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Fast myosin binding protein-C and cardiac contractility in heart failure

Award Number: R01HL105826
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/03/2025
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Fast myosin binding protein-C and cardiac contractility in heart failure - PROJECT SUMMARY: Heart failure (HF) is a complex clinical syndrome and a predominant cause of mortality in adults. The overall objective of this renewal is to continue to elucidate the mechanism of action of the myosin binding protein-C (MyBP-C) family of proteins on cardiac function. MyBP-C proteins regulate contractile structure and function in both cardiac and skeletal muscles. The present proposal is focused on defining the role of one of the MyBP-C proteins, fast myosin binding protein-C (fMyBP-C), as a negative regulator of cardiac contractility. fMyBP-C is minimally expressed at baseline in the heart but is significantly increased in the cardiomyocytes during HF. In the pilot studies, a novel transgenic mouse that expresses fMyBP-C (fMyBP-CTg) specifically in cardiomyocytes and at levels similar to those observed in HF develops cardiac hypertrophy, decreased maximal force and reduced myofilament Ca2+ sensitivity. In contrast, homozygous fMyBP-C knockout (fMyBP-CKO) mice, when challenged with transverse aortic coarctation (TAC)-induced pressure overload, shows significantly improved cardiac function, compared to controls. Furthermore, in vitro studies revealed that fMyBP-C negatively modulates cardiomyocyte contractility by increasing super-relaxed state of myosin, actomyosin interactions and thin filament activation. However, the molecular mechanisms underlying the regulation of fMyBP-C and, in turn, its impact on sarcomere function, are completely unknown. On the basis of the preliminary findings, our central hypothesis is that fMyBP-C upregulation reduces cardiac function during HF by reducing actomyosin interactions, preventing thin and thick filament interactions and decreasing the rate of force generation, resulting in contractile dysfunction and HF. SPECIFIC AIM 1 will use a novel fMyBP-CTg mouse model to determine the sufficiency of fMyBP-C expression in the cardiomyocytes in reducing cardiac contractility, actomyosin interactions and cross- bridges and developing HF, compared to controls, including cMyBP-C transgenic and null mice. Using the fMyBP-CKO mice, SPECIFIC AIM 2 will define the necessity of fMyBP-C to exacerbate (TAC)-induced pressure overload HF using fMyBP-CKO mice, compared to controls. In the same aim, a novel Mybpc2- mScarlet (fluorescence) knock-in mouse model will be used to fate map fMyBP-C expression during TAC- induced pressure overload. Using these mouse models, SPECIFIC AIM 3 will elucidate the molecular mechanism(s) underlying reduced cardiac contractility using cardiomyocytes from the fMyBP-CTg and fMyBP-CKO mice, as well as recombinant proteins and chimeras of cMyBP-C/fMyBP-C, on various biophysical, biochemical and functional studies in vitro, compared to wild-type controls. Together, these studies will determine the necessity and sufficiency of fMyBP-C to negatively regulate inotropy and cause HF. The results will lead to the identification of potential therapeutic targets to treat HF.


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: 2026 ( Subtotal = $0 )
2026	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	000	12	12/5/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $386,875 )
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	001	12	1/14/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$386,875
2025	2024	CINCINNATI UNIV OF	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cardiovascular Diseases Research	000	11	1/13/2025	NON-COMPETING CONTINUATION	$0
2025	2024	CINCINNATI UNIV OF	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cardiovascular Diseases Research	002	11	4/3/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $386,875

Issue Date FY: 2024 ( Subtotal = $405,000 )
2024	2024	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cardiovascular Diseases Research	000	11	12/18/2023	NON-COMPETING CONTINUATION	$405,000
														Subtotal = $405,000

Issue Date FY: 2023 ( Subtotal = $405,000 )
2023	2023	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cardiovascular Diseases Research	001	10	3/6/2023	NON-COMPETING CONTINUATION	$40,500
2023	2023	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cardiovascular Diseases Research	000	10	12/20/2022	NON-COMPETING CONTINUATION	$364,500
														Subtotal = $405,000

Issue Date FY: 2022 ( Subtotal = $405,000 )
2022	2022	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cardiovascular Diseases Research	001	9	12/22/2021	COMPETING CONTINUATION	$405,000
2022	2019	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cardiovascular Diseases Research	002	8	5/26/2022	NON-COMPETING CONTINUATION	$0
2022	2019	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cardiovascular Diseases Research	000	8	12/14/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $405,000

