# Dynamic changes of the Nav1.5 interactome and contributions to heart failure

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $679,651

## Abstract

The NaV1.5 voltage-gated Na+ channel encoded by SCN5A is the fundamental component of
macromolecular protein complexes that initiate the cardiac action potential. Abnormal NaV1.5 function is
a prominent substrate for inherited and acquired forms of cardiac arrhythmias, reflected by a staggering
array of identified NaV1.5 mutations. A small subset of these are associated with dilated cardiomyopathy
but the underlying mechanisms are not known. A leading hypothesis, that the arrhythmias drive the
cardiomyopathy, cannot explain why most arrhythmogenic NaV1.5 mutations do not cause
cardiomyopathy nor why knockout of the NaV1.5 interacting protein FGF13 leads to arrhythmias yet is
protective for pressure overload-induced heart failure (HF) despite associated NaV1.5 dysfunction.
Moreover, HF from other causes leads to pathological remodeling that disrupts regulation of the VGSC
macromolecular complex and increases arrhythmia risk through mechanisms that are poorly understood.
Complicating mechanistic insight is that there are different NaV1.5 pools defined by distinct subcellular
localizations with the cardiomyocyte, each hypothesized to have protein partners that uniquely define the
distinct pools and confer specific channel properties and functions. However, the critical partners remain
poorly understood because of challenges of low throughput “favorite” candidate approaches.
 We propose an unbiased multilevel discovery strategy, employing newly developed second
generation proximity labeling tools, novel mouse models, coupled with carefully calibrated cross
comparisons designed to increase the specificity of our findings. Exploiting the expertise from two labs
with individual and collaborative track records applying a large tool set to dissect complex physiologic
mechanisms and define perturbations in pathological states, we propose adaptable candidate validation
approaches to establish a comprehensive picture of NaV1.5 interactomes under physiological states and
when perturbed by disease. With these innovative approaches we propose to: 1) Define the static and
dynamic NaV1.5 channel interactomes and “neighborhoods” within distinct subcellular pools; 2) Elucidate
how HF alters the NaV1.5 microenvironment; and 3) Determine the HF-protective effects for ablation of
the NaV1.5 interactor, FGF13.
 With these aims, our goals are to define the contributions of the NaV1.5 macromolecular to
development and progression of HF and its associated arrhythmias and to unravel how HF perturbs the
NaV1.5 complex to increase arrhythmia risk and exacerbate HF in a vicious cycle.

## Key facts

- **NIH application ID:** 10478131
- **Project number:** 5R01HL160089-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Steven O Marx
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $679,651
- **Award type:** 5
- **Project period:** 2021-09-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10478131

## Citation

> US National Institutes of Health, RePORTER application 10478131, Dynamic changes of the Nav1.5 interactome and contributions to heart failure (5R01HL160089-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10478131. Licensed CC0.

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