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Thin Filaments and Muscle Regulation

Award Number: R01HL036153
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/1986
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Thin Filaments and Muscle Regulation - Thin filament-linked actin-binding proteins, troponin and tropomyosin, control actomyosin-based muscle contraction in cardiac and skeletal muscles. To elucidate mechanisms of muscle thin filament function at a fundamental molecular level, it is crucial to determine the changing structural interactions of these regulatory proteins that control muscle cooperative activation and relaxation via allosteric communication pathways between filament components. It follows that disease-related myofibrillar protein mutants can perturb muscle on-off switching by causing an imbalance in troponin-tropomyosin interactions on actin which, in turn, destabilizes relaxed or active states and the transitions between them. It is our premise that early stage intervention to correct such imbalances is paramount in diminishing or reversing resulting inexorable disease progression. In the current work, we will address these imbalances by taking a multifaceted structural approach to elucidate the mechanism of thin filament regulation and thus establish root causes of these perturbations. To accomplish this goal: 1. We will use cryo-electron microscopy, coupled with 3D-image reconstruction, to establish regulatory transitions of troponin and tropomyosin as well as test the impact of myosin-binding on thin filament actin and tropomyosin. 2. We will refine this experimental approach with computational tools that we have pioneered to bring cryo-EM structures even closer to an atomic level using protein-protein docking protocols and molecular dynamics. 3. We will compare structural interactions that occur in normal thin filaments with those in filaments containing mutant proteins linked to myopathies in order to assess how mutation-linked aberrant physiology can link to myopathology, while localizing druggable target pockets at protein-protein interfaces. To achieve our aims, (1) we will focus on identifying structural domains at the interface between of troponin subunit-T and actin-tropomyosin (Specific Aim 1); (2) we will reveal the structural mechanism used by regulatory domains of troponin subunit-I to trap tropomyosin in its relaxed-state position on actin (Specific Aim 2); (3) we will determine the impact of myosin structural interactions on actin-tropomyosin, less recognized but significant effectors of thin filament regulation (Specific Aim 3). The influence of myopathic-linked mutations in troponin, tropomyosin, actin and myosin will not only be predicted and tested structurally but assayed functionally by measuring in vitro motility and contractility in engineered heart tissue. Aiming to develop tools to counteract regulatory imbalances, we collaborate with associates at the Boston University Central for Molecular Discovery to identify small molecules to be trapped at druggable interfaces along thin filaments in order to potentially manipulate cooperative, regulatory pathways. Thus, our work on the molecular regulation of cardiac and skeletal muscle thin filaments and muscle contraction lies at the intersection of basic and translation biomedical research. Here, our overarching goal is to couple understanding of atomic level mutational “insults” that alter muscle control mechanisms to prospects of reversing early-stage defects in physiological function.


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 = $412,500 )
2025	2025	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Cardiovascular Diseases Research	000	35	2/28/2025	NON-COMPETING CONTINUATION	$412,500
														Subtotal = $412,500

Issue Date FY: 2024 ( Subtotal = $412,500 )
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Cardiovascular Diseases Research	000	34	1/5/2024	NON-COMPETING CONTINUATION	$412,500
														Subtotal = $412,500

Issue Date FY: 2023 ( Subtotal = $412,500 )
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Cardiovascular Diseases Research	000	33	3/16/2023	NON-COMPETING CONTINUATION	$412,500
														Subtotal = $412,500

Issue Date FY: 2022 ( Subtotal = $412,500 )
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Cardiovascular Diseases Research	002	32	5/25/2022	COMPETING CONTINUATION	$2,800
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Cardiovascular Diseases Research	000	32	2/7/2022	COMPETING CONTINUATION	$412,500
2022	2021	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Cardiovascular Diseases Research	001	31	5/25/2022	NON-COMPETING CONTINUATION	-$2,800
														Subtotal = $412,500

Issue Date FY: 2021 ( Subtotal = $412,500 )
2021	2021	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Cardiovascular Diseases Research	001	31	5/18/2021	NON-COMPETING CONTINUATION	$41,250
2021	2021	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Cardiovascular Diseases Research	000	31	1/8/2021	NON-COMPETING CONTINUATION	$371,250
														Subtotal = $412,500

