# Defining the roles of Orai3 channel in cardiomyocytes and cardiomyopathy.

> **NIH NIH R01** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2022 · $380,000

## Abstract

Abstract
 Dilated cardiomyopathy (DCM) is a severe condition, often idiopathic, that results in ventricular enlargement
and progressive systolic dysfunction. While usually treated with a combination of medications or using
implantable devices, cardiac transplantation is typically the ultimate treatment for DCM. The precise mechanisms
leading to ventricular dilatation and dysfunction are not well understood. However, during the last few years,
attention has focused on abnormalities of contractile and structural myocardial proteins and disorders of cardiac
energy metabolism. We identified Orai3, a Ca2+-selective ion channel and a member of the store-operated Ca2+
channels (SOCC), as a critical proactive factor required for maintenance of postnatal cardiac function. The goal
of this proposal is to investigate the roles of Orai3-mediated Ca2+ entry and associated molecular mechanisms
in cardiomyocytes. To pursue our goal, we have generated several lines of cardiomyocyte-specific Orai3
knockout (Orai3cKO) mice. While constitutive Orai3cKO mice are fertile and viable, they nevertheless develop DCM
that closely resembles many of the anatomical, pathophysiological, and clinical features of human DCM
culminating in heart failure (HF) and premature death. We discovered through our preliminary research that
Orai3-deficient cardiomyocytes exhibited loss of myofiber integrity and ultrastructural abnormalities associated
with severe dysregulation of mitochondrial proteins involved in oxidative metabolism and autophagy. Our
preliminary data strongly indicate that the Orai3 channel is an essential regulator of cardiac muscle function, and
the data provide evidence linking Orai3-mediated Ca2+ signaling to sarcomere cell integrity and bioenergetics
balance. We hypothesize that Orai3-mediated Ca2+ entry activates genetic programs through Ca2+
sensitive pathways that promote survival of post-natal cardiomyocytes. We plan to test our hypothesis by
pursuing the following Specific Aims: Aim 1: To characterize the DCM phenotype following loss of Orai3
expression in the adult myocardium; Aim 2: To elucidate mechanisms by which Orai3 loss leads to cardiac
function deterioration and DCM by analyzing inducible Orai3cKO mice; and Aim 3: To test the hypothesis that
Orai3-mediated Ca2+ entry regulates mitochondrial metabolism. This work will lead to discovery of the molecular
mechanisms by which Orai3 regulates heart function; identification of Orai as a novel mediator of DCM; and
potential identification of new strategies aimed at reversing or delaying the metabolic and functional
derangements seen in HF.

## Key facts

- **NIH application ID:** 10471846
- **Project number:** 5R01HL153638-03
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** Salvatore Mancarella
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $380,000
- **Award type:** 5
- **Project period:** 2020-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10471846

## Citation

> US National Institutes of Health, RePORTER application 10471846, Defining the roles of Orai3 channel in cardiomyocytes and cardiomyopathy. (5R01HL153638-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10471846. Licensed CC0.

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