# Inflammation-Associated Olfactory Dysfunction: Mechanisms and Therapy

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $477,920

## Abstract

Project Summary
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.

## Key facts

- **NIH application ID:** 9819775
- **Project number:** 5R01DC016106-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** ANDREW P LANE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $477,920
- **Award type:** 5
- **Project period:** 2017-12-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9819775

## Citation

> US National Institutes of Health, RePORTER application 9819775, Inflammation-Associated Olfactory Dysfunction: Mechanisms and Therapy (5R01DC016106-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9819775. Licensed CC0.

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