Thursday, April 25, 2024
4/25/2024
Summary: The overall objectives of this proposal are to 1) define the genomic and transcriptomic mechanisms by which the cardiomyocyte clock regulates ion channels that contribute to cardiac excitability; and 2) disrupt the cardiomyocyte clock to link changes in circadian-ordered gene expression with electrophysiological properties of atrial and ventricular cardiomyocytes. The outcomes will address significant gaps in our understanding for how the myocardial circadian clock regulates the expression of key cardiac ion channels and how abnormal cardiac clock function contributes to arrhythmia vulnerability. The mechanism regulating circadian timing, the molecular clock, exists in virtually all cell types in the body. A critical function of the molecular clock is to link time of day with a large-scale transcriptional program to support cellular homeostasis To date, our labs have used an inducible cardiomyocyte specific mouse model to knock out the core clock gene, Bmal1 (iCS¿Bmal1). These studies showed that disruption of the myocardial clock is sufficient to decrease ventricular K+ and Na+ channel gene expression, disrupt current levels, disrupt cardiac excitability, and increase arrhythmia susceptibility. These studies establish a critical role for the cardiomyocyte clock, independent of the central clock, in regulating the expression of different families of ion channel genes that impact the ionic balance needed for normal excitability. One goal of this project is to utilize large scale genomic and transcriptomic approaches with our mouse model system to define the circadian clock dependent control of temporal gene expression in both atrial and ventricular tissues. To address abnormal circadian clock function, our lab has used different models of circadian disruption, such as chronic phase advance or time restricted feeding to test links between circadian disruption and arrhythmia vulnerability in mouse models. We have found that disrupting either light or feeding time cues is sufficient to induce pathological changes in cardiac rhythms in normal mice and to accelerate sudden cardiac death in a genetic mouse model of arrhythmia susceptibility. These studies support our premise that disruption of day- night rhythms through environmental factors leads to altered myocardial clock function with outcomes that include modified ion channel expression, cardiac excitability and arrhythmia vulnerability. The aims of this proposal are designed to test the following hypotheses: 1) The molecular clocks in both atrial and ventricular cardiomyocytes are necessary to direct daily chromatin accessibility and transcriptional output including expression of key ion channel and ion channel regulatory genes. 2) Chronic disruption of the cardiomyocyte clock using altered time of feeding is sufficient to cause dysregulation of the cardiac clock resulting in an imbalance in cardiac ion channel expression and currents leading to altered excitability and increased arrhythmia vulnerability.
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