# Screening for modifiers of PKD severity using ENU Mutagenesis

> **NIH NIH R01** · SEATTLE CHILDREN'S HOSPITAL · 2021 · $631,841

## Abstract

ABSTRACT
There is abundant evidence from the analysis of human populations and mouse models that the severity of
Polycystic Kidney Disease (PKD) can be modified by interacting genetic loci. The identification of these loci
should provide insight into our understanding of the basic pathobiology of cystogenesis and disease
progression. Importantly, they can potentially reveal novel pathways of therapeutic intervention. We have
extensive experience in the characterization of a mouse model of cystic kidney disease, and specifically the
investigation of strain-specific modifiers of its severity. However, the yield of proven causal genes in mouse
studies of this type has been low. In contrast, we have been very successful using a different approach for
novel disease gene discovery, namely mutagenesis with the chemical ethyl-nitrosourea (ENU). We have
recently modified this method so that we can do our screen entirely on an inbred background, using Whole
Genome Sequencing methodology for positional cloning. The recent characterization of the PKD1RC mutant
mouse as having slowly progressive PKD, which is sensitive to strain-specific modifiers, compels our proposal
that we use ENU mutagenesis for the generation and discovery of modifiers of PKD1-induced cystic kidney
disease. To complement this phenotype-driven approach, we will also pursue an analysis of candidate loci that
may modify PKD severity. We have data to suggest that Sonic Hedgehog (SHH) signaling plays a role in
cystogenesis, and we will test whether the deletion of genes in this pathway affects disease severity in the
PKD1RC mouse model.

## Key facts

- **NIH application ID:** 10218141
- **Project number:** 5R01DK111682-04
- **Recipient organization:** SEATTLE CHILDREN'S HOSPITAL
- **Principal Investigator:** DAVID R. BEIER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $631,841
- **Award type:** 5
- **Project period:** 2018-09-19 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10218141

## Citation

> US National Institutes of Health, RePORTER application 10218141, Screening for modifiers of PKD severity using ENU Mutagenesis (5R01DK111682-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10218141. Licensed CC0.

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