# Cyst induction and growth in ADPKD

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2024 · $490,868

## Abstract

Abstract:
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the world’s most common life-threatening
genetic diseases. Mutations in the genes PKD1 and PKD2 account for 85% and 15% of all ADPKD cases,
respectively. ADPKD patients are heterozygous for either PKD1 or PKD2 deleterious mutations; homozygous
mutations are considered incompatible with life. Interestingly, loss-of-heterozygosity studies and genome
sequencing of patients’ cysts, have documented the clonal nature of the epithelial cysts in ADPKD. Altogether,
these data support the two-hit model in which one mutation in either PKD1 or PKD2 is inherited, but a second
(somatic) mutation is required for the clonal expansion of the epithelial cells and progression of cystic disease.
While these data strongly support the two-hit model, there is scarce data reporting if, when, and how, a second
mutation in an individual renal cell affects the behavior of that cell and its environment in vivo.
We have generated a series of mouse lines that recapitulates the two-hit model. In an otherwise Pkd2
heterozygous animal, we can induce a second mutation during embryonic development but also at later
timepoints. Our data confirms that single mutant cells are responsible for the generation of cysts and that all
cells in the cyst arise from the originally mutated cell. Most importantly, our data reveals that not all mutant
cells become cysts.
We hypothesize that cyst inception is modulated by additional intrinsic and extrinsic factors affecting mutant
cells. Specifically, we hypothesize that cyst inception and/or growth is driven by tubular identity, external
sources of proliferation and the microenvironment created by the chimeric nature of the disease. We will test
these hypotheses in three aims employing mouse models as well as kidney explants and iPSC-derived kidney
organoids.

## Key facts

- **NIH application ID:** 10976067
- **Project number:** 1R01DK129238-01A1
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Cristina Cebrian Ligero
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $490,868
- **Award type:** 1
- **Project period:** 2024-08-15 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10976067

## Citation

> US National Institutes of Health, RePORTER application 10976067, Cyst induction and growth in ADPKD (1R01DK129238-01A1). Retrieved via AI Analytics 2026-06-13 from https://api.ai-analytics.org/grant/nih/10976067. Licensed CC0.

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