# Establishing and Mimicking Patterning Mechanisms in the Distal Nephron Tubule and Kidney Organoid

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2023 · $650,207

## Abstract

During embryonic and fetal stages, the kidneys develop millions of nephrons that generate highly specialized
cells. These cells ensure that blood flowing into the kidney is filtered and required substances are reabsorbed
while unwanted metabolites and solutes are led to the bladder for excretion. Birth defects are common in the
kidney, ~ 1/100 of all births have a so-called Congenital Anomaly of the Kidney and Urinary Tract (CAKUT). At
the most severe end of CAKUT, newborns are missing kidney functionality, and their life expectancy is less than
one year. Most abnormalities have no current effective interventions and genetic changes lack context. There is
thus a critical need to understand where developmental defects arise and to generate new therapies restoring
or replacing kidney function. In our work we have used single cell omics and molecular characterizations of
human and mouse kidneys to provide a blueprint for how nephrons form and maps for to replicate this in human
stem cell-derived kidney organoids. In doing so we provide a genetic and developmental context to genes
identified in CAKUT patients. In this proposal we will follow these leads and address three outstanding questions
in developmental nephrology. In Aim 1, we investigate the embryonic origins of distal nephron tubule segments.
We will perform the first single cell omic analysis linking developing and adult kidneys. This provides a roadmap
for how cells differentiate. We will use new genetic mouse lineage-tracing tools to test how cells in the early distal
nephron relate to functional cells in mature kidneys. These experiments will map where genes are required as
the nephron develops. In Aim 2, we will investigate how proteins that turn genes on and off control the
development of the distal nephron. We will use a technique called Cut&Run to analyze how genes often mutated
in CAKUT, control DNA and gene expression. We will also activate signaling pathways and alter the expression
of genes linked to CAKUT. This will allow us to directly study how distal nephron cells form provide causality
between gene expression and regulation. We will use our new system to generate hundreds of nephrons from
human stem cells in - synchronized nephroids. In this system, nephrons develop at the same time and pace,
unlike in the body where nephrons from many developmental stages form near each other. Our system provides
a unique advantage to study, manipulate, and isolate cells from nephrons at the same developmental stage. The
data we collect will show how genes are activated. In Aim 3 we address a fundamental question in developmental
nephrology - how is the nephron initially patterned? To do this we will use synthetic cellular organizers that
secrete signaling proteins to pattern our synchronized nephroids. We will study how signal ligands control
nephron formation and patterning. This also has a practical application as we can gain control over nephroid
patterning. Our system will inform our e...

## Key facts

- **NIH application ID:** 10719178
- **Project number:** 1R01DK136802-01
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Nils Olof Lindstrom
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $650,207
- **Award type:** 1
- **Project period:** 2023-08-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10719178

## Citation

> US National Institutes of Health, RePORTER application 10719178, Establishing and Mimicking Patterning Mechanisms in the Distal Nephron Tubule and Kidney Organoid (1R01DK136802-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10719178. Licensed CC0.

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