# Identification of the genetic mechanisms governing mammalian nephron endowment

> **NIH NIH F30** · CINCINNATI CHILDRENS HOSP MED CTR · 2021 · $51,036

## Abstract

PROJECT SUMMARY & ABSTRACT
Mammalian kidney function is critically dependent on the number of nephrons generated during renal
development. Nephrons are the filtration unit of the renal system and arise from a nephron progenitor cell (NPC)
population at the periphery of the developing tissue. NPCs interact with the surrounding ureteric bud (UB) and
stromal compartments, balancing self-renewal and differentiation into segmented nephron structures via a
mesenchymal-to-epithelial transition. Consequently, nephron endowment is a quantitative outcome determined
by several processes including UB branching and NPC dynamics. Two noteworthy aspects of mammalian renal
development are: (1) a 10-fold variation in nephron number (NN) between human kidneys from different
individuals, ranging from 200,000 to >2.5 million units per kidney and (2) the synchronous depletion of remaining
progenitors at postnatal day 3 in mice (gestational week 34-37 in humans). These facts pose compelling research
questions, as the genetic contributions to these aspects of renal organogenesis are not currently known. From
a clinical standpoint, a low nephron endowment, which is particularly prevalent in premature birth cohorts,
contributes to high blood pressure and chronic kidney disease (CKD). These conditions pose an immense
disease burden worldwide, particularly as there is no known postnatal generation of new nephrons. While various
genetic and perinatal factors are demonstrated to reduce NN, there remains a clear need to identify genetic
contributions to the variation in and upper limits of nephron endowment. The principal investigator herein has
identified that distinct mouse strains can be used to model and dissect the genetic basis of differences in nephron
number, as several inbred strains and diversity outbred hybrids exhibit distinct, consistent NN phenotypes.
Therefore, this proposal sets forth a strategy to identify and subsequently target genetic loci that modify NN
outcomes, leveraging QTL mapping algorithms, sequencing data and known gene expression patterns in renal
tissue. Secondarily, on a mechanistic basis, it is unclear whether NN variation arises from altered cessation
timing, intrinsic changes in NPC activity, or a combination thereof; cellular energetics and mitochondrial function
have been implicated. Thus, this proposal will also investigate a mitochondrial mutant mouse model, which
exhibits NN elevated above baseline littermate controls, to identify mechanisms by which nephrogenesis can be
enhanced. Collectively, by identifying targets and mechanisms that segregate with either high or low nephron
number, this research will contribute to the ability to develop diagnostic screens and interventional treatment
strategies for deficient nephrogenesis, respectively.
Comprehensively, this research plan will aptly be executed in the fulfillment of a fellowship research training plan
aimed at fostering the development of an independent physician-scientist in academ...

## Key facts

- **NIH application ID:** 10247020
- **Project number:** 5F30DK123841-03
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Alison Jarmas
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $51,036
- **Award type:** 5
- **Project period:** 2019-09-12 → 2023-09-11

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247020

## Citation

> US National Institutes of Health, RePORTER application 10247020, Identification of the genetic mechanisms governing mammalian nephron endowment (5F30DK123841-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10247020. Licensed CC0.

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