# Intermediary Metabolism Control of Nephron Progenitor Lifespan

> **NIH NIH R01** · TULANE UNIVERSITY OF LOUISIANA · 2020 · $228,000

## Abstract

Low nephron number at birth is a significant contributor and predisposing factor to kidney disease and high
blood pressure in adult life. Despite the strong association, currently no interventions are available to improve
nephron endowment at birth. Maintenance of an abundant Nephron Progenitor Cell (NPC) population is a
major determinant of nephron number at birth and is determined in part by the balance between NPC renewal
and differentiation. Studies show that NPCs have a limited lifespan, with Young NPCs (E13.5) predominantly
expanding the NPC pool by self-renewal and Old NPCs (P0) exiting the self-renewing pool poised to
differentiate en masse. Our recent studies show cell-intrinsic differences in NPCs metabolic pathway usage
with developmental age. This metabolic shift correlates spatiotemporally with the switch from NPC renewal to
differentiation. The long term goal of our research program is to harness this significant difference in metabolic
states to maneuver NPC fate in vitro and in vivo. The overall hypothesis to be tested is that the changing
metabolite milieu within the NPCs due to the metabolic shift from glycolysis to OxPhos during development will
reprogram the NPC epigenome to favor renewal shutdown and promote differentiation. The hypothesis
presents a new paradigm for NPC self-renewal and differentiation decisions, linking existing knowledge on
growth factor signaling in NPC to an energy metabolism driven cell-fate switch. The focus of this application is
to determine how metabolic manipulations impact the NPC open chromatin landscape to regulate NPC fate.
Both glycolysis and OxPhos are easily measured and easily manipulated. This proposal aims to identify fuel
dependency and metabolic flexibility of young versus old NPCs. We combine genetic, epigenetic and metabolic
approaches to test our hypothesis. The studies proposed in Aim1 will determine whether glycolysis is
necessary and/or sufficient to promote NPC renewal, and conversely, whether OxPhos is necessary and
sufficient to promote differentiation. Aim 2 will test the hypothesis that a metabolism-epigenetic axis controls
NPC lifespan and demonstrate that metabolic manipulations directly modify the open chromatin landscape to
regulate gene expression and NPC fate. We combine genetic, epigenetic and metabolic approaches to test our
hypothesis, using open chromatin landscape profiling (ATAC-Seq), ChIP-Seq, and metabolic manipulations on
mesenchyme cultures and isolated NPCs from wild type and glycolysis-impaired mouse NPCs. Identifying the
preferred fuel(s) and metabolic pathways utilized by Young versus Old NPCs, and their degree of flexibility in
fuel metabolism would guide how to nutritionally modulate NPCs transcriptional program and thus their fate.

## Key facts

- **NIH application ID:** 9969349
- **Project number:** 5R01DK118231-03
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **Principal Investigator:** Samir S El-Dahr
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $228,000
- **Award type:** 5
- **Project period:** 2018-09-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9969349

## Citation

> US National Institutes of Health, RePORTER application 9969349, Intermediary Metabolism Control of Nephron Progenitor Lifespan (5R01DK118231-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9969349. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*