# Regulation of tissue stem cell lineages by nuclear receptor signaling

> **NIH NIH R35** · TRUSTEES OF INDIANA UNIVERSITY · 2024 · $379,398

## Abstract

PROJECT SUMMARY
Stem cells are required for tissue maintenance and repair during the lifetime of an organism. Altered organism
physiology can influence tissue homeostasis through disruption of endocrine tissues, resulting in changes in fat
cell metabolism, steroid and hormone levels, and secretion of circulating factors within the body. Secreted
factors communicate the physiological status of distant organs to one another. Nuclear receptors (NRs) are
broadly expressed transcription factors with ligand-binding domains that mediate the effects of circulating
factors throughout an organism. NRs are major regulators of energy homeostasis, including carbohydrate
metabolism, fatty acid synthesis, and beta oxidation and play important roles in stem cell differentiation,
metabolism, and tissue homeostasis. However, the mechanisms used by NRs to modulate the transcriptional
landscapes in multiple organs and cell types to control distal stem cell lineages for proper tissue function are
understudied. The Drosophila melanogaster ovary is an ideal model to understand how inter-organ
communication mediated by NR signaling influences germline stem cell (GSC) lineages. Previous studies have
shown that NRs act directly in GSCs to regulate oogenesis; however, there is emerging evidence that the
activity of NRs in peripheral tissues indirectly influence the GSC lineage. For example, the NR Seven-Up (Svp)
acts within adipocytes to influence GSC maintenance and early germline cyst survival and in hepatocyte-like
cells to regulate survival of vitellogenic egg chambers. In addition, Hr4 is required in adult muscle to maintain
GSCs and promote follicle growth. The goal of our research program is to determine how signaling
downstream of transcription factors in different tissues influences circulating factors that regulate stem cell
lineages and tissue function. In this proposal, we will use a combination of genetics, cell biology, and next-
generation sequencing to address two major questions using NRs and the Drosophila ovary as models: 1) How
do transcription factors coordinate their activity in multiple tissues and cell types to regulate stem cell behavior?
2) How is NR directed energy homeostasis maintained in organs to ensure survival of stem cell lineages and
maintain tissue function? Overall, these projects will provide the foundation towards understanding the
downstream mechanisms used by transcription factors in peripheral tissues to influence the behavior of adult
stem cell lineages. Furthermore, this work will inform future studies focused on understanding how disrupted
endocrine signaling results in tissue and organ failure.

## Key facts

- **NIH application ID:** 10903963
- **Project number:** 5R35GM150517-02
- **Recipient organization:** TRUSTEES OF INDIANA UNIVERSITY
- **Principal Investigator:** Lesley Nicole Weaver
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $379,398
- **Award type:** 5
- **Project period:** 2023-08-15 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10903963

## Citation

> US National Institutes of Health, RePORTER application 10903963, Regulation of tissue stem cell lineages by nuclear receptor signaling (5R35GM150517-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10903963. Licensed CC0.

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