# Targeting Pannexin 1 as a Novel Mechanism for Arrhythmia and Fibrosis in Duchenne Cardiomyopathy

> **NIH NIH K08** · VIRGINIA COMMONWEALTH UNIVERSITY · 2024 · $148,214

## Abstract

PROJECT SUMMARY
Cardiovascular disease is the primary cause of death for patients with Duchenne muscular dystrophy (DMD).
Arrhythmia and cardiac fibrosis leading to dilated cardiomyopathy are the primary mechanisms of cardiac
mortality. Pannexins (Pxs), which are large conductance ion and small molecule channels, have been
implicated in other fibroproliferative diseases and are thought to be arrhythmogenic in other model of cardiac
disease. Loss of dystrophin, the primary defect in DMD, leads to elevated intracellular calcium (Ca2+) which is
also a primary effector of Pxs. The goal of this project is to investigate the mechanisms by which Px1
modulates the development of cardiac fibrosis and arrhythmogenesis in models of DMD cardiomyopathy.
Our preliminary data demonstrate a novel role for Px1 in the development of cardiac fibrosis and inducible
arrhythmia seen in the D2-mdx model of DMD. Genetic ablation of Px1 in the D2-mdx model (mdxPx1-/-)
rescues the cardiac phenotype, including normalization of cardiac fibrosis.as assessed by histopathology and
significant reduction in isoproterenol-induced ventricular ectopy. Based on these data, we hypothesize that
pathologically elevated intracellular Ca2+, a hallmark of this disease, leads to Px1 activation and results in
signaling cascades that activate apoptotic, oxidative, and inflammatory pathways that ultimately lead to
fibroblast activation and the development of cardiac fibrosis. We also hypothesize that Px1 channels represent
an independent mechanism for ventricular arrhythmia via generation of delayed after-depolarizations (DADs).
We with test these hypotheses using the 3 specific aims outlined in this proposal. In Aim 1, we will use
transgenic mice with global Px1 deletion in addition to pharmacological Px inhibition to determine if Px1
activation results in triggered arrhythmia. In Aim 2, we will identify the mechanism by which Px1 contributes to
cardiac fibrosis in DMD cardiomyopathy using pharmacological and genetic strategies. As Pxs are expressed
in both cardiomyocytes and cardiac fibroblasts, Aim 3 will test if fibroblast migration is dependent on Px1
activation in cardiomyocytes and/or fibroblasts using co-culture techniques for human induced pluripotent stem
cell cardiomyocytes (hiPSC-CMs) and cardiac fibroblasts. The completion of these studies will help to improve
our understanding of the mechanisms of cardiovascular disease in DMD and will provide the basis for further
investigation of a novel therapeutic target that has the potential to delay or prevent cardiac mortality in DMD
patients. Additionally, this proposal will allow a promising young physician scientist to gain important skill in
basic and translational studies in cardiac electrophysiology, cell signaling, and inflammation/fibrosis biology
under the expert guidance of a highly accomplished and dedicated mentorship committee. These new skills will
provide the foundation for a successful transition from junior investigator ...

## Key facts

- **NIH application ID:** 10753534
- **Project number:** 5K08HL155852-04
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Frank J Raucci
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $148,214
- **Award type:** 5
- **Project period:** 2021-01-07 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10753534

## Citation

> US National Institutes of Health, RePORTER application 10753534, Targeting Pannexin 1 as a Novel Mechanism for Arrhythmia and Fibrosis in Duchenne Cardiomyopathy (5K08HL155852-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10753534. Licensed CC0.

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