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Structural Dynamics of Cardiac Myosin-Binding Protein C Regulation

Award Number: R01HL141564
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2019
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Structural Dynamics of Cardiac Myosin-Binding Protein C Regulation - PROJECT SUMMARY Hypertrophic cardiomyopathy (HCM) is a disease affecting more than 1 in 500 individuals and is an unmet medical need with limited FDA-approved treatments. ~40% of HCM cases are associated with mutations in the gene encoding cardiac myosin-binding protein C (MyBP-C). MyBP-C is a thick filament-associated protein that is critical for normal myocardial performance and centrally positioned in the sarcomere to regulate interactions between myosin and actin responsible for force development. We previously demonstrated that increased phosphorylation of MyBP-C, enhances actin-myosin interactions to accelerate contraction kinetics in myocardium, whereas the decreased MyBP-C phosphorylation, reduces actin-myosin proximity and decelerate contraction. However, it is remains unknown how MyBP-C functions under varied states, including myofilament activation, phosphorylation, and HCM mutations. The structural dynamics of MyBP-C and its interactions with actin and/or myosin to modulate force development in myocardium are key to understanding this mechanism of action. We have developed innovative biophysical tools that, for the first time, enable determination of these mechanisms by evaluation of: (1) MyBP-C structural dynamics, (2) how it interacts with actin and myosin in relaxed and activated muscle, (3) how these interactions are affected by phosphorylation and (4) known pathologic mutations. We will test the central hypothesis that MyBP-C function is determined by dynamic structural changes of its domains that determine interactions of MyBP-C with thin (actin) and thick (myosin) filaments and that the equilibrium of these interactions is affected by phosphorylation and HCM mutations. The proposed aims further develop our innovative biophysical tools to measure structural dynamics underlying MyBP- C regulation of contraction in normal and diseased states. These tools include site-directed fluorescence spectroscopy, computational simulations, thin and thick filament function, and mechanical measurements. We will examine how the activation state of the myocardium (Aim 1), phosphorylation of MyBP-C (Aim 2), and HCM mutations (Aim 3) affect MyBP-C’s structural dynamics and interactions to modulate cardiac contractility. The proposed studies resolve interactions in real myocardial space and capture structural dynamics in real time using high-resolution approaches during the contractile cycle. This involves monitoring distances between points on proteins and the order (or disorder) of those distances under physiological conditions, in interacting proteins and functioning myocardium. Fluorescence lifetime data components, thin and thick filament activation, mechanics, and simulations will be used to define models of MyBP-C regulation. The proposed aims offer unprecedented mechanistic resolution of MyBP-C for its functions in health and HCM disease. This mechanistic understanding is critical to lay the foundation for determining the qualitative and quantitative impact of MyBP-C-targeted drugs that are currently being identified by our group for the development of new therapies to treat HCM and other cardiac disorders.


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 = $563,569 )
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	000	7	2/20/2025	NON-COMPETING CONTINUATION	$563,569
2025	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	002	6	3/18/2025	COMPETING CONTINUATION	$99,949
2025	2023	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	001	5	3/18/2025	NON-COMPETING CONTINUATION	-$99,949
														Subtotal = $563,569

Issue Date FY: 2024 ( Subtotal = $638,191 )
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	001	6	2/29/2024	COMPETING CONTINUATION	$575,711
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	002	6	6/14/2024	COMPETING CONTINUATION	$62,480
2024	2023	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	000	5	2/28/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $638,191

Issue Date FY: 2023 ( Subtotal = $319,457 )
2023	2023	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	000	5	12/21/2022	NON-COMPETING CONTINUATION	$345,375
2023	2023	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	003	5	3/10/2023	NON-COMPETING CONTINUATION	$38,375
2023	2022	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	001	4	2/7/2023	SUPPLEMENT FOR EXPANSION	-$64,293
2023	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	002	3	2/22/2023	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $319,457

Issue Date FY: 2022 ( Subtotal = $448,043 )
2022	2022	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	002	4	6/29/2022	NON-COMPETING CONTINUATION	$38,375
2022	2022	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	000	4	12/31/2021	NON-COMPETING CONTINUATION	$345,375
2022	2022	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	001	4	1/4/2022	SUPPLEMENT FOR EXPANSION	$64,293
														Subtotal = $448,043

Issue Date FY: 2021 ( Subtotal = $415,282 )
2021	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	000	3	12/18/2020	NON-COMPETING CONTINUATION	$345,375
2021	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	002	3	9/2/2021	SUPPLEMENT FOR EXPANSION	$31,532
2021	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	001	3	5/24/2021	NON-COMPETING CONTINUATION	$38,375
														Subtotal = $415,282

Issue Date FY: 2020 ( Subtotal = $383,750 )
2020	2020	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	000	2	1/28/2020	NON-COMPETING CONTINUATION	$383,750
														Subtotal = $383,750

Issue Date FY: 2019 ( Subtotal = $383,750 )
2019	2019	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	000	1	12/24/2018	NEW	$383,750
														Subtotal = $383,750

Grand Total All Awards = $3,152,042

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Structural Dynamics of Cardiac Myosin-Binding Protein C Regulation

Award Number: R01HL141564

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2019

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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