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Impact of cardiomyocyte cell cycle activity on atrial structural and functional remodeling following myocardial infarction

Award Number: R01HL158597
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Impact of cardiomyocyte cell cycle activity on atrial structural and functional remodeling following myocardial infarction - Both experimental and clinical studies have demonstrated that chronic myocardial infarction is associated with adverse remodeling of the left atrium, which in turn has an adverse impact on left atrial function. Left atrial dilatation is a powerful and independent predictor of mortality after myocardial infarction, but the mechanisms underlying the remodeling process are only poorly understood. Surprisingly, we have observed very high rates of cardiomyocyte cell cycle activity in the left atrium of infarcted mice. However, the role that cardiomyocyte cell cycle activity plays in mitigating or exacerbating structural and/or functional remodeling following myocardial infarction is not known. To directly address this question, we have generated a transgenic mouse model wherein infarct-induced left atrial cell cycle activity is silenced secondary to p16-Ink4a (p16) expression (p16 is a potent inhibitor of the proliferative kinase Cdk4 and transgenic expression in adult animals has previously been shown to be a potent cell cycle inhibitor). Here we propose to compare wild-type and p16 transgenic mice to determine the impact of atrial cardiomyocyte cell cycle activation on left atrial structural and functional remodeling following infarction. The experiments proposed in Aim 1 will determine the degree to which cardiomyocyte cell cycle activity impacts structural atrial remodeling following myocardial infarction. Left atrial structural analyses will be performed (a) at the tissue level to quantitate myocardial mass, cardiomyocyte number, fibrosis, immune cell infiltration, autonomic innervation and capillary density, (b) at the cardiomyocyte level to quantitate the extent of cell cycle progression and cellular hypertrophy as well as frequency of cardiomyocyte apoptosis, and (c) at the molecular level to quantitate transcriptome changes. The experiments proposed in Aim 2 will determine the degree to which cardiomyocyte cell cycle activity impacts atrial function following myocardial infarction. Atrial functional analyses will be performed (a) at whole organism level to quantitate echocardiographic and hemodynamic parameters, (b) at the intact heart level to quantitate calcium and voltage transient parameters in the left atrium (via optical mapping) and of cell clusters within the intact heart (via two-photon laser scanning microscopy), and (c) at the isolated cell level to quantitate fractional shortening and calcium handling kinetics. Importantly, cross-referencing the cell and molecular data from Aim 1 with the imaging and functional data from Aim 2 should enable us to better determine which cell cycle-mediated changes have a relevant impact on cardiac function. Such information may suggest interventions aimed at reversing compromised left atrial function in infarcted hearts.


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: 2025 ( Subtotal = $577,087 )
2025	2025	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cardiovascular Diseases Research	000	4	2/28/2025	NON-COMPETING CONTINUATION	$577,087
														Subtotal = $577,087

Issue Date FY: 2024 ( Subtotal = $628,383 )
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cardiovascular Diseases Research	000	3	2/20/2024	NON-COMPETING CONTINUATION	$577,087
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cardiovascular Diseases Research	001	3	6/20/2024	NON-COMPETING CONTINUATION	$51,296
														Subtotal = $628,383

Issue Date FY: 2023 ( Subtotal = $641,207 )
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cardiovascular Diseases Research	000	2	3/3/2023	NON-COMPETING CONTINUATION	$641,207
														Subtotal = $641,207

Issue Date FY: 2022 ( Subtotal = $641,207 )
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cardiovascular Diseases Research	000	1	4/22/2022	NEW	$641,207
														Subtotal = $641,207

Grand Total All Awards = $2,487,884

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Impact of cardiomyocyte cell cycle activity on atrial structural and functional remodeling following myocardial infarction

Award Number: R01HL158597

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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