The loss of the sense of smell is a common symptom of chronic rhinosinusitis (CRS) that markedly diminishes the quality of life of affected patients. The cellular and molecular mechanisms that modulate olfaction in CRS remain unknown. Current evidence suggests that olfactory loss may occur by obstruction of the olfactory cleft or by dysfunction or damage of the olfactory neuroepithelium subsequent to inflammation. In CRS, a variety of cytokine mediators are secreted into the olfactory epithelium by infiltrating leukocytes, but very little is understood about the effect of these cytokines on the peripheral olfactory system. Tumor necrosis factor alpha (TNF-1) is a prominent cytokine in CRS that also has diverse effects on neurons. A mouse model of inducible TNF-1 expression within the olfactory epithelium generated by the PI demonstrates olfactory inflammation with loss of odorant sensitivity, death of olfactory neurons, and suppression of regeneration. In many cell types, TNF-1 and other cytokines relevant in CRS directly alter ion homeostasis and other aspects of cellular physiology through multiple signaling pathways including activation of MAP kinases and the transcription factor NF-:B. It is our hypothesis that inflammatory mediators present in CRS cause olfactory dysfunction through their direct effects on OSNs and olfactory progenitor cells. The primary goal of this proposal is to study how acute and chronic inflammation affects the function and structure of the olfactory epithelium, using our mouse model. The central hypothesis of this proposal is that inflammation induced by cytokines causes the loss of olfaction through three principal mechanisms: 1) desensitization of OSNs to odorants;2) induction of OSN apoptosis;and 3) inhibition of olfactory epithelial regeneration. An integrated approach involving mouse genetic and molecular techniques will be utilized to dissect the underlying mechanisms of olfactory loss in chronic olfactory inflammation. Complementary studies will be performed on human olfactory mucosal samples to identify the cytokines playing a role in the pathogenesis of CRS-associated olfactory dysfunction, and potential therapeutic agents will be investigated in the mouse model. The experiments described in this proposal will afford new insights into the signaling pathways that mediate inflammatory mediator effects on neural function and potentially lead to new therapeutic approaches in treating CRS- associated olfactory loss.

Public Health Relevance

The loss of the sense of smell is a common symptom of chronic sinusitis that markedly diminishes the quality of life of affected patients, but the causes of this condition are poorly understood. In this proposal, we utilize a novel transgenic mouse model to study how inflammation disrupts the olfactory system. The experiments using this model will provide new insights into the role of inflammatory cytokines in causing human olfactory dysfunction in sinusitis, which will potentially lead to new and more effective therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC009026-05
Application #
8304239
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Sullivan, Susan L
Project Start
2008-02-01
Project End
2016-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$348,500
Indirect Cost
$136,000
Name
Johns Hopkins University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Pozharskaya, Tatyana; Liang, Jonathan; Lane, Andrew P (2013) Regulation of inflammation-associated olfactory neuronal death and regeneration by the type II tumor necrosis factor receptor. Int Forum Allergy Rhinol 3:740-7
Pozharskaya, Tatyana; Lane, Andrew P (2013) Interferon gamma causes olfactory dysfunction without concomitant neuroepithelial damage. Int Forum Allergy Rhinol 3:861-5
Sultan, Babar; May, Lindsey A; Lane, Andrew P (2011) The role of TNF-? in inflammatory olfactory loss. Laryngoscope 121:2481-6
Lane, Andrew P; Turner, Justin; May, Lindsey et al. (2010) A genetic model of chronic rhinosinusitis-associated olfactory inflammation reveals reversible functional impairment and dramatic neuroepithelial reorganization. J Neurosci 30:2324-9
Turner, Justin H; Liang, Kai Li; May, Lindsey et al. (2010) Tumor necrosis factor alpha inhibits olfactory regeneration in a transgenic model of chronic rhinosinusitis-associated olfactory loss. Am J Rhinol Allergy 24:336-40
Turner, Justin H; May, Lindsey; Reed, Randall R et al. (2010) Reversible loss of neuronal marker protein expression in a transgenic mouse model for sinusitis-associated olfactory dysfunction. Am J Rhinol Allergy 24:192-6