# Use of kidney organoids to investigate developmental programs and the effects of fetal exposures

> **NIH NIH R21** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $421,067

## Abstract

Abstract
 In utero exposures to insults such as pregestational diabetes can have significant repercussions for
proper growth and development. Exposure to the diabetic milieu can lead to diabetic embryopathy, a disruption
in normal cellular programs during critical stages of development which leads to congenital anomalies affecting
multiple organs. Kidney anomalies resulting from genetic and in utero perturbations are the leading cause of
chronic kidney disease in children, markedly affecting quality of life. However, there is a significant gap in our
understanding of how such insults affect these early developmental programs, precluding the generation of
interventional strategies. The limitations of mouse models and differences between human and mouse kidney
programs necessitate the development of alternate systems in which to study in utero exposures. Kidney
organoids represent an attractive model for their recapitulation of developmental programs in an easily
manipulatable environment. Yet, studies with kidney organoids thus far have almost exclusively focused on
genetic diseases and injury affecting cells of the mature nephron. To this end, we will exploit iPSC-derived
kidney organoids for their ability to recapitulate human developmental processes and test how in utero
exposures to the pregestational diabetic milieu affect kidney development programs. We will focus on
programs of nephron progenitors, the precursor of all the cells in the nephron, and podocytes, a nephron
progenitor descendant critical to establishing and maintaining proper blood filtration. We will mimic the
pregestational diabetic environment in culture and interrogate the effects on nephron progenitor programs by
single cell (sc)RNA-seq and the assay for transposase-accessible chromatin with sequencing (ATAC-seq) as
the organoids progress through this stage of differentiation (Aim 1). We will also assess the effects on maturing
podocytes utilizing similar methodology (Aim 2). We expect to identify alterations to the normal differentiation
programs of these cells and uncover critical pathways affected by the diabetic milieu. These findings will serve
as the foundations for future studies and aid the development of novel interventional strategies then help
mitigate the effects of in utero insults. Our studies will enable new directions for kidney organoid research,
laying the groundwork for future studies into in utero insults and congenital anomalies in this ex vivo,
manipulatable system.

## Key facts

- **NIH application ID:** 10988821
- **Project number:** 1R21HD113970-01A1
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Lori L O'Brien
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $421,067
- **Award type:** 1
- **Project period:** 2024-09-03 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10988821

## Citation

> US National Institutes of Health, RePORTER application 10988821, Use of kidney organoids to investigate developmental programs and the effects of fetal exposures (1R21HD113970-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10988821. Licensed CC0.

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