Grants and Contracts Details
Description
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
Status | Finished |
---|---|
Effective start/end date | 9/1/20 → 5/31/23 |
Funding
- University of Florida: $920,032.00
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.