The influence of circadian rhythms on heart (patho)physiology is highlighted by increased frequency of myocardial infarctions as well as complications after cardiac surgery in the morning, and different molecular components of the clock were shown to have a role in cardiovascular function. The nuclear receptors REV-ERBa and related REV-ERBb (encoded by Nr1d1/2) are robust oscillators, core components of the clock and have previously been observed to be the link between circadian rhythmicity and (lipid) metabolism in healthy as well as disease conditions in organs such as skeletal muscle and (fatty) liver. However, despite a proposed connection between rhythmic REV-ERB expression and different outcomes of cardiac surgery performed in the morning/afternoon, very little is known about both REV-ERBa and b in the heart. The research proposed here will examine the cardiac-specific function of REV-ERBs on a physiological as well as a molecular level.To study REV-ERBs in the heart, we have generated cardiomyocyte-specific double knock-out (Rev-erbaFFbFF; aMHC-Cre (CM-DKO)) mice, which we find to die at the age of 6-9 months. We propose to study the mechanisms by which chronic cardiac loss of REV-ERBs results in premature lethality. By comparing CM-DKO and Cre- littermate control mice, we aim to better understand the role and interplay of these transcriptional regulators in circadian cardiometabolism and heart failure. In Aim 1 we will characterize our cardiomyocyte-specific Rev-erba/b double knock-out (CM-DKO) mouse model. To assess different phases of disease development and progression, structural and functional cardiac parameters will be assessed in a serial manner.In aim 2 we will determine the molecular mechanism of REV-ERB function in the heart. Since both REV-ERBa/b are essential transcriptional regulators of circadian clock-controlled output genes in a range of tissues, I will study how REV-ERBs affect (circadian) gene regulation in the heart. Therefore, I will perform RNA-sequencing (at different time points across 24 hours) in control as well as REV-ERB CM-DKO hearts. To identify genes that are directly regulated by REV-ERB, I will perform CUT&RUN in a newly engineered HA-(epitope) REV-ERBa tagged model. The results of our proposed experiments will contribute significantly to a better understanding of the molecular mechanisms of the circadian clock in the heart as well as the role of REV-ERB in cardiometabolism and heart disease.
|Program type||Postdoctoral Fellowship|
|Effective start/end date||01/01/2020 → 12/31/2021|