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Role of Cardiac Myosin Binding Protein-C in the Regulation of Myocardial Contraction

Award Number: R01HL080367
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2005
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Role of Cardiac Myosin Binding Protein-C in the Regulation of Myocardial Contraction - TITLE: Role of Cardiac Myosin Binding Protein-C in the Regulation of Myocardial Contraction ABSTRACT: The overall goal of this project is to understand how cardiac myosin binding protein-C (cMyBP-C) regulates heart muscle contraction and relaxation. cMyBP-C is a critical regulator of cardiac function, with dysfunction of cMyBP-C commonly occurring in heart failure and mutations in cMyBP-C being the most common genetic cause of HCM. However, the regulatory effects of cMyBP-C are complex and most likely involve dynamic interactions with both thick (myosin containing) and thin (actin containing) filaments, making it challenging to sort out what are likely to be reciprocal or interrelated effects of cMyBP-C on each filament. To overcome these and other challenges, we recently developed a novel method that allows us to rapidly remove and replace (“cut and paste”) cMyBP-C at its endogenous position in sarcomeres, thus affording us the opportunity to quickly test cMyBP-C effects on both filament systems. In Aim 1 we will test the functional significance of the “middle domains” of cMyBP-C which were recently implicated as regulators of thick filament relaxation by stabilizing the “interacting heads motif” conformation of myosin on the thick filament as well as novel regulators of cMyBP-C function including Ca2+-Calmodulin (CaM) that we show in exciting new preliminary data may regulate cMyBP-C binding to the thin filament. Because HCM mutations and posttranslational modifications (PTMs) also occur in the middle domains and have been correlated with diastolic dysfunction we will also test effects of selected mutations and PTMs in these domains. Experiments will include measurements of steady state force in permeabilized cardiomyocytes as well as rates of activation and relaxation in myofibrils and the activation state of thick filaments determined by myosin DRX/SRX ratios. In Aim 2 we will use the cut and paste approach combined with X-ray diffraction to determine structural effects of cMyBP-C on the activation/relaxation states of thick and thin filaments in sarcomeres. Specifically, we will test the hypothesis that C-links between thick and thin filaments modulate the on/off states of thick and thin filaments and contribute to thick filament activation in response to passive stretch or active load. Results from these studies will provide new insights into how cMyBP- C regulates heart function during health and disease.


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 = $567,216 )
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	000	17	4/7/2025	NON-COMPETING CONTINUATION	$510,495
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	001	17	7/16/2025	NON-COMPETING CONTINUATION	$56,721
														Subtotal = $567,216

Issue Date FY: 2024 ( Subtotal = $622,935 )
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	002	16	6/10/2024	COMPETING CONTINUATION	$60,955
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	001	16	3/29/2024	COMPETING CONTINUATION	$561,980
2024	2021	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	000	15	12/28/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $622,935

Issue Date FY: 2021 ( Subtotal = $489,508 )
2021	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	001	15	3/26/2021	NON-COMPETING CONTINUATION	$489,508
2021	2020	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	000	14	11/6/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $489,508

Issue Date FY: 2020 ( Subtotal = $489,508 )
2020	2020	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	000	14	5/1/2020	NON-COMPETING CONTINUATION	$489,508
														Subtotal = $489,508

Issue Date FY: 2019 ( Subtotal = $489,508 )
2019	2019	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	000	13	4/11/2019	NON-COMPETING CONTINUATION	$489,508
														Subtotal = $489,508

Issue Date FY: 2018 ( Subtotal = $524,508 )
2018	2018	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	001	12	6/27/2018	COMPETING CONTINUATION	$524,508
2018	2016	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	000	11	3/28/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $524,508

Issue Date FY: 2016 ( Subtotal = $377,080 )
2016	2016	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Cardiovascular Diseases Research	000	11	1/27/2016	NON-COMPETING CONTINUATION	$371,505
2016	2015	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Cardiovascular Diseases Research	001	10	2/5/2016	NON-COMPETING CONTINUATION	$5,575
														Subtotal = $377,080

Issue Date FY: 2015 ( Subtotal = $366,072 )
2015	2015	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Cardiovascular Diseases Research	000	10	1/29/2015	NON-COMPETING CONTINUATION	$366,072
														Subtotal = $366,072

