# Hedgehog signaling in taste cell maintenance and regeneration

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $337,892

## Abstract

PROJECT SUMMARY/ABSTRACT
Taste sensation is a critical component of basic human survival, as it contributes centrally to the discrimination
of substances whose ingestion sustains us and others that are detrimental to our well-being. Even in modern
times, with safe and abundant sources of nutrients all around us, taste sensation becomes a significant clinical
issue when its loss, often associated with the cytotoxic treatments employed in cancer therapy, causes unwanted
weight reduction and a significant decrement in quality of life. An intriguing manifestation of this problem occurs
in cancer patients treated with a Hedgehog (Hh) pathway antagonist, who experience cumulative loss of taste
sensation over time, suggesting that Hh pathway activity may play a critical in maintaining the taste system. An
additional clue to the basis of taste maintenance is the 140 year-old observation that surgical denervation causes
taste bud degeneration. Finally, we observe that gustatory neurons and their projections display the lipid-
modified Hh protein ligand encoded by Sonic hedgehog (Shh) on their surface. These observations together
lead to the central hypothesis addressed in this proposal: that a neuronal Hh signal induces and specifies the
position of de novo taste receptor cell (TRC) formation from stem or progenitor cells of the lingual epithelium.
Our proposal addresses TRC replacement to offset TRC turnover during ordinary homeostasis, as well as the
wholesale regeneration required when near-complete loss is inflicted by chemotherapy or Hh pathway
antagonism. This hypothesis also represents a new biological principle, namely, that precisely localized delivery
of a potent inductive signal (Hh) by processes from distant neurons can sustain postnatal tissue pattern
(maintenance) or impose correct pattern during de novo organ formation after severe injury (regeneration). To
determine how neuronal Shh signaling supports TRC maintenance (Aim 1), we propose to identify the critical
features that allow Shh-expressing neurons to induce TRCs de novo, determine the temporal characteristics of
the requirement for neuronal provision of the Shh signal, and determine the potential contribution of epithelial
Shh signal to TRC maintenance. To understand regeneration (Aim 2) we will treat mice with a Hh pathway
antagonist that is particularly efficient in ablating TRCs, then track TRC regeneration during a recovery period to
determine whether Hedgehog pathway activity is limiting, determine the cellular presentation of the Shh signal,
and identify other cues that may contribute to regeneration. Finally, we will determine the mechanism of Shh
delivery via neuronal processes (Aim 3) by using specially marked Shh protein and testing the contributions of
other factors known to function in release of Hh protein in other settings. The results of our study will expand our
biological understanding of taste organ homeostasis and of sensory organ regeneration generally, but also
s...

## Key facts

- **NIH application ID:** 9918153
- **Project number:** 5R01DC016892-03
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** PHILIP A BEACHY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $337,892
- **Award type:** 5
- **Project period:** 2018-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9918153

## Citation

> US National Institutes of Health, RePORTER application 9918153, Hedgehog signaling in taste cell maintenance and regeneration (5R01DC016892-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9918153. Licensed CC0.

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