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Cardiac microtubules as regulators of diastolic function.

Award Number: R01HL171614
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/12/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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Cardiac microtubules as regulators of diastolic function. - Abstract Diastolic heart disease (DHD) is the leading cause of death and disability worldwide. With no FDA approved therapies to improve diastolic function, the NIH has placed special emphasis on collaborative initiatives bridging basic science and clinical data to understanding the molecular mechanism of DHD. The hallmarks of diastolic heart disease are a stiffening left ventricle and an inability for the heart muscle to relax, both of which occur in DHD by mechanisms that are poorly understood. Building on recent work that the cardiac microtubule network (MTN) can both stiffens and impairs the relaxation of failing cardiomyocytes, in Aim 1 we determine the relative contribution of the MTN to myocardial stiffness in intact preparations of HTN and DHD ventricular myocardium. We isolate the myocyte and fibrotic contribution to stiffening and use complimentary reductionist approaches to isolate the relative contributions of actomyosin activity, passive titin stiffness, and the MTN to myocyte mechanics. In Aim 2 we extend these findings into a clinically analogous ex-vivo working myocardial slice preparation to dissect the MTN impediment to the phases of diastole in HTN and DHD. The working preparation allows us to contextualize the findings in Aim 1 with the emergent properties arising from cyclically contracting loaded myocardium. Thus, by carefully designing a series of complementary assays we will resolve the molecular contributions to cardiac stiffening and impaired relaxation in DHD, and in doing so determine the potential for MTN-targeting therapies in DHD.


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 = $486,329 )
2025	2025	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Cardiovascular Diseases Research	000	2	11/11/2024	NON-COMPETING CONTINUATION	$486,329
														Subtotal = $486,329

Issue Date FY: 2024 ( Subtotal = $540,365 )
2024	2024	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Cardiovascular Diseases Research	001	1	5/31/2024	NEW	$54,036
2024	2024	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Cardiovascular Diseases Research	000	1	12/12/2023	NEW	$486,329
														Subtotal = $540,365

Grand Total All Awards = $1,026,694

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Cardiac microtubules as regulators of diastolic function.

Award Number: R01HL171614

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/12/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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