# Understanding Polycystin-1 Structure-GPCR Function for the Development of New Therapeutic Approaches in ADPKD

> **NIH NIH R01** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2020 · $322,608

## Abstract

Summary
Autosomal dominant polycystic kidney disease (ADPKD) is the most common potentially lethal genetic
disease. Eighty-five percent of the cases of ADPKD are due to mutation of the PKD1 gene of which
approximately ¼-1/3 are due to missense mutations and small, in-frame deletions that may be amenable to
functional rescue. PKD1 encodes polycystin-1 (PC1), a large and complex protein thought to function as an
atypical G protein-coupled receptor (GPCR). The loss of PC1-G protein regulation is now known to be
fundamental to the pathogenesis of PKD, yet we know essentially nothing about the mechanism whereby PC1
regulates G protein signaling activity. Our long-term goal is to understand the mechanism underlying PC1-G
protein regulation in order to target and functionally restore or augment this function as a treatment for ADPKD.
Based on the structural and functional similarities between PC1 and the adhesion class of GPCRs, and
intriguing results from our preliminary studies, we propose that a mechanism involving a cryptic tethered
peptide ligand is responsible for the regulation of G protein signaling by PC1, and furthermore, is involved in
the pathogenesis of renal cyst formation. The major goals of this proposal, therefore, are to determine the
structure-function relationships behind the tethered ligand-mediated regulation of G protein signaling by PC1
and to demonstrate the relevance of this regulatory mechanism in the pathogenesis and potential treatment of
ADPKD. Specifically, we intend to determine the essential properties of the tethered peptide ligand of PC1
responsible for its regulation of G protein signaling, map the regions of PC1 involved in tethered ligand-
dependent signaling, and determine the conditions for the peptide ligand-dependent rescue of renal
cystogenesis. The proposed studies will employ transfection of established cell lines along with standard
molecular biology methods and biochemical assays to assess the signaling capability of modified expression
constructs of PC1 and of soluble tethered ligand-derived peptides, and will include the treatment of cystic
kidneys with soluble tethered ligand-derived peptides in both ex vivo and in vivo model systems. Successful
completion of this project is expected to reveal molecular details of the regulation of G protein signaling by PC1
via its cryptic, tethered ligand, and to demonstrate the potential of this regulatory mechanism as a novel
therapeutic target. Elucidating the mechanism of PC1-regulated G protein signaling will advance our
understanding of the molecular pathogenesis of ADPKD, which is imperative for the development new
therapies for the treatment or prevention of this disease.

## Key facts

- **NIH application ID:** 9867162
- **Project number:** 1R01DK123590-01
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** ROBIN Lee MASER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $322,608
- **Award type:** 1
- **Project period:** 2020-01-15 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9867162

## Citation

> US National Institutes of Health, RePORTER application 9867162, Understanding Polycystin-1 Structure-GPCR Function for the Development of New Therapeutic Approaches in ADPKD (1R01DK123590-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9867162. Licensed CC0.

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