Chronic rhinosinusitis with polyps (CRSwNP) is a significant health problem in the United States. This disorder, which is often particularly recalcitrant to medical and surgical therapy, is characterized by persistent eosinophilic inflammation of the sinonasal mucosa, with thickened secretions that are frequently colonized with bacteria and/or fungi. The cellular and molecular mechanisms that underlie CRSwNP remain poorly understood. The epithelium of nose and sinuses participates actively in host immunity, serving as a barrier and first line of defense against inhaled pathogens and other potential threats. During the past funding period, we investigated how sinonasal epithelial cells (SNEC) contribute to CRSwNP through production of innate pro-eosinophilic mediators and by bidirectional communication with the adaptive immune system. Our studies using human tissue and mouse models have suggested that SNEC are triggered by epithelial damage to produce mediators that promote eosinophilic inflammation. We hypothesize that this pathway is a normal aspect of healing and repair, but is suppressed by signals associated with microbial infection. To test these hypotheses, we will initially, in aim 1, examine sinus mucosa from patients with acute and chronic sinus inflammatory disease to define the pattern of pro-eosinophilic mediator expression during the resolution phase after intervention. We will also explore in vitro the interplay of damage-associated molecules, microbial molecular patterns, and Th1 cytokines in determining SNEC pro-eosinophilic gene expression.
In aim 2, we will utilize mouse models of sinonasal eosinophilic inflammation in combination with knockout mice that lack antimicrobial immunity-associated genes. As part of this aim, the first transgenic animal model of chronic rhinosinusitis will be generated, with great potential to further a wide range of future CRSwNP research. Finally, in aim 3, we will dissect subcellular pathways that regulate abnormal pro-eosinophilic mediator expression in SNEC derived from CRSwNP patients. These studies will significantly advance current knowledge about CRSwNP and create an opportunity to develop innovative therapies for this debilitating and costly medical condition.

Public Health Relevance

Chronic rhinosinusitis with nasal polyps is a common and costly condition in the US that is often reclacitrant to current medical and surgical treatments. Our research has shown that the lining cells of the sinus mucus membrane produce factors that may be important in polyp inflammation, which we propose to further investigate in human sinus tissue and newly developed animal models. If successful, this work will improve our understanding of chronic rhinosinusitis with polyps and lead to a new opportunity to develop effective drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI072502-06A1
Application #
8503831
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Togias, Alkis
Project Start
2007-08-01
Project End
2017-04-30
Budget Start
2013-05-20
Budget End
2014-04-30
Support Year
6
Fiscal Year
2013
Total Cost
$380,700
Indirect Cost
$145,700
Name
Johns Hopkins University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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