# Towards a molecular biology of human olfaction in health and disease

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $682,219

## Abstract

Project Summary/Abstract
The olfactory epithelium is the peripheral organ for smell, housing millions of primary olfactory sensory
neurons. Insults such as inflammation, infection, toxins or trauma can damage the olfactory epithelium and
perturb olfactory function, causing lasting anosmia, hyposmia or parosmia. We lack both a basic understanding
of what goes wrong when people lose their sense of smell, and effective therapies for sensorineural olfactory
disorders, as highlighted by our current inability to treat post-COVID olfactory dysfunction impacting millions of
people. Thus, there is an urgent unmet need to define mechanisms driving olfactory neuronal homeostasis and
dysfunction in humans. In rodents, each olfactory neuron harbors a unique transcriptome based upon the
singular olfactory receptor it expresses, organized into coherent gene expression programs. Fixed gene
expression programs specify each neuron’s identity, and flexible programs are dynamically adjusted based
upon odor exposure. These findings have enabled genome-wide characterization of odor responses in vivo in
mice, across the entire olfactory neuron population. However, humans express far fewer olfactory receptors
than mice, and neither their specific receptive odor repertoire nor their dynamic in vivo transcriptional variation
have been well-defined. Unlike in rodents, we know little about how gene expression is organized in human
olfactory neurons, how populations of human olfactory neurons respond to defined odors, or how odor-evoked
olfactory neuron activity is altered in the setting of disease. The experiments proposed here will identify
organized patterns of gene expression in olfactory neurons isolated from human biopsies, in both controls and
in subjects with objective smell loss, via two specific aims: Specific Aim 1 will establish the axes of
transcriptional variation in human OSNs; Specific Aim 2 will assess responses to odor at the single cell level in
the human olfactory epithelium. Olfactory mucosal biopsies from normosmic or hyposmic subjects will be
analyzed using single cell RNA-sequencing. Presenting a specific odorant to subjects prior to biopsy and
sequencing, an approach termed Act-seq will be employed to query the responses of the entire olfactory
neuron array to a given odor in vivo. Act-seq will be compared from normosmic or post-Covid hyposmic
olfactory samples. Completion of the proposed work will (1) directly define human odor-induced alterations in
olfactory cells in normal or diseased conditions, (2) provide the first in vivo human olfactory receptor de-
orphanization, and (3) produce novel datasets that will be broadly useful to the neurobiology and
chemosensory research communities. These results, defining mechanisms driving olfactory neuronal
homeostasis and dysfunction in humans, will form a basis for future clinical research trials aimed at promoting
recovery of olfaction.

## Key facts

- **NIH application ID:** 10977307
- **Project number:** 1R01DC021422-01A1
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Sandeep R Datta
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $682,219
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10977307

## Citation

> US National Institutes of Health, RePORTER application 10977307, Towards a molecular biology of human olfaction in health and disease (1R01DC021422-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10977307. Licensed CC0.

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