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cardiovascular Diseases Research	000	8	2/10/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $413,612 )
2019	2019	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cardiovascular Diseases Research	000	8	3/29/2019	NON-COMPETING CONTINUATION	$413,612
														Subtotal = $413,612

Issue Date FY: 2018 ( Subtotal = $412,322 )
2018	2018	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cardiovascular Diseases Research	001	7	7/14/2018	NON-COMPETING CONTINUATION	$8,249
2018	2018	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cardiovascular Diseases Research	000	7	3/16/2018	NON-COMPETING CONTINUATION	$404,073
														Subtotal = $412,322

Issue Date FY: 2017 ( Subtotal = $391,511 )
2017	2017	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cardiovascular Diseases Research	001	6	4/7/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$391,511
2017	2017	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cardiovascular Diseases Research	003	6	4/11/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$337,573
2017	2016	LOYOLA UNIVERSITY OF CHICAGO	2160 S FIRST AVE	MAYWOOD	IL	60153	COOK	USA	Cardiovascular Diseases Research	000	5	4/4/2017	COMPETING CONTINUATION	$0
2017	2016	LOYOLA UNIVERSITY OF CHICAGO	2160 S FIRST AVE	MAYWOOD	IL	60153	COOK	USA	Cardiovascular Diseases Research	002	5	4/11/2017	COMPETING CONTINUATION	-$337,573
														Subtotal = $391,511

Issue Date FY: 2016 ( Subtotal = $383,017 )
2016	2016	LOYOLA UNIVERSITY OF CHICAGO MEDICAL CENTER	6525 NORTH SHERIDAN STREET	CHICAGO	IL	60626	COOK	USA	Cardiovascular Diseases Research	000	5	3/1/2016	COMPETING CONTINUATION	$383,017
														Subtotal = $383,017

Issue Date FY: 2014 ( Subtotal = $329,648 )
2014	2014	LOYOLA UNIVERSITY OF CHICAGO MEDICAL CENTER	6525 NORTH SHERIDAN STREET	CHICAGO	IL	60626	COOK	USA	Cardiovascular Diseases Research	000	4	12/5/2013	NON-COMPETING CONTINUATION	$302,738
2014	2014	LOYOLA UNIVERSITY OF CHICAGO MEDICAL CENTER	6525 NORTH SHERIDAN STREET	CHICAGO	IL	60626	COOK	USA	Cardiovascular Diseases Research	001	4	3/11/2014	NON-COMPETING CONTINUATION	$26,910
														Subtotal = $329,648

Issue Date FY: 2013 ( Subtotal = $320,229 )
2013	2013	LOYOLA UNIVERSITY OF CHICAGO MEDICAL CENTER	6525 NORTH SHERIDAN STREET	CHICAGO	IL	60626	COOK	USA	Cardiovascular Diseases Research	001	3	7/4/2013	NON-COMPETING CONTINUATION	$17,491
2013	2013	LOYOLA UNIVERSITY OF CHICAGO MEDICAL CENTER	6525 NORTH SHERIDAN STREET	CHICAGO	IL	60626	COOK	USA	Cardiovascular Diseases Research	000	3	12/23/2012	NON-COMPETING CONTINUATION	$302,738
														Subtotal = $320,229

Issue Date FY: 2012 ( Subtotal = $336,375 )
2012	2012	LOYOLA UNIVERSITY OF CHICAGO MEDICAL CENTER	6525 NORTH SHERIDAN STREET	CHICAGO	IL	60626	COOK	USA	Cardiovascular Diseases Research	001	2	4/5/2012	NON-COMPETING CONTINUATION	$33,637
2012	2012	LOYOLA UNIVERSITY OF CHICAGO MEDICAL CENTER	6525 NORTH SHERIDAN STREET	CHICAGO	IL	60626	COOK	USA	Cardiovascular Diseases Research	000	2	12/9/2011	NON-COMPETING CONTINUATION	$302,738
														Subtotal = $336,375

Issue Date FY: 2011 ( Subtotal = $325,485 )
2011	2011	LOYOLA UNIVERSITY OF CHICAGO MEDICAL CENTER	6525 NORTH SHERIDAN STREET	CHICAGO	IL	60626	COOK	USA	Cardiovascular Diseases Research	000	1	12/17/2010	NEW	$325,485
														Subtotal = $325,485

Grand Total All Awards = $4,514,074

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Fast myosin binding protein-C and cardiac contractility in heart failure

Award Number: R01HL105826

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/03/2025

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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