Administrative Supplement -Circadian Clock Regulation of Myocardial Ion Channel Expression and Function

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Abstract This diversity supplement proposal aims 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 and contractile properties of cardiomyocytes. The outcomes will address significant gaps in our understanding of how the myocardial circadian clock regulates the expression of critical cardiac ion channels and how abnormal cardiac clock function contributes to arrhythmia and contractile 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 the time of day with a large-scale transcriptional program to support cellular homeostasis. The Delisle and Esser labs have used an inducible cardiomyocyte-specific mouse model to knock out the core clock gene, Bmal1 (iCSΔBmal1). Their 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. Additionally, this supplement aims to understand how disruption to the molecular cardiomyocyte clock alters the mechanical function of ventricular cardiomyocytes. Dr. Blair will generate new preliminary data on how an abnormal circadian clock in the heart contributes to contractile dysfunction, an extension of the parent award's goal of understanding how an altered circadian clock increases arrhythmia vulnerability. This proposal aims 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) Disruption of the cardiomyocyte clock will result in an imbalance in cardiac ion channel expression and currents, leading to altered excitability, increased arrhythmia vulnerability, and contractile dysfunction.