Issue Date FY: 2020 ( Subtotal = $412,500 )
2020	2020	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Cardiovascular Diseases Research	000	30	12/24/2019	NON-COMPETING CONTINUATION	$391,875
2020	2020	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Cardiovascular Diseases Research	001	30	3/7/2020	NON-COMPETING CONTINUATION	$20,625
														Subtotal = $412,500

Issue Date FY: 2019 ( Subtotal = $412,500 )
2019	2019	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Cardiovascular Diseases Research	000	29	1/15/2019	NON-COMPETING CONTINUATION	$412,500
														Subtotal = $412,500

Issue Date FY: 2018 ( Subtotal = $510,110 )
2018	2018	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Cardiovascular Diseases Research	000	28	12/18/2017	COMPETING CONTINUATION	$411,771
2018	2018	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Cardiovascular Diseases Research	002	28	5/1/2018	COMPETING CONTINUATION	$2,868
2018	2018	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Cardiovascular Diseases Research	001	28	4/25/2018	COMPETING CONTINUATION	$95,471
														Subtotal = $510,110

Issue Date FY: 2008 ( Subtotal = $406,250 )
2008	2008	BOSTON UNIVERSITY	25 BUICK STREET	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	18	1/15/2008	COMPETING CONTINUATION	$406,250
														Subtotal = $406,250

Issue Date FY: 2007 ( Subtotal = $306,262 )
2007	2007	BOSTON UNIVERSITY	25 BUICK STREET	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	17	12/4/2006	NON-COMPETING CONTINUATION	$306,262
														Subtotal = $306,262

Issue Date FY: 2006 ( Subtotal = $315,410 )
2006	2006	BOSTON UNIVERSITY	25 BUICK STREET	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	16	11/21/2005	NON-COMPETING CONTINUATION	$315,410
														Subtotal = $315,410

Issue Date FY: 2005 ( Subtotal = $323,000 )
2005	2005	BOSTON UNIVERSITY	25 BUICK STREET	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	15	11/25/2004	NON-COMPETING CONTINUATION	$323,000
														Subtotal = $323,000

Issue Date FY: 2004 ( Subtotal = $323,000 )
2004	2004	BOSTON UNIVERSITY	25 BUICK STREET	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	14	11/10/2003	NON-COMPETING CONTINUATION	$323,000
														Subtotal = $323,000

Issue Date FY: 2003 ( Subtotal = $323,000 )
2003	2003	BOSTON UNIVERSITY	25 BUICK STREET	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	13		COMPETING CONTINUATION	$323,000
														Subtotal = $323,000

Issue Date FY: 2002 ( Subtotal = $296,210 )
2002	2002	BOSTON UNIVERSITY	25 BUICK STREET	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	12	11/15/2001	NON-COMPETING CONTINUATION	$296,210
														Subtotal = $296,210

Issue Date FY: 2001 ( Subtotal = $287,583 )
2001	2001	BOSTON UNIVERSITY	25 BUICK STREET	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	11	11/6/2000	NON-COMPETING CONTINUATION	$287,583
														Subtotal = $287,583

Issue Date FY: 2000 ( Subtotal = $279,206 )
2000	2000	Trustees Of Boston University	25 BUICK STREET	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	10	11/29/1999	NON-COMPETING CONTINUATION	$279,206
														Subtotal = $279,206

Issue Date FY: 1999 ( Subtotal = $263,798 )
1999	1999	Trustees Of Boston University	25 BUICK STREET	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	9	12/8/1998	COMPETING CONTINUATION	$263,798
														Subtotal = $263,798

Issue Date FY: 1998 ( Subtotal = $250,036 )
1998	1998	Trustees Of Boston University	25 BUICK STREET	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	8	11/21/1997	NON-COMPETING CONTINUATION	$250,036
														Subtotal = $250,036

Grand Total All Awards = $6,771,365

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Thin Filaments and Muscle Regulation

Award Number: R01HL036153

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/1986

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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