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Dual filament control of myocardial power and hemodynamics

Award Number: R01HL148785
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/25/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2029

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Dual filament control of myocardial power and hemodynamics - Abstract The heart’s pumping capacity is determined by myofilament loaded shortening and power output since the ventricles always work against an afterload to eject blood. The molecular mechanism to explain afterload dependence of ventricular function has eluded cardiac muscle physiologists and cardiologists for decades, and this mechanism could be pivotal for novel small molecule therapies aimed to help heart failure patients. In the previous cycle of the project, the MPI team (a) collectively published 33 peer-reviewed papers, (b) discovered a thin filament mechanism to enhance power reserve capacity in myofilaments from human failing hearts, (c) demonstrated phosphorylation-dependent MyBP-C induced interfilamentary drag, (d) integrated our FiberSim and FiberVent computational models, and (e) adapted cMyBP-C’s putative regulatory functions to our FiberSim model to derive new hypotheses for the current proposal. The new objectives are to (i) use biochemical, biophysical, and transgenic tools to discern cMyBP-C’S role in regulating myofilament power and afterloaded cardiac contractions and (ii) integrate these control mechanisms into our multi-scale computational model that can predict how sarcomere-level modifications impact hemodynamics. The experimental approach is strategically designed to address three independent yet complementary aims. Aim 1 will test the novel hypotheses that cMyBP-C is the load sensor, phosphorylation of cMyBP-C enhances the load-dependence, and these effects translate to ventricular function. Experiments will manipulate cMyBP-C’s phosphorylation state to optimize the load dependence of myofilament power and the afterload dependence of ventricular performance. Aim 2 tests the hypothesis that cMyBP-C tunes load dependence by its N-terminal position, which is modulated by its phosphorylation state using innovative FRET and fluorescent polarization methodologies. In Aim 3, computer models of sarcomere and organ-level function will be deployed to test molecular mechanisms of load-dependent contraction and hemodynamics. This work extends beyond the sarcomere and has the potential to identify high-value therapeutic targets to optimize ventricular performance in heart failure patients.


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 = $669,778 )
2025	2025	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	000	5	8/14/2025	COMPETING CONTINUATION	$669,778
														Subtotal = $669,778

Issue Date FY: 2023 ( Subtotal = $467,110 )
2023	2023	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	000	4	7/7/2023	NON-COMPETING CONTINUATION	$467,110
														Subtotal = $467,110

Issue Date FY: 2022 ( Subtotal = $467,110 )
2022	2022	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	000	3	7/27/2022	NON-COMPETING CONTINUATION	$467,110
														Subtotal = $467,110

Issue Date FY: 2021 ( Subtotal = $467,110 )
2021	2021	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	000	2	8/20/2021	NON-COMPETING CONTINUATION	$467,110
														Subtotal = $467,110

Issue Date FY: 2020 ( Subtotal = $480,860 )
2020	2020	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	000	1	8/21/2020	NEW	$480,860
														Subtotal = $480,860

Grand Total All Awards = $2,551,968

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Dual filament control of myocardial power and hemodynamics

Award Number: R01HL148785

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/25/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2029

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