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Computer modeling of myosin binding protein C and its effects on cardiac contraction

Award Number: R01HL146676
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2019
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Computer modeling of myosin binding protein C and its effects on cardiac contraction - ABSTRACT This collaboration develops a comprehensive mathematical model of phosphorylation-dependent cardiac myosin binding protein C (cMyBP-C) regulation. The resulting model will be leveraged to predict how to best manipulate cMyBP-C phosphorylation to prevent or reverse contractile dysfunction in heart failure with reduced, or preserved ejection fraction. Recent attempts to treat cardiac disease by modifying myofilament-level function have been mostly disappointing. The main problem is that it has been difficult to enhance contraction without compromising relaxation, and vice versa. In vivo, of course, autonomic control can enhance both contraction and relaxation at the same time. During exercise, for example, the heart contracts more forcefully and it also relaxes faster to allow time for the ventricles to fill as heart rate increases. While numerous mechanisms contribute to this behavior, cMyBP-C is one of the main sarcomere-level effectors. It’s therefore possible that cMyBP-C could be strategically manipulated to create innovative new treatments for cardiac disease. The main barrier to developing these treatments is that cMyBP-C’s function is complex and regulated by at least 9 phosphorylation residues. The functional roles of the individual residues are not equivalent and the large number of potential combinations means that approaches based solely on cell and animal-based experiments are impractical. This challenge will be overcome by developing computational models that can capture and predict cMyBP-C’s complex impact on contractile function at both the sarcomere and whole organ levels. The multidisciplinary team comprises three experienced investigators with complementary skills: Julian Stelzer, PhD, Kenneth Campbell, PhD, and Brett Colson, PhD. The proposal has 3 Aims: Aim 1 combines high-throughput screens and computer modeling to predict cMyBP-C phospho-variants that enhance contraction and relaxation. Aim 2 tests these predictions in mice using AAV9 gene delivery. Aim 3 determines whether phospho-variants of cMyBP-C can rescue contractile function in mice and in samples of myocardium isolated from patients with disease. The proposal is innovative and advances understanding of cMyBP-C biology and clinical translation. The team’s commitment to sharing open-source code and experimental data will benefit research focused on heart failure.


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 = $681,335 )
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	003	6	7/16/2025	NON-COMPETING CONTINUATION	$68,133
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	000	6	3/5/2025	NON-COMPETING CONTINUATION	$613,202
2025	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	002	5	4/30/2025	COMPETING CONTINUATION	$54,481
2025	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	001	4	4/30/2025	NON-COMPETING CONTINUATION	-$54,481
														Subtotal = $681,335

Issue Date FY: 2024 ( Subtotal = $711,835 )
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	000	5	3/10/2024	COMPETING CONTINUATION	$711,835
														Subtotal = $711,835

Issue Date FY: 2022 ( Subtotal = $551,684 )
2022	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	001	4	5/31/2022	NON-COMPETING CONTINUATION	$55,171
2022	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	000	4	4/5/2022	NON-COMPETING CONTINUATION	$496,513
														Subtotal = $551,684

Issue Date FY: 2021 ( Subtotal = $551,684 )
2021	2021	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	000	3	3/12/2021	NON-COMPETING CONTINUATION	$551,684
														Subtotal = $551,684

Issue Date FY: 2020 ( Subtotal = $551,216 )
2020	2020	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	000	2	3/23/2020	NON-COMPETING CONTINUATION	$551,216
														Subtotal = $551,216

Issue Date FY: 2019 ( Subtotal = $594,809 )
2019	2019	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	000	1	3/29/2019	NEW	$594,809
														Subtotal = $594,809

Grand Total All Awards = $3,642,563

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Computer modeling of myosin binding protein C and its effects on cardiac contraction

Award Number: R01HL146676

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2019

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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