# Circadian Regulation of Cardiac Electrophysiology

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2024 · $683,130

## Abstract

Abstract.
Circadian clocks play a fundamental role in aligning physiological and behavioral processes to predictable
changes in the daily environment. For decades, circadian signaling has been implicated in the development of
cardiac arrhythmias and sudden cardiac death (SCD) in individuals with cardiovascular disease. However,
numerous critical knowledge gaps persist regarding the connection between circadian clocks, circadian
rhythms, and SCD. This research proposal addresses these knowledge gaps by investigating the molecular
mechanisms underlying the circadian regulation of ion channel transcripts and proteins that impact arrhythmia
susceptibility.
Aim 1 will elucidate the molecular mechanisms responsible for the circadian regulation of cardiac ion channel
genes essential for cardiac excitability. Through comprehensive promoter analyses utilizing real-time
bioluminescence assays (LumiCycle), we will identify the conserved cis-regulatory element(s) essential for
circadian activity. The identified cis-regulatory element(s) will be validated using Chromatin
Immunoprecipitation and electrophoretic mobility shift assays.
Aim 2 focuses on determining how circadian alignment and misalignment affect the transcription and
translation of genes essential for normal cardiac electrophysiology. We will explore the impact of time-restricted
feeding on the transcriptional and translational regulation of myocardial genes important for cardiac excitability
by employing mRNA-seq and Ribo-seq technology.
Aim 3 will determine the physiological implications of circadian alignment and misalignment on cardiac
electrophysiology, autonomic regulation, and arrhythmia susceptibility. We will assess the impact of
manipulating feeding-fasting cycles on cardiac electrophysiology and arrhythmia susceptibility utilizing an
arrhythmogenic mouse model with impaired cardiac conduction and ventricular refractoriness (Scn5a+/-). We
will also investigate how feeding-fasting cycles modulate the autonomic nervous system's regulation of cardiac
electrophysiology using an inducible cardiomyocyte-specific Rrad knockout mouse model (iCSΔRrad).
This interdisciplinary project lies at the interface between chronobiology and cardiac electrophysiology, and it
will generate new knowledge to provide valuable insight into how circadian clocks and alignment impact the
risk for cardiac arrhythmias. In addition, the results of this project are expected to identify novel
chronotherapeutic strategies that can readily be adopted to mitigate arrhythmogenic risk in vulnerable
populations.

## Key facts

- **NIH application ID:** 10852377
- **Project number:** 1R01HL172813-01
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Brian P Delisle
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $683,130
- **Award type:** 1
- **Project period:** 2024-07-09 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10852377

## Citation

> US National Institutes of Health, RePORTER application 10852377, Circadian Regulation of Cardiac Electrophysiology (1R01HL172813-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10852377. Licensed CC0.

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