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Circadian Regulation of Cardiomyocyte Size and Function

Award Number: K01HL177045
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 01/01/2025
PERIOD OF PERFORMANCE END DATE: 12/31/2029

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Circadian Regulation of Cardiomyocyte Size and Function - PROJECT SUMMARY The overall objectives of this study are to 1) establish hiPSC-CMs as robust models for mechanistic studies of how intrinsic circadian regulation impacts cardiomyocyte size and function and 2) determine whether mutations that impact cellular size and function also disrupt cardiomyocyte clock rhythms. In the heart, disruptions in circadian rhythms stemming from irregular sleep, jet lag, or shift work can lead to heart attacks, arrhythmias, and cardiac dysfunction. Prior research shows that disrupting the clock via Bmal1 knockout in mouse cardiomyocytes induces age-dependent hypertrophic cardiomyopathy (HCM) with adverse myocardium remodeling, marked by enlarged cardiomyocytes. These data underscore the importance of studying circadian regulation on cardiomyocyte size and function. Most of our current understanding of how circadian clock disruption leads to cardiac abnormalities is derived from animal studies influenced by the suprachiasmatic nucleus (SCN) pacemaker. Consequently, our understanding is limited to how intrinsic cardiomyocyte circadian clocks function independently of the SCN. To address this gap, developing an in vitro cell model will be crucial. Such a model would enable circadian regulation of cardiomyocyte size and function to be studied separately from SCN influence, providing valuable insights into how the intrinsic clock autonomously governs cellular processes. Understanding these mechanisms is essential for unraveling the intricate relationship between circadian rhythms and cardiac health at the cellular level. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have emerged as invaluable disease and drug screening models. These cells also offer a unique opportunity to investigate the circadian regulation of cardiomyocyte size and function in a controlled in vitro environment independent of SCN influence. Due to their inherent immaturity, interventions targeting clock function in these cells at an early stage can elucidate the mechanisms by which circadian rhythms influence changes in cell size and function. Moreover, hiPSC-CMs serve as established models for inherited genetic mutations, offering a distinctive chance to explore how inherited genetic disorders, such as hypertrophic cardiomyopathy, which results in enlarged cardiomyocytes and hypercontractile function, disturb circadian rhythms. The results of these aims will 1) establish hiPSC-CM as a model to obtain critical new information on how the intrinsic cardiomyocyte clock impacts cell size and function and 2) inform us of the potential of targeting the clock to treat genetic cardiomyopathy. The training provided in this K01 will enable the candidate to become an expert in circadian regulation of cardiomyocyte size and function and establish an independent research career.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $144,909 )
2026	2026	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Cardiovascular Diseases Research	000	2	2/10/2026	NON-COMPETING CONTINUATION	$144,909
														Subtotal = $144,909

Issue Date FY: 2025 ( Subtotal = $143,829 )
2025	2025	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Cardiovascular Diseases Research	000	1	12/30/2024	NEW	$143,829
														Subtotal = $143,829

Grand Total All Awards = $288,738

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Circadian Regulation of Cardiomyocyte Size and Function

Award Number: K01HL177045

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 01/01/2025

PERIOD OF PERFORMANCE END DATE: 12/31/2029

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