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. Traditionally, olfactory loss has been thought to occur by obstruction of the olfactory cleft or damage to the olfactory neuroepithelium subsequent to inflammation. While this is true in some cases, it is likely that there are other cellular and molecular mechanisms that modulate olfactory function in CRS. A hallmark feature of CRS is the presence of inflammatory cytokine mediators produced by infiltrating leukocytes. Among these cytokines, tumor necrosis factor alpha (TNF-1) is particularly interesting because of its central role in CRS- associated inflammation and its recognized functions in regulating neurogenesis and patterned neuronal cell death. The PI has recently generated a mouse model of inducible TNF-1 expression specifically within the olfactory epithelium. TNF-1 induction in this model causes loss of odorant sensitivity and, under certain conditions, death of olfactory sensory neurons (OSNs). In many cell types, TNF-1 and other cytokines relevant in CRS directly alter calcium homeostasis 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. Our induced olfactory inflammation mouse model provides a novel tool with which to study the effect of acute and chronic inflammation on the function and structure of the olfactory epithelium. The central hypothesis of this proposal is that inflammation induced by TNF-1 promotes 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 physiological and molecular techniques will be utilized to dissect the underlying mechanisms of olfactory loss in chronic olfactory inflammation. The experiments described in this proposal will afford new insights into the signaling pathways that mediate inflammatory cytokine effects on neural function and potentially lead to new therapeutic approaches in treating CRS-associated olfactory loss.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
Project #
Application #
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Davis, Barry
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Schools of Medicine
United States
Zip Code
Victores, Andrew J; Chen, Mengfei; Smith, Amy et al. (2018) Olfactory loss in chronic rhinosinusitis is associated with neuronal activation of c-Jun N-terminal kinase. Int Forum Allergy Rhinol 8:415-420
Chen, Mengfei; Reed, Randall R; Lane, Andrew P (2017) Acute inflammation regulates neuroregeneration through the NF-?B pathway in olfactory epithelium. Proc Natl Acad Sci U S A 114:8089-8094
Sousa Garcia, Davi; Chen, Mengfei; Smith, Amy K et al. (2017) Role of the type I tumor necrosis factor receptor in inflammation-associated olfactory dysfunction. Int Forum Allergy Rhinol 7:160-168
Jung, Yong Gi; Lane, Andrew P (2016) Inhibition of Inflammation-Associated Olfactory Loss by Etanercept in an Inducible Olfactory Inflammation Mouse Model. Otolaryngol Head Neck Surg 154:1149-54
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