# Ion Channel Function and Regulation of the Polycystin-1/2 Complex in Kidney Physiology and Polycystic Kidney Disease

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2022 · $537,114

## Abstract

Project Summary/Abstract
The long-term goals of our laboratories are to understand the biological functions of polycystin proteins (PC1
and PC2) encoded by autosomal dominant polycystic kidney disease (ADPKD) genes PKD1 and PKD2, and to
determine the pathogenic pathways when they are mutated. By so doing, we seek to establish a firm mechanistic
understanding of the ADPKD pathogenesis, which can be used to guide the rational development of therapies.
A great obstacle to the development of effective ADPKD therapies has been the lack of a precise understanding
of polycystins’ key biological function and how its malfunction initiates and drives the disease process. We have
most recently discovered that the complex formed by PC1 and PC2 (PC1/PC2), with both of proteins lining the
channel pore, functions as a calcium-permeable ion channel, in contrast to the homomeric PC2 channel which
primarily conducts sodium and potassium. This finding indicates that the polycystin complex gains unique ion
channel properties from the assembly of PC1 and the resulting PC1/PC2 channel plays a key role in kidney
physiology and ADPKD. In this multi-PI application, we will use our newly developed gain-of-function (GOF)
PC1/PC2 channel mutant to determine how the PC1/PC2 ion channel function is regulated at a molecular level
by extracellular and intracellular domains and how Ca2+ plays a role in this regulation. We will develop a new
ADPKD mouse model that is defective in PC1/PC2 ion channel function and use it to determine that the channel
function is essential for proper kidney development and inactivation of this function is the real culprit for ADPKD.
To determine whether enhancing the PC1/PC2 ion channel function can be used as a therapeutic strategy, we
will develop another new mouse model with the GOF of PC1/PC2 channel function and use it to determine that
it can rescue the disease in a PKD1 mutant mouse that mimics human ADPKD. We anticipate that the proposed
studies will provide new insights into the fundamental molecular mechanism of function and regulation of the
PC1/PC2 channel and define its channel function as the key determinant of ADPKD. Overall, the project will
likely lead to a better understanding of normal kidney development, reveal the primary culprit for developing
ADPKD when PC1 or PC2 are mutated, and help form the basis for targeting the PC1/PC2 channel for
preventative and therapeutic purposes.

## Key facts

- **NIH application ID:** 10405087
- **Project number:** 5R01DK125404-03
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Feng Qian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $537,114
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10405087

## Citation

> US National Institutes of Health, RePORTER application 10405087, Ion Channel Function and Regulation of the Polycystin-1/2 Complex in Kidney Physiology and Polycystic Kidney Disease (5R01DK125404-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10405087. Licensed CC0.

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