# Not so sweet: Investigating the role of c-Kit in sweet cell homeostasis

> **NIH NIH F31** · UNIVERSITY OF COLORADO DENVER · 2023 · $35,911

## Abstract

Project Summary
The sense of taste is mediated by multicellular taste buds that each house 50-100 rapidly renewing taste
receptor cells (TRCs). TRCs are categorized into three main types: type I glial-like cells, type II cells that detect
sweet, bitter or umami, and type III cells that detect sour. As TRCs renew, the three types are maintained in
relatively stable proportions, allowing the sense of taste to remain stable over time. However, rapid turnover of
taste cells makes the taste system prone to disruption by certain drugs and diseases. Cancer patients with
metastatic renal cell carcinoma (mRCC) being treated with tyrosine kinase inhibitors (TKIs) often experience
taste dysfunction, or dysgeusia. The primary targets of TKIs used to treat mRCC are the receptor tyrosine
kinases (RTKs) VEGFR and PDGFRβ, which are not expressed in taste tissue. However, these TKIs also
inhibit many off-target RTKs like Met, Ret, PDGFRα, and c-Kit. According to our single-cell RNA sequencing
(scRNAseq) data, these RTKs are expressed in taste tissue in subsets of progenitors and differentiated taste
cells. This suggests inhibition of these off-target RTKs may be the cause of dysgeusia and that some or all of
these RTKs are necessary for proper TRC renewal and taste homeostasis. To test the role of off-target RTKs
in taste homeostasis, I treated lingual organoids with the TKIs Axitinib, Cabozantinib and Sunitinib, which
inhibit different combinations of off-target RTKs and frequently cause dysgeusia in patients. I found these
drugs did not affect progenitor cell proliferation but instead decreased the expression of certain differentiated
taste cell markers. Specifically, all three TKIs decreased expression of the sweet cell marker Tas1r2, and
Tas1r2 was the only marker affected by all three drugs. Importantly, the only off-target RTK inhibited by all
three drugs is c-Kit, which we find in our scRNAseq data to be most highly expressed in sweet-sensing type II
TRCs. These data strongly implicate c-Kit in sweet cell homeostasis. Further analysis of our scRNAseq data
reveals that c-Kit's ligand - stem cell factor (SCF), is expressed by type I and type III TRCs, raising the
possibility of c-Kit mediated crosstalk within taste buds. These data in sum lead me to my hypothesis that c-Kit
signaling, stimulated by crosstalk with other TRC types, is necessary for the differentiation and/or
survival of sweet-sensing type II TRCs. To test this hypothesis, my first aim is to determine if c-Kit inhibition
by TKI treatment leads to deficits in sweet taste in vivo by treating mice with Axitinib and performing
behavioral, electrophysiological and cellular assays. My second aim is to determine if c-Kit is necessary for
sweet cell differentiation or survival. I will use two genetic c-Kit knockout models under different Cre drivers to
knock out c-Kit expression at different points in TRC differentiation. Lastly, I will investigate c-Kit mediated
crosstalk by genetically knocking out S...

## Key facts

- **NIH application ID:** 10620211
- **Project number:** 5F31DC020634-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Christina M Piarowski
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $35,911
- **Award type:** 5
- **Project period:** 2022-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10620211

## Citation

> US National Institutes of Health, RePORTER application 10620211, Not so sweet: Investigating the role of c-Kit in sweet cell homeostasis (5F31DC020634-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10620211. Licensed CC0.

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