# Metabolic regulation of the stem cell niche

> **NIH NIH R15** · UNIVERSITY OF LOUISVILLE · 2024 · $437,366

## Abstract

PROJECT SUMMARY/ABSTRACT
Adult stem cells constitute a group of progenitor cells capable of tissue regeneration during life through the ability
to both self-renewal and produce specialized cells upon division. In tissues, stem cells reside in
microenvironments called “niches” that integrate systemic cues and provide signals for stem cell maintenance.
With age, a decline in both stem and niche cell maintenance has been observed. Over the years, the use of the
stem cell systems present in Drosophila melanogaster has revealed mechanisms behind the loss of stem cell
function in age. For instance, aged flies have a smaller number of male germline stem cells, as well as niche
(hub) cells. Recent evidence, however, points to a strong conserved correlation between age-related changes
in metabolism and stem cell dysfunction. Given the power of Drosophila genetics, the readily accessible
molecular tools, the well-characterized stem and niche cell populations and the relatively short lifespan, the fly
testis niche is an ideal model for the intersectional study of metabolism, aging and stem cell biology. Our long-
term goal is to understand how changes in lipid metabolism affect stem cell niche homeostasis. The PI’s
published works build a model where the ectopic accumulation of lipids in the fly testis niche is detrimental to
stem cell function. Excess lipid accumulation in stem cells led to their loss through differentiation. Accordingly,
lipid accumulation has been shown to be detrimental to stem cell maintenance across species. The overall
objective of this proposal is to understand mechanistically how the stem cell niche is affected by the age-related
ectopic accumulation of lipids. Preliminary data in this proposal shows that lipid droplets accumulate specifically
in niche (hub) cells of the fly testis. Moreover, we also describe the activation of pathways involved in lipid
accumulation (Target of Rapamycin, TOR and Sterol regulatory element binding protein, SREBP) in niche cells.
Of note, both environmental and genetic manipulations that result in the activation of SREBP led to niche cell
loss through the unexpected conversion into stem cells. Hence, our central hypothesis is that the age-related
ectopic activation of TOR and SREBP contribute to lipid accumulation and loss of niche cell maintenance and
function. We will test this hypothesis through two specific aims: 1) testing if suppressing the age-related ectopic
activation of TOR and SREBP in niche (hub) cells is sufficient to prevent the decay in niche cell maintenance
and function; 2) characterizing the mechanism of SREBP-mediated hub cell loss. The merit of this study relies
on its novelty – showing that changes in lipid metabolism can promote the conversion from a niche cell into a
stem cell – and on the generation of a useful paradigm for testing how age-related changes in metabolism yield
in loss of stem cell niches. The proposed studies will also strengthen the undergraduate student researc...

## Key facts

- **NIH application ID:** 10974071
- **Project number:** 1R15AG085260-01A1
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** Rafael S Demarco
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $437,366
- **Award type:** 1
- **Project period:** 2024-08-15 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10974071

## Citation

> US National Institutes of Health, RePORTER application 10974071, Metabolic regulation of the stem cell niche (1R15AG085260-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10974071. Licensed CC0.

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