# The Molecular Regulation of Horizontal Basal Cell Activation in the Olfactory Epithelium

> **NIH NIH R01** · TUFTS UNIVERSITY BOSTON · 2024 · $626,021

## Abstract

PROJECT SUMMARY
The capacity of the olfactory epithelium (OE) for replenishing the population of olfactory sensory neurons and
for regenerating the epithelium after injury depends on the persistence and maintained function of stem cells
within that adult tissue. Decline in sensory function in the elderly is accompanied by pathological changes in
the OE that emerge because the normally active olfactory stem and progenitor cells, namely globose basal
cells (GBCs), become disordered and eventually depleted. In this setting, the reserve stem cells, namely the
horizontal basal cells (HBCs), remain dormant despite the neurogenic exhaustion and disappearance of GBCs;
in contrast, if the OE is damaged by an olfactotoxin, the HBCs activate and contribute to the repair of the
epithelium. A therapeutic strategy that accomplishes controllable activation of HBCs in the setting of an
exhausted OE offers possibly the best approach to treating age-related olfactory dysfunction. We have
demonstrated that the transcription factor p63 is the master switch that regulates HBC activation – a
precipitous decline in p63 levels is necessary and sufficient for activation. Further, signaling by Notch1
maintains p63 levels and restrains activation; we hypothesize that the ligand for Notch1 is Jagged1 expressed
by sustentacular cells, since their selective death is sufficient to activate HBCs. We propose 2 Aims in this
application to build on previous advances. Aim 1 focuses on Notch signaling and asks how precisely do the
complexities of the Notch pathway in the OE regulate HBCs? Additional questions address the other signals
that derive from Sus cells to regulate HBCs. Finally, we will extend our studies manipulating Notch signaling
in tissue culture to human HBCs. Aim 2 focuses on the activation process following injury and asks how does
proteasomal degradation of p63 contribute to the decline in protein levels in mouse and in human HBCs?
When completed, we will have achieved a much more thorough understanding of the process by which HBCs
are shifted out of dormancy so that they might contribute to epithelial regeneration. That understanding of
mechanism in both mouse, where genetic manipulations offer profound analytic power, and in humans will
advance our efforts aimed at identifying therapeutic strategies for alleviating olfactory sensory dysfunction,
particularly the sensory loss which accompanies aging.

## Key facts

- **NIH application ID:** 10765638
- **Project number:** 5R01DC017869-05
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** JAMES E. SCHWOB
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $626,021
- **Award type:** 5
- **Project period:** 2020-02-07 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10765638

## Citation

> US National Institutes of Health, RePORTER application 10765638, The Molecular Regulation of Horizontal Basal Cell Activation in the Olfactory Epithelium (5R01DC017869-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10765638. Licensed CC0.

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