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-?) is a prominent cytokine in CRS that also has diverse effects on neurons. A mouse model of inducible TNF-? 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-? and other cytokines relevant in CRS activate multiple signaling pathways including the MAP kinase JNK and the transcription factor NF-?B. It is our hypothesis that inflammatory mediators present in CRS cause olfactory dysfunction through direct effects on OSNs and olfactory progenitor cells mediated by these pathways. The primary goal of this proposal is to study how chronic inflammation affects the function and structure of the olfactory epithelium, using our mouse model. The central hypothesis of this proposal is that the balance of activation of JNK and NF-?B in OSNs leads to initial functional loss and eventual cell death. In progenitor cells, we hypothesize that cytokines, also acting through NF-?B and JNK, disrupt proliferation and differentiation. 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 signaling pathways playing a role in the pathogenesis of CRS- associated olfactory dysfunction. Potential therapeutic agents blocking the JNK pathway will be investigated in the mouse model. The experiments described in this proposal will afford new insights into the mechanisms that mediate inflammatory mediator effects on neural function and lead directly to clinical trials of novel therapeutic approaches for treating CRS-associated olfactory loss.
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 mouse models and human tissue samples to study how inflammation disrupts the olfactory system. The experiments 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.