Grants and Contracts Details
Description
Circadian clock regulation of cardiomyocyte activity and function is crucial for maintaining a healthy heart, as
disruption to the cardiomyocyte clock has been linked to cardiac arrhythmias, contractile dysfunction, cellular
hypertrophy, and metabolic abnormalities. While the adverse effects of cardiomyocyte clock dysfunction are
evident, our understanding of how a functional and synchronized clock promotes cardiac development and
cellular health remains unclear. Additionally, it is poorly understood whether cellular stressors that lead to
cardiomyocyte dysfunction can drive dysregulation of clock function. This study aims to determine how
circadian clock development drives cardiomyocyte maturation and function and how persistent hypertrophic
stimuli lead to cardiomyocyte clock dysfunction. Human-induced pluripotent stem cell-derived cardiomyocytes
(hiPSC-CMs) offer a unique opportunity to investigate how the activation and synchronization of the
cardiomyocyte clock drive maturation and development, given the fact that we can follow the development of
the cardiomyocyte clock at the onset of beating post differentiation. Preliminary data indicates that hiPSC-CMs
harbor the machinery for the cardiomyocyte clock. Yet, they do not exhibit oscillations indicative of a functional
clock at day 30 post-differentiation, a timepoint commonly used for experimentation. Using temperature,
serum, and overexpression of clock gene entrainment techniques, I will train the clock to oscillate in a manner
indicative of a functional clock. I will then utilize mechanical, electrophysiological, and mitochondrial assays to
determine how circadian clock development drives the maturation of hiPSC-CMs. I will also use hiPSC-CMs
harboring mutations associated with hypertrophic growth to determine if a constant hypertrophic stimulus can
lead to circadian clock dysfunction. Lastly, leveraging my mentor-provided training in transcriptomics, the study
will employ RNA-Seq, Nascent-Seq, and ATAC-Seq on samples collected at 4-hour intervals over 24 hours to
define the circadian time series of steady-state mRNA levels, new transcription, and chromatin accessibility.
The conceptual and technical training in circadian biology and transcriptomics outlined in the career
developmental plan of this K01 will enable the candidate to transition from his current research track position to
the tenure line and position himself as an expert in circadian regulation of cardiomyocyte maturation and
function.
Status | Active |
---|---|
Effective start/end date | 1/1/25 → 12/31/29 |
Funding
- National Heart Lung and Blood Institute: $143,829.00
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