Chronic rhinosinusitis (CRS) is a prevalent inflammatory disease with major public health impact. Genetic and environmental factors contribute to risk, but interactions between them are poorly understood. In this application, we propose to a systems genetics approach to discover genes and pathways involved in epithelial response to two important pathogens involved in CRS: human rhinovirus (HRV), which shows clinical and epidemiologic association with CRS, and Staphylococcus aureus (SA), which has been implicated in CRS-related epithelial inflammation. In this application, we propose the hypothesis that epithelial respose to HRV and SA trigger a cascade of events that result in chronic sinus inflammation, and that inter-individual differences in response to these pathogens are associated with disease susceptibility and severity. To test this hypothesis, we will examine changes in global gene expression (RNA) and methylation patterns in primary cultured sinonasal epithelial cells treated with HRV, SA, or vehicle (control) and perform expression quantitative trait locus (eQTL) and methylation quantitative trait locus (meQTL) mapping of transcript levels and methylation patterns, respectively, to identify functional SNPs (eQTL, meQTL) underlying variation in response to these stimuli, and differences between CRS and non-CRS subjects. Functional SNPs will be taken fonrt/ard for association studies in a large cohort of ethnically diverse, well-characterized subjects with sinus disease to identify risk alleles, modifiers of disease course, and modifiers of response to environmental exposures. We will employ state-of-the-art genomic and bioinformative tools and harness the benefits ofthe Chronic Rhinosinusitis Integrative Program (CRISP) project that includes broad expertise in epidemiology, genetics, molecular and cellular biology, and clinical studies to discover and characterize the genetic architecture of CRS. Evaluating the molecular responses to these key pathogens would constitute a major contribution toward better understanding of CRS and provide a paradigm for elucidating genetic and environmental risk factors for this disorder and other common, complex diseases ofthe upper airway.

Public Health Relevance

Chronic rhinosinusitis (CRS) affects millions of people in the U.S. We will characterize transcriptional and epigenomic responses to two key microbes implicated in CRS, characterize genetic variation that influences responses, and identify risk alleles/modifiers of disease course in subjects with CRS. This study will yield a major contribution to the field, and lead to novel diagnostic/prognostic biomarkers &therapeutic targets.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1)
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Northwestern University at Chicago
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Rosati, Mariel G; Peters, Anju T (2016) Relationships among allergic rhinitis, asthma, and chronic rhinosinusitis. Am J Rhinol Allergy 30:44-7
Tan, Bruce K; Klingler, Aiko I; Poposki, Julie A et al. (2016) Heterogeneous inflammatory patterns in chronic rhinosinusitis without nasal polyps in Chicago, Illinois. J Allergy Clin Immunol :
Stevens, Whitney W; Schleimer, Robert P (2016) Aspirin-Exacerbated Respiratory Disease as an Endotype of Chronic Rhinosinusitis. Immunol Allergy Clin North Am 36:669-680
Stevens, Whitney W; Schleimer, Robert P; Kern, Robert C (2016) Chronic Rhinosinusitis with Nasal Polyps. J Allergy Clin Immunol Pract 4:565-72
Ajmani, Gaurav S; Suh, Helen H; Pinto, Jayant M (2016) Effects of Ambient Air Pollution Exposure on Olfaction: A Review. Environ Health Perspect 124:1683-1693
Poposki, Julie A; Keswani, Anjeni; Kim, Julie K et al. (2016) Tissue proteases convert CCL23 into potent monocyte chemoattractants in patients with chronic rhinosinusitis. J Allergy Clin Immunol 137:1274-1277.e9
Jairaman, Amit; Maguire, Chelsea H; Schleimer, Robert P et al. (2016) Allergens stimulate store-operated calcium entry and cytokine production in airway epithelial cells. Sci Rep 6:32311
Schleimer, Robert P; Schnaar, Ronald L; Bochner, Bruce S (2016) Regulation of airway inflammation by Siglec-8 and Siglec-9 sialoglycan ligand expression. Curr Opin Allergy Clin Immunol 16:24-30
Divekar, Rohit; Hagan, John; Rank, Matthew et al. (2016) Diagnostic Utility of Urinary LTE4 in Asthma, Allergic Rhinitis, Chronic Rhinosinusitis, Nasal Polyps, and Aspirin Sensitivity. J Allergy Clin Immunol Pract 4:665-70
Bose, Sumit; Grammer, Leslie C; Peters, Anju T (2016) Infectious Chronic Rhinosinusitis. J Allergy Clin Immunol Pract 4:584-9

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