Towards a molecular biology of human olfaction in health and disease

Active Project Grant Awarded Last action

Award ID
R01DC021422
Recipient
Awarding agency
Obligated
$2,019,572

Award facts

Completion date 44% complete
Place of performance
Durham, NC 27710, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

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.

Transactions

Action Obligated Date
Amendment $665,196
Amendment $672,157
Original award $682,219

Subawards

Subrecipient Amount Awarded
President And Fellows Of Harvard College The Datta lab will be in charge of sequencing all of the human samples derived from biopsied olfactory epithelia, aligning that sequencing to an up-do-date… $1,009,922

Quick answers

Who received award R01DC021422?

R01DC021422 was awarded to Duke University by National Institute on Deafness and Other Communincation Disorders (National Institutes of Health) on September 1, 2024.

How much is award R01DC021422 worth?

$2,019,572 has been obligated on R01DC021422.

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