# Targeting Protein Trafficking in Arrhythmogenic Cardiomyopathy

> **NIH NIH K08** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2022 · $179,280

## Abstract

ABSTRACT
This proposal is to support the career development of Joseph Palatinus, MD, PhD, to become an
independent physician scientist with a focus on basic/translational research by targeting
protein trafficking as a means to prevent and treat arrhythmias and sudden cardiac death
(SCD). The PI will have as a primary mentor Professor Robin Shaw, MD PhD, who is world
renowned expert in protein trafficking and cardiomyocyte biology. The comprehensive training
program is composed of laboratory-based research, coursework, workshops, grantsmanship
seminars, scientific conferences (local and international), and career guidance by a mentoring
committee. The committee includes the mentors and leverages the combined experience and
technical knowledge of 5 leading independent cardiovascular investigators at the Eccles
Cardiovascular Research and Training Institute at the University of Utah as well as Dr. Jeffery
Saffitz at Harvard Medical School, a world expert on Arrhythmogenic cardiomyopathy. The
research proposed will apply the alternatively translated isoform of Connexin 43 (Cx43),
dubbed GJA1-20k (and an established actin stabilizing protein), to the Desmoglein 2 (DSG2)
mutant model of ACM. Preliminary data has demonstrated disrupted actin organization in both
cellular and animal models of a DSG2 mutation which, in the heart is associated with a loss of
gap junction trafficking to the intercalated disk and downstream cardiac dysfunction. It is
hypothesized that GJA1-20k will lead to recovery of gap junction localization, suppression of
arrhythmias and prevention of SCD in the DSG2 mutant model of ACM by directly interacting
with and stabilizing cellular actin. Two specific aims are proposed: 1) Is actin dysregulation
responsible for the trafficking defects observed in the DSG2 mutant model? And 2) Does GJA1-
20k rescue the cardiomyopathic and arrhythmogenic phenotype of ACM and prevent SCD? High
resolution confocal microscopy, proximity ligation immunolabeling, electron microscopy, co-
immunoprecipitation, echocardiography, and in vivo telemetry monitoring are some of the
advanced techniques which will be used to develop a mechanistic understanding of actin
dependent trafficking mediated by GJA1-20k. The results from this study are expected to
develop a novel paradigm to treat and prevent arrhythmogenic SCD by targeting protein
trafficking.

## Key facts

- **NIH application ID:** 10485228
- **Project number:** 5K08HL155886-02
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Joseph A. Palatinus
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $179,280
- **Award type:** 5
- **Project period:** 2021-09-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10485228

## Citation

> US National Institutes of Health, RePORTER application 10485228, Targeting Protein Trafficking in Arrhythmogenic Cardiomyopathy (5K08HL155886-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10485228. Licensed CC0.

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