Project 2 investigates the pathogenic mechanisms of CRS in collaboration with Project 1 (GHS) and Project 3 (UC) to test important hypotheses with clinical and potential therapeutic relevance in CRS. The four overarching hypotheses are: i) that nasal polyp (NP) tissue promotes activation, proliferation and differentiation of B lineage cells leading to their expansion and autoimmune antibody production in the NP;ii) that autoimmunity is responsible for recalcitrant disease in patients that require frequent surgical intervention;iii) that exacerbations of CRS are triggered by human rhinovirus (HRV), explaining their predominance during the respiratory virus season, and;iv) that infection of CRS patients with HRV activates B lineage cells in patients with CRS. We will test these hypotheses using laboratory investigations to understand observations made in humans and testing discoveries made in the laboratory in human subjects. To test the hypothesis that NP tissue supports B lineage cell expansion, we will assess proliferation in the B lineage cell populations within NP tissue. We will assess class switch recombination in NP using PCR based to detect AID and excision circles. We will use a tissue explant model to study the activation and expansion of B lineage cells. To test the association of autoimmunity with recalcitrant CRS disease, we will use a longitudinal study to determine whether autoimmunity is a predictor of recalcitrant disease. We will perform a cross sectional study with 150 patients from GHS to determine whether patients with a history of multiple surgeries have a greater prevalence of autoimmunity in the upper airways. We will determine whether HRV is an important cause of exacerbations of CRS two ways. First, we will collaborate with Project 1 to recruit 100 CRS patients undergoing an exacerbation. Microfluidic array analysis will identify the viral or bacterial pathogens associated with the exacerbation. We will also utilize experimental challenge of CRS and control subjects with HRV and test the hypothesis that HRV induces CRS exacerbations. We will monitor B lineage cells and epithelial cells from infected subjects will be subjected to microarray analysis in order to validate genes discovered in Project 3 to be important HRV and CRS associated genes.

Public Health Relevance

CRS patients are often treated with prolonged courses of antibiotics, anti-inflammatory drugs and surgery to keep their nasal passages and sinuses clear. Our goal is to discover the causes of inflammation in the nose and sinuses of people with CRS in the hopes that we can develop new ways to treat this condition. We also propose to identify the microorganisms associated with sudden worsening of CRS so that we can better understand the triggers of this disease that adversely impacts the lives of tens of millions of Americans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
1P01AI106683-01
Application #
8592173
Study Section
Special Emphasis Panel (ZAI1-LAR-I (M2))
Project Start
Project End
Budget Start
2013-08-05
Budget End
2014-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$383,425
Indirect Cost
$69,251
Name
Northwestern University at Chicago
Department
Type
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Ober, Carole (2016) Asthma Genetics in the Post-GWAS Era. Ann Am Thorac Soc 13 Suppl 1:S85-90
Correia, Camil; Lopez, Kevin J; Wroblewski, Kristen E et al. (2016) Global Sensory Impairment in Older Adults in the United States. J Am Geriatr Soc 64:306-13
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
Min, Jin-Young; Ocampo, Christopher J; Stevens, Whitney W et al. (2016) Proton pump inhibitors decrease eotaxin-3/CCL26 expression in patients with chronic rhinosinusitis with nasal polyps: Possible role of the nongastric H,K-ATPase. J Allergy Clin Immunol :
Thompson, Christopher F; Price, Caroline P E; Huang, Julia He et al. (2016) A pilot study of symptom profiles from a polyp vs an eosinophilic-based classification of chronic rhinosinusitis. Int Forum Allergy Rhinol 6:500-7
Bose, Sumit; Grammer, Leslie C; Peters, Anju T (2016) Infectious Chronic Rhinosinusitis. J Allergy Clin Immunol Pract 4:584-9
Nicodemus-Johnson, Jessie; Myers, Rachel A; Sakabe, Noburu J et al. (2016) DNA methylation in lung cells is associated with asthma endotypes and genetic risk. JCI Insight 1:e90151
Hulse, Kathryn E (2016) Immune Mechanisms of Chronic Rhinosinusitis. Curr Allergy Asthma Rep 16:1
Hulse, K E; Stevens, W W; Tan, B K et al. (2015) Pathogenesis of nasal polyposis. Clin Exp Allergy 45:328-46
Lam, Kent; Schleimer, Robert; Kern, Robert C (2015) The Etiology and Pathogenesis of Chronic Rhinosinusitis: a Review of Current Hypotheses. Curr Allergy Asthma Rep 15:41

Showing the most recent 10 out of 40 publications