that initiate allergy and asthma;and better define the role of the TFF2/IL-33 pathway in the pathogenesis of allergic disorders.

Public Health Relevance

Allergic disorders are a major public health burden worldwide. Although epithelial cells are increasingly recognized as critical participants in the pathogenesis of allergic inflammation, there is currently no therapy that specifically targets the epithelium. The design of epithelial-specific therapy would be an important advance in the treatment of allergic disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI070235-07
Application #
8300064
Study Section
Special Emphasis Panel (ZAI1-PA-I (M1))
Program Officer
Dong, Gang
Project Start
2006-09-15
Project End
2016-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
7
Fiscal Year
2012
Total Cost
$1,403,151
Indirect Cost
$368,137
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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) β-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

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