# Cellular/molecular substrates linking channel dysfunction and pathological cardiac remodeling

> **NIH NIH R01** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2020 · $487,500

## Abstract

Summary
Cardiac performance significantly impacts quality of life; cardiac dysfunction and arrhythmia increase with age
and can lead to heart disease, the number one cause of death in the United States. Atrial fibrillation (AF) is the
most common type of cardiac arrhythmia and AF significantly increases the risk of heart failure and stroke. A
genetic basis for AF is indicated in one third of patients and pro-fibrotic and apoptotic effects of sustained AF in
patients and animal models have been documented. A major barrier to understanding the interplay between
electrical and structural cardiac remodeling is the overwhelming complexity of mammalian systems. In order to
define fundamental molecular/genetic links, I propose to use a simpler, genetically tractable model, Drosophila.
The fruit fly has proven extremely useful in elucidating the first conserved genetic networks responsible for
heart development and in identifying cellular mechanisms underlying adult heart function and disease. I have
identified important similarities in ion channel function and cardiac arrhythmias between flies and humans
including early afterdepolarizations that lead to tachyarrhythmias. Genetic analyses of hearts from flies with
mutations in these channels reveal interesting differences in wnt and hippo signaling pathways and suggest
possible connections between them. Individually, these pathways have been implicated in human heart
cardiomyopathies and there are tantalizing suggestions that these pathways may be involved in maintenance
and regeneration of adult cardiac function. I will use the fly cardiac model I have developed to elucidate
underlying genetic/molecular connections between these pathways in both “healthy” and “diseased” hearts with
subsequent validation in the vertebrate zebrafish heart model. The interplay between electrical activity, Ca2+
handling, and cardiac function/structure is likely a balancing act for post-mitotic organs with limited
regenerative capacity; understanding this will be important in developing effective therapies to treat human
cardiomyopathies.

## Key facts

- **NIH application ID:** 9834961
- **Project number:** 5R01HL132241-04
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** Karen Ocorr
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $487,500
- **Award type:** 5
- **Project period:** 2016-12-15 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9834961

## Citation

> US National Institutes of Health, RePORTER application 9834961, Cellular/molecular substrates linking channel dysfunction and pathological cardiac remodeling (5R01HL132241-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9834961. Licensed CC0.

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