Circadian Regulation of Cardiomyocyte Size and Function

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.
StatusActive
Effective start/end date1/1/2512/31/29

Funding

  • National Heart Lung and Blood Institute: $143,829.00

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