# Regulation and Dysregulation of Cardiac EC coupling by Calmodulin

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2020 · $575,397

## Abstract

Project Summary/Abstract
Genetic and acquired defects in Ca release channels, ryanodine receptors (RyR2s), underlie a spectrum of
lethal cardiac disorders ranging from arrhythmias to heart failure (i.e. ryanopathies). Although RyR2 is
considered to be a logical target for the treatment of these disorders, effective therapies based on
normalization of RyR2 function are lacking. This is in part due to the complex nature of RyR2 regulation. In
this proposal, we will test the hypothesis that intelligently-engineered proteins coupled with AAV-mediated
gene transfer provide a strategy for the rational design of therapies to treat ryanopathies. Based on
calmodulin's (CaM) role in regulating RyR2, we propose a novel cardiac gene therapy approach against
ryanopathies using RyR2-specific and multi-target CaMs, i.e therapeutic CaMs (TCaMs). This strategy is
based on the concept suggested by our initial studies that various regulators of RyR2 function converge on a
common mechanism of refractoriness that controls RyR2 activity dynamics and Ca signaling stability during the
cardiac cycle. Genetic and acquired RyR2 defects, including mutations in RyR2, CASQ2 and CaM, alter RyR2
refractoriness resulting in disturbed Ca cycling, premature aberrant Ca release and consequent arrhythmias.
Therapeutic CaMs (TCaMs) designed to reset RyR2 refractoriness, regardless of the underlying etiology, will
provide a general treatment strategy for ryanopathies. To accomplish this goal, we will use multi-scale studies
(from molecule to whole animal) that combine the expertise of a protein biochemistry (Davis) lab and a cellular
physiology (Gyorke) lab using novel and cutting edge protein delivery approaches for engineered CaMs and
state-of-the art multi-compartmental and multicellular imaging tools for testing their functional effects.
Additionally, studies using genetic mouse models and preparations from a clinically relevant canine heart
failure (HF) model will provide a “proof-of-principle” for new therapeutic strategies based on desynchronization
of aberrant Ca release by CaM-mediated slowing of Ca signaling refractoriness. We propose to: 1) Test the
hypothesis that different genetic forms of CPVT impair RyR2 function through a common mechanism:
shortening Ca signaling refractoriness; and 2) Engineer “therapeutic”(T)CaMs for the treatment of
ryanopathies.

## Key facts

- **NIH application ID:** 9977792
- **Project number:** 5R01HL138579-04
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Jonathan Paul Davis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $575,397
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-04-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977792

## Citation

> US National Institutes of Health, RePORTER application 9977792, Regulation and Dysregulation of Cardiac EC coupling by Calmodulin (5R01HL138579-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9977792. Licensed CC0.

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