# Mechanism-inspired Strategies to Prevent Pathogenic Late Na Current in Cardiac Arrhythmias

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $546,855

## Abstract

PROJECT SUMMARY
PI: Manu Ben-Johny, Ph.D.
NaV1.5 channels are fundamentally involved in the normal function and pathophysiology of the heart. NaV1.5
dysfunction is linked to a variety of life-threatening cardiac diseases, including congenital and acquired cardiac
arrhythmias, cardiomyopathies, and heart failure. An emerging commonality for these pathologies is increased
late Na current, that results in sustained Na influx during the plateau phase of the cardiac action potential.
Understanding mechanisms that regulate late Na current is pivotal to understanding NaV1.5 dysfunction in
cardiac pathophysiology and for developing long-sought pharmacology. Our recent studies and preliminary data
suggest that late Na current is powerfully tuned by a Na channel modulator named fibroblast growth factor
homologous factor (FHF) that is endogenous to cardiomyocytes. Yet, how FHF accomplishes this important
mode of NaV1.5 regulation and its relevance to disease pathogenic mechanisms is not fully determined. In this
collaborative project, we seek (1) to dissect the molecular mechanism of FHF regulation of late Na current, and
(2) to identify the physiological and pathophysiological relevance of this modulatory scheme. Armed with in depth
mechanistic insights, we seek to engineer novel peptide-based inhibitors of late Na current. In particular, as FHF
undergoes extensive alternative-splicing, we evaluate isoform-specificity of late Na current regulation using a
novel FRET assay and through extensive single-channel analysis. To probe the physiological impact of FHF
regulation of late Na current, we virally manipulate FHF levels in cardiomyocytes differentiated from long-QT and
mixed-syndrome patient-derived induced pluripotent stem cells as well as transgenic mouse ventricular
myocytes. In so doing, this proposal promises new biophysical and physiological insights into modulation of
cardiac NaV1.5 and inform upon mechanisms underlying variable clinical manifestations of Na channelopathies.

## Key facts

- **NIH application ID:** 10791875
- **Project number:** 5R01HL163576-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Manu Ben Johny
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $546,855
- **Award type:** 5
- **Project period:** 2023-02-17 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10791875

## Citation

> US National Institutes of Health, RePORTER application 10791875, Mechanism-inspired Strategies to Prevent Pathogenic Late Na Current in Cardiac Arrhythmias (5R01HL163576-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10791875. Licensed CC0.

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