Circadian Regulation of Cardiac Electrophysiology

Abstract The proposed grant aims to investigate the connection between circadian clocks, 24-hour rhythms, and sudden cardiac death (SCD), with the goal of determining their respective contributions to arrhythmogenic risk. The specific aims of the project are as follows: The overall hypotheses of the project are: Circadian clock transcription factors directly regulate the expression of cardiac ion channel genes critical for normal cardiac excitability. The cardiomyocyte circadian clock regulates daily rhythms in ion channel protein translation. Modifying behavioral or environmental time-keeping cues can alter the circadian clock regulation of ion channel expression and circadian rhythms in autonomic function, thereby impacting arrhythmogenesis. The project aims to generate new knowledge and insights at the intersection of chronobiology and cardiac electrophysiology, potentially leading to the discovery of novel chronotherapeutic strategies to reduce arrhythmogenic risk. Aim 1: Determine the mechanism and functional significance of circadian regulation of cardiac ion channel genes critical for normal cardiac excitability. Analyze the promoter activity of specific cardiac ion channel genes (Kcnh2, Gja1, Rrad, and Gjc1) to identify conserved cis-regulatory elements responsible for circadian oscillations. Validate these elements using various experimental techniques. Investigate the circadian regulation of translation of cardiac ion channel and ion channel regulatory proteins using Riboseq. Aim 2: Determine how modifying behavioral and environmental time-keeping cues impact cardiac electrophysiology, the autonomic regulation of cardiac electrophysiology, and cardiac arrhythmia susceptibility. Examine the effects of time-restricted feeding (TRF), chronic light cycle advance (LCA), or dim light at night (DLAN) on cardiac electrophysiology in mouse models with disrupted circadian-regulated genes (Gja1 or Rrad). Extend the studies to determine how TRF, LCA, or DLAN affect cardiac electrophysiology and arrhythmia susceptibility in genetic mouse models of specific arrhythmias (Scn5a+/- and Ryr2+/ R2474S mice).