# Myosin Activation as a Novel Therapeutic Strategy for Polycystic Kidney Disease

> **NIH NIH F31** · UNIVERSITY OF WASHINGTON · 2021 · $29,564

## Abstract

ABSTRACT
Autosomal dominant polycystic kidney disease (ADPKD) affects 1 in every 400-1000 people worldwide,
causing progressive fluid-filled cyst production in the kidneys, liver, and other organs, resulting in organ failure.
PKD is caused by mutations in the polycystin proteins polycystin-1 (PC1) or polycystin-2 (PC2). A clear
understanding of how polycystin dysfunction leads to cysts mechanistically is still elusive, due, in part, to the
lack of cyst producing model systems that accurately phenocopy the disease. Stem cell derived human kidney
organoids model PKD cystogenesis in a specific way and have potential to accelerate drug discovery and
development for PKD.
Using these PKD organoids, a drug screen was performed identifying blebbistatin, a myosin inhibitor, as a
potent cyst agonist. Subsequently, I discovered that EMD, a myosin activator, showed pre-clinical promise in
treating PKD cystogenesis in PKD organoids at both early and late stages of disease. Based upon preliminary
data and clues from the literature, I hypothesize that PC1 and PC2 positively regulate non-muscle myosin
contractility within the tubular epithelium to prevent cystogenesis.
Utilizing the unique kidney organoid in vitro system, I propose to analyze myosin modulator compounds and
non-muscle myosin dynamics in organoids to pinpoint the myosin domain that governs cyst expansion to
inform pre-clinical drug development. Second, I aim to optimize in vivo delivery and treatment strategies of
EMD in a mouse model of PKD. Finally, I will utilize the insight that PC1 structurally resembles an atypical
adhesion G-protein coupled receptor to analyze whether biochemically activating PC1 can stimulate organoid
contraction to link polycystin function to myosin control. Together, these experiments will establish myosin
activation as a therapeutic strategy to treat PKD and determine mechanisms of PC1 as a regulator of myosin
contractility. The goal of this work is to expedite drug discovery for PKD by utilizing model systems that best
represent the disease, and mechanistic studies that inform polycystin function in cystogenesis.

## Key facts

- **NIH application ID:** 10313782
- **Project number:** 1F31DK130550-01
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Louisa M Helms
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $29,564
- **Award type:** 1
- **Project period:** 2021-09-01 → 2022-03-27

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10313782

## Citation

> US National Institutes of Health, RePORTER application 10313782, Myosin Activation as a Novel Therapeutic Strategy for Polycystic Kidney Disease (1F31DK130550-01). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10313782. Licensed CC0.

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