Common underlying biologic pathways link allergic diseases such as asthma, allergic rhinitis, allergic dermatitis, and eosinophilic esophagitis with the epithelium being a nexus. Each of these diseases has been associated with genetic variation;further some genes have been implicated across multiple allergic diseases. While this work clearly points to some shared underlying genetic effects, identification of variants which predispose individuals to specific allergic disease could advance therapeutic treatments and improve prediction. The overall objective of this U19 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. As the Data Integration and Analysis core, our objective is to provide the quantitative expertise to accomplish the overall objective. The rationale for this core is that to synthesize information across the individual projects, data must be analyzed in a consistent manner. This component does not have its own scientific aims but its expertise in quantitative genetics, genomics, statistics, and epidemiology creates the capacity for rigorous research that will be applied to advance the goals of the overall Center as well as assist the project investigators with their specific hypotheses and aims.
The specific aims of this core are therefore as follows: 1) To provide statistical genetic expertise for analyses proposing to elucidate the associations between epithelial genes and allergic disorders, 2) To integrate results from the three Center projects in order to further clarify the shared and unique contributions of epithelial genes in allergic diseases, 3) To validate findings utilizing multiple well-established public and private cohorts. The successful completion of the proposed studies will identify shared and unique pathways of diverse allergic diseases (asthma, allergic rhinitis, allergic dermatitis, and eosinophilic esophagitis). Clinically, this research is significant as we expect that this work will help delinieate the relationship of pathways related to allergic disease states and ultimately identify therapeutic targets which will have individualized effects. Further, this research is innovative as the targeted focus on the genetics of the epithelium across disease influencing different musocal surfaces (lung, Gl tract, skin) is an innovative approach which will reduce multiple testing while increasing the biologic interpretability of the findings.
The proposed research is relevant to public health because identifying shared and unique genetic influences of allergic disorders will improve our understanding of the impact of therapies across disease states. Thus, the proposed research is relevant to NIH's mission because it will provide fundamental knowledge necessary to improve treatment of allergic disorders.
|Sivaprasad, Umasundari; Kinker, Kayla G; Ericksen, Mark B et al. (2015) SERPINB3/B4 contributes to early inflammation and barrier dysfunction in an experimental murine model of atopic dermatitis. J Invest Dermatol 135:160-9|
|Ji, Hong; Zhang, Xue; Oh, Sunghee et al. (2015) Dynamic transcriptional and epigenomic reprogramming from pediatric nasal epithelial cells to induced pluripotent stem cells. J Allergy Clin Immunol 135:236-44|
|Wen, Ting; Dellon, Evan S; Moawad, Fouad J et al. (2015) Transcriptome analysis of proton pump inhibitor-responsive esophageal eosinophilia reveals proton pump inhibitor-reversible allergic inflammation. J Allergy Clin Immunol 135:187-97|
|Sherrill, Joseph D; Rothenberg, Marc E (2014) Genetic and epigenetic underpinnings of eosinophilic esophagitis. Gastroenterol Clin North Am 43:269-80|
|Biagini Myers, Jocelyn M; Martin, Lisa J; Kovacic, Melinda Butsch et al. (2014) Epistasis between serine protease inhibitor Kazal-type 5 (SPINK5) and thymic stromal lymphopoietin (TSLP) genes contributes to childhood asthma. J Allergy Clin Immunol 134:891-899.e3|
|Sherrill, J D; Kiran, K C; Blanchard, C et al. (2014) Analysis and expansion of the eosinophilic esophagitis transcriptome by RNA sequencing. Genes Immun 15:361-9|
|Zhang, Zhonghua; Xiao, Chang; Gibson, Aaron M et al. (2014) EGFR signaling blunts allergen-induced IL-6 production and Th17 responses in the skin and attenuates development and relapse of atopic dermatitis. J Immunol 192:859-66|
|Krishnamurthy, Purna; Sherrill, Joseph D; Parashette, Kalyan et al. (2014) Correlation of increased PARP14 and CCL26 expression in biopsies from children with eosinophilic esophagitis. J Allergy Clin Immunol 133:577-80|
|Jung, YunJae; Rothenberg, Marc E (2014) Roles and regulation of gastrointestinal eosinophils in immunity and disease. J Immunol 193:999-1005|
|Sherrill, J D; Kc, K; Wu, D et al. (2014) Desmoglein-1 regulates esophageal epithelial barrier function and immune responses in eosinophilic esophagitis. Mucosal Immunol 7:718-29|
Showing the most recent 10 out of 42 publications