Issue Date FY: 2014 ( Subtotal = $364,350 )
2014	2014	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Cardiovascular Diseases Research	002	9	3/25/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$29,743
2014	2014	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Cardiovascular Diseases Research	001	9	1/22/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$334,607
2014	2013	UNIVERSITY OF CALIFORNIA	1850 RESEARCH PARK DRIVE	DAVIS	CA	95618	YOLO	USA	Cardiovascular Diseases Research	000	8	1/21/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $364,350

Issue Date FY: 2013 ( Subtotal = $359,705 )
2013	2013	UNIVERSITY OF CALIFORNIA	1441 RESEARCH PARK DRIVE	DAVIS	CA	95616	YOLO	USA	Cardiovascular Diseases Research	000	8	1/9/2013	NON-COMPETING CONTINUATION	$340,057
2013	2013	UNIVERSITY OF CALIFORNIA	1850 RESEARCH PARK DRIVE	DAVIS	CA	95618	YOLO	USA	Cardiovascular Diseases Research	002	8	1/21/2014	NON-COMPETING CONTINUATION	$0
2013	2013	UNIVERSITY OF CALIFORNIA	1441 RESEARCH PARK DRIVE	DAVIS	CA	95616	YOLO	USA	Cardiovascular Diseases Research	001	8	6/24/2013	NON-COMPETING CONTINUATION	$19,648
														Subtotal = $359,705

Issue Date FY: 2012 ( Subtotal = $367,883 )
2012	2012	UNIVERSITY OF CALIFORNIA	1441 RESEARCH PARK DRIVE	DAVIS	CA	95616	YOLO	USA	Cardiovascular Diseases Research	000	7	2/9/2012	COMPETING CONTINUATION	$367,883
														Subtotal = $367,883

Issue Date FY: 2009 ( Subtotal = $559,222 )
2009	2009	UNIVERSITY OF CALIFORNIA	1441 RESEARCH PARK DRIVE	DAVIS	CA	95616	YOLO	USA	Cardiovascular Diseases Research	001	6	7/20/2009	NON-COMPETING CONTINUATION	$324,278
2009	2009	UNIVERSITY OF CALIFORNIA	1441 RESEARCH PARK DRIVE	DAVIS	CA	95616	YOLO	USA	Trans-NIH Recovery Act Research Support	000	5	7/15/2009	SUPPLEMENT FOR EXPANSION	$234,944
														Subtotal = $559,222

Issue Date FY: 2008 ( Subtotal = $324,278 )
2008	2008	UNIVERSITY OF CALIFORNIA	1441 RESEARCH PARK DRIVE	DAVIS	CA	95616	YOLO	USA	Cardiovascular Diseases Research	000	5	7/30/2008	NON-COMPETING CONTINUATION	$324,278
														Subtotal = $324,278

Issue Date FY: 2007 ( Subtotal = $330,539 )
2007	2007	UNIVERSITY OF WASHINGTON	3917 UNIVERSITY WAY NE	SEATTLE	WA	98105	KING	USA	Cardiovascular Diseases Research	000	3	8/20/2007	NON-COMPETING CONTINUATION	$330,539
														Subtotal = $330,539

Issue Date FY: 2006 ( Subtotal = $339,423 )
2006	2006	UNIVERSITY OF WASHINGTON	3917 UNIVERSITY WAY NE	SEATTLE	WA	98105	KING	USA	Cardiovascular Diseases Research	000	2	8/14/2006	NON-COMPETING CONTINUATION	$339,423
														Subtotal = $339,423

Issue Date FY: 2005 ( Subtotal = $347,500 )
2005	2005	UNIVERSITY OF WASHINGTON	3917 UNIVERSITY WAY NE	SEATTLE	WA	98105	KING	USA	Cardiovascular Diseases Research	000	1	8/19/2005	NEW	$347,500
														Subtotal = $347,500

Grand Total All Awards = $6,919,235

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Role of Cardiac Myosin Binding Protein-C in the Regulation of Myocardial Contraction

Award Number: R01HL080367

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2005

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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