# A Novel Role for NFATC1 in Modulating Cardiac Excitability

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2020 · $753,756

## Abstract

PROJECT SUMMARY / ABSTRACT
The overall goal of this proposal is to explore the molecular and electrophysiological role of NFATC1 as a novel
atrial fibrillation (AF) susceptibility gene and to define the previously unknown contribution of NFATC1 to atrial
excitability. AF, the most common sustained arrhythmia encountered in clinical practice, has an economic burden
exceeding $7 billion in annual health care costs. Emerging evidence implicates cardiac transcription factors in
the pathogenesis in both familial forms of AF and AF in the general population. We identified a mutation in the
cardiac transcription factor NFATC1 in a high-risk Utah pedigree defined by young onset AF. NFATC1 is a Ca2+-
dependent transcription factor postulated to play a role in cardiac development, but up until now has never been
associated with cardiac excitability. Our exciting preliminary data identify a novel role for NFATC1 in modulating
atrial excitability, in that nfatc1 null zebrafish develop spontaneous atrial tachyarrhythmia and juvenile sudden
death. Aim 1 seeks to define the biochemical, molecular and electrophysiological basis of the mutant NFATC1
dysfunction, using the HL-1 atrial cell line, a human cell culture model (patient-specific and genome-edited
induced pluripotent stem cell derived cardiomyocytes, iPSC-CMs), and a whole animal model (transgenic
zebrafish). Aim 2 characterizes the role of NFATC1 in modulating atrial excitability by exploring the molecular
and electrophysiological basis for the atrial tachyarrhythmia in nfatc1 null zebrafish. Aim 3 will define NFATC1-
controlled transcriptional networks and gene pathways that regulate cardiac excitability, using single-cell RNA-
Seq, ChIP-Seq and ChIP-Mass Spectroscopy in human atrium and NFATC1 null and WT iPSC-CMs.
Our proposal leverages human genetics, genome-editing techniques, state-of-the-art Next-Gen sequencing
modalities and bioinformatics, and electrophysiology to comprehensively characterize the novel role of NFATC1
in cardiac excitability and AF pathogenesis. An understanding of a key transcriptional network that regulates ion
channel gene expression and atrial excitability will provide a broader, and more comprehensive understanding
of arrhythmia susceptibility and lay the foundation for novel AF therapies.

## Key facts

- **NIH application ID:** 10026527
- **Project number:** 1R01HL153025-01
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** MARTIN TRISTANI-FIROUZI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $753,756
- **Award type:** 1
- **Project period:** 2020-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10026527

## Citation

> US National Institutes of Health, RePORTER application 10026527, A Novel Role for NFATC1 in Modulating Cardiac Excitability (1R01HL153025-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10026527. Licensed CC0.

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