# Deciphering polycystin-dependent electric signaling of primary cilia in the renal system

> **NIH NIH K99** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $90,000

## Abstract

Project Summary/Abstract
Primary cilia are unique organelles that protrude from the cell membrane of almost all vertebrate cells. Defective
primary cilia, caused by mutations in proteins required for cilia formation or signaling, can result in ciliopathies,
pleiotropic diseases affecting multiple organs. In particular, Autosomal Dominant Polycystic Kidney Disease
(ADPKD), the most prevalent monogenic disease leading to end-stage renal disease (ESRD), is considered
ciliopathy. The polycystin channel complex, formed by the transmembrane proteins PC-1 and PC-2, is
abundantly expressed primary cilia, and mutations in PC-1 and PC-2 account for the vast majority of ADPKD.
To date, we only have a limited functional understanding of how the polycystin complex commands the electric
signaling of primary cilia via cation flux (K+, Na+, and Ca2+) due to technical challenges in characterizing channel
activity of ciliary membranes. To better understand, I established ciliary patch-clamp recordings to measure the
activity of endogenous polycystin channels directly from the ciliary membrane. I published in 2020 that the C-
type lectin domain (CTL) of the PC-1 N-terminus plays a crucial role in polycystin activation, highlighting the
indispensable participation of PC-1 subunits. In this proposal, using my established assays, I will determine
how ADPKD-causing mutations within the N-terminus of PC-1 impair polycystin function. Further, I will
establish ciliary patch-clamp recordings of primary cilia within kidney organoids, allowing me for the
first time to functionally connect the molecular phenotype of impaired channel activity with the
macroscopic phenotype of cyst formation. During the mentored K99 phase, I will characterize the functional
impact of pathogenic variants within the PC-1 subunit using the ciliary patch-clamp recording. To understand the
endogenous regulation of the polycystin complex, I will determine the specificity and potency for the cilia-
enriched oxysterols to activate the polycystin complex in the cell or ciliary membrane. To complete this aim, I will
receive further training in cilia biology in the Delling lab. In parallel, co-mentor Dr. Meyeon Park will guide me to
understand the clinical significance of pathogenic mutants in PC-1.
To expand knowledge of polycystin complex under more physiological conditions, I plan to measure electric
signaling of primary cilia using kidney organoids during the R00 phase. Kidney organoids provide a powerful tool
for understanding development and disease and finding new treatments and regenerative approaches.
Characterizing ciliary ion channels in organoids will establish an essential milestone to understand the role of
primary cilia in different segments of renal tubules and cyst development. During this time, the candidate will
complete mentored training in the Department of Physiology in preparation for the independent R00 phase with
the help of Dr. Benjamine S. Freedman at the University of Washingto...

## Key facts

- **NIH application ID:** 10693400
- **Project number:** 5K99DK131361-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Kotdaji Ha
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $90,000
- **Award type:** 5
- **Project period:** 2022-09-02 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10693400

## Citation

> US National Institutes of Health, RePORTER application 10693400, Deciphering polycystin-dependent electric signaling of primary cilia in the renal system (5K99DK131361-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10693400. Licensed CC0.

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