The overall goal of the studies in this project is to test the hypothesis that inflammatory responses in polypoid chronic rhinosinusitis are mediated, in part, by the expression of CCL23 in sinus tissue. Chronic rhinosinusitis (CRS) is a heterogeneous disease characterized by local inflammation of the upper airways and sinuses that is unresponsive to antibiotic therapy and which persists for at least 12 weeks. It is one of the most common chronic diseases in adults in the United States, affecting 20-30 million Americans, and has a severe impact on patients'quality of life and healthcare costs. Because current medications, none of which are FDA approved specifically for the treatment of CRS, have variable efficacy, over 250,000 surgical procedures are required annually in the United States. Therefore it is necessary that we better understand the pathogenic mechanisms of this disease in order to generate novel medical treatments. CRS is clinically classified into CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). Both forms are characterized by intense inflammatory cell infiltration which drives symptoms of the disease, but CRSwNP is the more severe form of the two. We have made exciting findings that CC chemokine ligand 23 (CCL23) is one of the most highly up-regulated genes in nasal polyps from patients with CRSwNP. We also have found that high levels of CCL23 are significantly correlated with eosinophilia and macrophage accumulation in nasal polyps. In addition, we have found that nasal polyp extracts can truncate CCL23. Since a known truncated form of CCL23 has higher CR1 binding activity than other known CCR1 ligands, we hypothesize that CCL23 and its truncated products play an important pathogenic role in CRSwNP. We propose experiments to test this hypothesis using in vitro and in vivo approaches. We are compelled to test this hypothesis in humans, because the CCL23 gene has not been found in rodents. Studies in Aim 1 will examine whether nasal polyp proteases play an important role in the truncation of CCL23. Studies in Aim 2 will examine whether novel truncated products of CCL23 have higher CCL23 activity than the full-length form and known truncated forms, and examine whether CCL23 activity is upregulated in nasal polyps. Studies in Aim 3 will examine whether truncated CCL23 plays an important role in cell recruitment in nasal polyps. In this project, we will collaborate with Dr. Juan Jaen of ChemoCentryx, who is an expert in the field. We believe that the proposed studies will answer whether CCL23, truncated CCL23 and the receptor CCR1 are potential targets for medical treatment of CRS.

Public Health Relevance

Chronic rhinosinusitis (CRS) is a disease that affects about 30 million Americans in whom it causes considerable morbidity and leads to over 250,000 surgeries per year. We have discovered that the chemokine CCL23 is up-regulated in patients with polypoid CRS (CRSwNP) and levels of CCL23 are significantly correlated with tissue inflammation, which is characterized by intense inflammatory cell infiltration. The studies in this grant will test our hypothesis that the over production of CCL23 may be causing the initiation and activation of polypoid chronic rhinosinusitis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL113913-02
Application #
8665469
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Noel, Patricia
Project Start
2013-05-23
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
$173,813
Indirect Cost
$61,313
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Mahdavinia, Mahboobeh; Suh, Lydia A; Carter, Roderick G et al. (2015) Increased noneosinophilic nasal polyps in chronic rhinosinusitis in US second-generation Asians suggest genetic regulation of eosinophilia. J Allergy Clin Immunol 135:576-9
Mahdavinia, Mahboobeh; Carter, Roderick G; Ocampo, Christopher J et al. (2014) Basophils are elevated in nasal polyps of patients with chronic rhinosinusitis without aspirin sensitivity. J Allergy Clin Immunol 133:1759-63
Hulse, Kathryn E; Chaung, Katrina; Seshadri, Sudarshan et al. (2014) Suppressor of cytokine signaling 3 expression is diminished in sinonasal tissues from patients with chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol 133:275-7.e1