Monday, June 23, 2025 6/23/2025

Cardiac Myosin Binding Protein-C in Development and Reversal of Heart Failure

Award Number: R01HL145534
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/15/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2025

Group Awards By:

View Award Description

Cardiac Myosin Binding Protein-C in Development and Reversal of Heart Failure - Heart failure (HF) afflicted 6.5 million Americans in 2017, carries 5-year mortality of ~50%, and will likely increase to > 8 million by 2030. The lack of significant improvement in mortality for the last 46 years, the reality of needing to discontinue effective medications due to hypotension in heart failure with reduced ejection fraction (HFrEF), and the paucity of effective treatment for heart failure with preserved ejection fraction (HFpEF) combine to suggest that new treatments are needed. Cardiac myosin binding protein-C (cMyBPC) resides on the thick filament of the heart muscle. Phosphorylation of cMyBPC at its M-domain increases cross-bridge cycling rate. Because increasing cross-bridge cycling rate can improve both contractility and lusitropy, we hypothesize that phosphorylation of cMyBPC provides a novel central mechanism that can prevent and treat HF due to different causes. Using mouse models that mimic de-phosphorylated and phosphorylated cMyBPC at 3 serine (S) sites in the M-domain, we recently discover that cMyBPC phosphorylation mitigates both aged-related development of HFpEF and trans-aortic constriction (TAC) surgery induced HFrEF, as seen by improved survival and better preservation of diastolic function. Thus, cMyBPC phosphorylation holds potential to treat both HFrEF and HFpEF. However, we find evidence that 2 new S phosphorylation sites outside our study of 3 S sites add significant functional effects. Consequently, we have made 2 new knock-in mouse models to include the new sites for elucidating the effects of maximally phosphorylated cMyBPC(5SD) and dephosphorylated cMyBPC(5SA) M-domain. We also find evidence that pressure stress can activate focal adhesion kinase (FAK) to phosphorylate tyrosine (Y) residue(s) in cMyBPC. This discovery leads to a new supporting hypothesis that pressure stress triggers FAK to phosphorylate cMyBPC to increase contractility as a compensatory response. With these discoveries in mind, we intend to determine the efficacy of maximal M-domain phosphorylation and elucidate the novel FAK-cMyBPC mechanism. Aim #1: Determine the efficacy and companion mechanisms of phosphorylated cMyBPC to preserve cardiac function under HF inducing conditions of aging, pressure stress, and obesity. We will challenge mice with 2-yr aging, TAC, or high fat diet. We will use a combination of functional and biochemistry techniques to determine the underlying mechanisms. Ability of cMyBPC(5SD) mouse to resist deterioration and effectiveness of using cMyBPC(5SD) gene therapy to reverse failing WT hearts will quantify the efficacy of cMyBPC phosphorylation for prevention and treatment respectively. Aim #2: Elucidate signaling mechanism and functional results of pressure stress induced tyrosine phosphorylation of cMyBPC. We will identify Y site(s), confirm FAK-cMyBPC interaction, and elucidate effects of FAK phosphorylating cMyBPC on models ranging from intact papillary muscle to new knock-in mouse. Impact: Efficacy results and mechanistic insights stemming from this study provide evidence for translating cMyBPC phosphorylation to new HF treatment.


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 = $0 )
2025	2023	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Cardiovascular Diseases Research	000	5	12/12/2024	NON-COMPETING CONTINUATION	$0
2025	2023	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Cardiovascular Diseases Research	001	5	3/31/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $461,754 )
2023	2023	TEXAS A & M UNIVERSITY SYSTEM HEALTH SCIENCE CENTER	6003 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Cardiovascular Diseases Research	001	5	3/10/2023	NON-COMPETING CONTINUATION	$46,175
2023	2023	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Cardiovascular Diseases Research	000	5	12/12/2022	NON-COMPETING CONTINUATION	$415,579
														Subtotal = $461,754

Issue Date FY: 2022 ( Subtotal = $461,754 )
2022	2022	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Cardiovascular Diseases Research	000	4	12/31/2021	NON-COMPETING CONTINUATION	$415,578
2022	2022	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Cardiovascular Diseases Research	001	4	6/15/2022	NON-COMPETING CONTINUATION	$46,176
														Subtotal = $461,754

Issue Date FY: 2021 ( Subtotal = $491,894 )
2021	2021	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Cardiovascular Diseases Research	000	3	12/18/2020	NON-COMPETING CONTINUATION	$442,704
2021	2021	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Cardiovascular Diseases Research	001	3	5/24/2021	NON-COMPETING CONTINUATION	$49,190
														Subtotal = $491,894

Issue Date FY: 2020 ( Subtotal = $484,193 )
2020	2020	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Cardiovascular Diseases Research	001	2	3/13/2020	NON-COMPETING CONTINUATION	$24,209
2020	2020	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Cardiovascular Diseases Research	000	2	12/12/2019	NON-COMPETING CONTINUATION	$459,984
2020	2019	TEXAS A&M UNIVERSITY SYSTEM, THE	8441 RIVERSIDE PARKWAY BLDG 1 STE 3100	BRYAN	TX	77807	BRAZOS	USA	Cardiovascular Diseases Research	002	1	3/18/2020	NEW	$0
														Subtotal = $484,193

Issue Date FY: 2019 ( Subtotal = $487,231 )
2019	2019	TEXAS A&M UNIVERSITY SYSTEM,THE	200 TECHNOLOGY WAY, STE 2079	COLLEGE STATION	TX	77845	BRAZOS	USA	Cardiovascular Diseases Research	000	1	1/18/2019	NEW	$487,231
														Subtotal = $487,231

Grand Total All Awards = $2,386,826

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Cardiac Myosin Binding Protein-C in Development and Reversal of Heart Failure

Award Number: R01HL145534

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/15/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2025

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer