Circadian Clock Regulation of Myocardial Ion Channel Expression and Function

The overall objective of this proposal is to define the molecular mechanisms by which circadian rhythms and the cardiac molecular clock regulate cardiac excitability to impact the risk for arrhythmias. 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 expression contributes to arrhythmia vulnerability. The molecular mechanism regulating circadian timing, the molecular clock, exists in virtually all cell types in the body. One fundamental function of the molecular clock is to link time of day with a large-scale transcriptional program to support cellular homeostasis. Our lab used different models of circadian disruption, such as chronic light phase advance or time restricted feeding, to study the interaction between lifestyle factors, circadian disruption and arrhythmia vulnerability in mouse models. Consistent with studies in humans and rodents, we 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 mouse model of long QT syndrome. These studies provide evidence that altered lighting or feeding behavior, likely through clock disruption can impact the heart to modulate arrhythmia vulnerability. Overall hypotheses: The molecular clock in both atrial and ventricular cardiomyocytes is necessary to direct daily chromatin accessibility and transcriptional output including expression of key ion channel and ion channel regulatory genes. Chronic disruption of the cardiomyocyte clock using altered time of feeding is sufficient to cause dysregulation of the cardiac clock output resulting in an imbalance in cardiac ion channel expression and currents leading to altered excitability and increased arrhythmia vulnerability. We will test these hypotheses in the following two aims. Aim 1. To determine the molecular clock controlled genomic and transcriptomic landscape in the heart. Aim 2. To determine how disruption in feeding rhythms impacts clock gene expression, cardiac excitability, cardiac action potentials (APs), and ionic currents