# The taste and smell of intestinal stem cells and its impact on proliferation and lifespan

> **NIH NIH R21** · CORNELL UNIVERSITY · 2020 · $235,500

## Abstract

Dysfunctional stem cells are a telltale sign of aging, particularly in a dynamic organ such as the gut. The gut
epithelium indeed requires constant regeneration throughout an animal’s lifespan to maintain its functionality in
the face of the wear and tear of digestion. The gut and its stem cells need to recognize and adapt to variations
in the luminal content, which comprises food, microbes and xenobiotics. However, the key signals, receptors
and pathways underlying environmental sensing by intestinal stem cells (ISCs) remain largely unknown. We
propose to use the powerful genetic model organism Drosophila melanogaster (Dmel) to investigate this question
in vivo. Our preliminary data show that chemosensory proteins, specifically gustatory and olfactory receptors
(GRs and ORs, respectively), are expressed in Dmel midgut progenitor cells. In addition, we found that
progenitor-specific lack of one of these receptors, Gr28a, results in age dependent impairment of ISC-mediated
epithelium renewal and an overall decreased lifespan. These results therefore suggest that progenitor cells can
“sense” and respond to their environment directly, through the use of smell and taste receptors. In this proposed
research, we aim to characterize the role of GRs and ORs that are expressed in progenitor cells and determine
how they affect ISC activity and organismal lifespan. We also aim to identify the ligands of these receptors as
they could allow nutritional intervention to modulate ISC activity and expand lifespan. Altogether, we will test the
hypothesis that these receptors provide a means for progenitors to sense chemical cues in the lumen and adjust
ISC proliferation and differentiation accordingly, thus maintaining gut integrity and increasing lifespan. We
propose four aims to explore how progenitor cells sense their environment through GR/ORs, in order to maintain
optimal intestinal function and longevity. We will first characterize the impact of Gr28a on ISCs and lifespan
through genetic manipulation (Aim1). We will then evaluate the molecular cues that modulate ISC activity through
Gr28a by using chemically defined diets and by manipulation of the microbiota (Aim2). Next, we will characterize
the downstream genetic components that mediate the Gr28a phenotype by coupling transcriptomic analyses
and testing epistatic interaction between Gr28a and candidate genes identified in our transcriptome analysis
(Aim3). Finally, we will explore the impact of a panel of additional GR/ORs in regulating ISCs (Aim4). Altogether,
we will identify new nutritional and microbial molecular cues that control ISCs, as well as the cellular receptors
that mediate these effects. These experiments will demonstrate a role for GRs/ORs in the control of ISCs and
provide new mechanistic insight into the complexity of the interactions between ISCs, nutrients and gut microbes.
This work will therefore improve our understanding of how diet and microbes can impact epithelial homeostasis
in h...

## Key facts

- **NIH application ID:** 9876327
- **Project number:** 1R21AG065733-01
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Nicolas Buchon
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $235,500
- **Award type:** 1
- **Project period:** 2019-12-15 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9876327

## Citation

> US National Institutes of Health, RePORTER application 9876327, The taste and smell of intestinal stem cells and its impact on proliferation and lifespan (1R21AG065733-01). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/9876327. Licensed CC0.

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