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Integrative Approach to Divergent Remodeling in Thin Filament Cardiomyopathies

Award Number: R01HL075619
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2003
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Integrative Approach to Divergent Remodeling in Thin Filament Cardiomyopathies - Project Summary: The cardiac thin filament is the essential regulator of cardiac contractility and relaxation at the molecular level. It is comprised of five discrete proteins: cTnC, cTnI, cTnT, actin and tropomyosin that have co-evolved to sustain efficient cardiac performance at rest, during exercise and, importantly, to respond to pathologic stressors. Mutations in genes encoding each of these proteins have been definitively linked to the development of a range of human genetic cardiomyopathies, including hypertrophic (HCM) and dilated (DCM) forms. Despite 25 years of study by many groups including ours, to define the direct link(s) between the biophysical insult and the resultant complex cardiomyopathy, many questions remain and significantly limit our ability to use genotype to prognosticate and eventually even treat individuals with genetic cardiomyopathies. The recent development of Mavacamten, a first-in-class, targeted myosin inhibitor is a game-changing advance that was predicated on decades of basic research into the fundamental biology of the sarcomere. Thus, the question is no longer “if” we can target the sarcomere, but for the thin filament the question is “what function to target” and eventually “when to treat”. The cardiac thin filament is a highly dynamic allosteric “machine” where most of the component proteins are comprised of a-helices connected by variably sized unstructured linkers, where dynamic flexibility is the rule, not the exception and this has limited the availability of high resolution structure for these regions. Most of the known pathogenic mutations in cTnI and cTnT are clustered within these highly flexible domains, where there is likely a “distribution” of tolerance, whereby mutations impair function (enough to cause disease) but do not break it. We thus propose that by examining the range of these dynamic perturbations within these domains we can identify new structural and dynamic disease mechanisms that can be functionally binned, studied and modulated. We provide proof-of-principle preliminary data in this proposal. Over the recent funding period we expanded our structural methodologies to include Time-Resolved FRET with a Single Donor – Dual Acceptor approach that allows us to use actin as an anchor to refine highly flexible structures. We will next use known, highly divergent (HCM vs DCM) mutations within each flexible domain to probe both structure and dynamics with the premise that these mutations will define the limits of “tolerability” in either direction and use spectroscopy and measurements of Ca2+ dissociation and association kinetics coupled to computation to define and test these hypotheses. Finally, we will “close the loop” by utilizing our existing extensively characterized transgenic animal models based on the same mutations used to set our limits and perform 3-timepoint RNA-Seq to discover unique early transcriptional signatures to help link these perturbations to the resultant early remodeling cascade that eventually leads to distinct patterns of ventricular remodeling. The long term goal is to use this coupled structural – dynamic – transcriptomic platform to identify new targets, both primary and secondary for future therapeutics and even biomarker discovery.


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 = $512,798 )
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	000	21	11/20/2024	NON-COMPETING CONTINUATION	$512,798
														Subtotal = $512,798

Issue Date FY: 2024 ( Subtotal = $558,379 )
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	000	20	11/8/2023	NON-COMPETING CONTINUATION	$512,798
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	001	20	6/24/2024	NON-COMPETING CONTINUATION	$45,581
														Subtotal = $558,379

Issue Date FY: 2023 ( Subtotal = $569,776 )
2023	2023	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	001	19	2/17/2023	NON-COMPETING CONTINUATION	$56,978
2023	2023	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	000	19	11/22/2022	NON-COMPETING CONTINUATION	$512,798
														Subtotal = $569,776

Issue Date FY: 2022 ( Subtotal = $569,776 )
2022	2022	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	004	18	4/15/2022	COMPETING CONTINUATION	$0
2022	2022	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	000	18	11/30/2021	COMPETING CONTINUATION	$569,776
2022	2022	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	003	18	4/14/2022	COMPETING CONTINUATION	$512,728
2022	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	002	17	4/14/2022	NON-COMPETING CONTINUATION	-$468,182
2022	2020	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	001	16	4/14/2022	NON-COMPETING CONTINUATION	-$44,546
														Subtotal = $569,776

Issue Date FY: 2021 ( Subtotal = $468,182 )
2021	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	000	17	12/18/2020	NON-COMPETING CONTINUATION	$421,364
2021	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	001	17	5/18/2021	NON-COMPETING CONTINUATION	$46,818
														Subtotal = $468,182

Issue Date FY: 2020 ( Subtotal = $468,182 )
2020	2020	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	000	16	4/30/2020	NON-COMPETING CONTINUATION	$468,182
														Subtotal = $468,182

Issue Date FY: 2019 ( Subtotal = $468,182 )
2019	2019	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	000	15	12/19/2018	NON-COMPETING CONTINUATION	$468,182
														Subtotal = $468,182

Issue Date FY: 2018 ( Subtotal = $468,182 )
2018	2018	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	003	14	4/12/2018	COMPETING CONTINUATION	$406,662
2018	2018	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	001	14	12/7/2017	COMPETING CONTINUATION	$468,182
2018	2016	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	002	13	4/12/2018	EXTENSION WITH OR WITHOUT FUNDS	-$406,662
2018	2016	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	000	13	12/6/2017	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $468,182

Issue Date FY: 2016 ( Subtotal = $378,750 )
2016	2016	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Cardiovascular Diseases Research	000	13	5/9/2016	EXTENSION WITH OR WITHOUT FUNDS	$378,750
														Subtotal = $378,750

Issue Date FY: 2015 ( Subtotal = $373,068 )
2015	2015	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Cardiovascular Diseases Research	000	12	5/8/2015	NON-COMPETING CONTINUATION	$373,068
														Subtotal = $373,068

Issue Date FY: 2014 ( Subtotal = $371,175 )
2014	2014	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Cardiovascular Diseases Research	002	11	5/1/2014	NON-COMPETING CONTINUATION	$371,175
2014	2013	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Cardiovascular Diseases Research	001	10	11/19/2013	COMPETING CONTINUATION	$360,570
2014	2013	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Cardiovascular Diseases Research	000	10	11/15/2013	COMPETING CONTINUATION	-$360,570
														Subtotal = $371,175

Issue Date FY: 2013 ( Subtotal = $360,570 )
2013	2013	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Cardiovascular Diseases Research	005	10	11/15/2013	COMPETING CONTINUATION	-$360,570
2013	2013	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Cardiovascular Diseases Research	006	10	11/19/2013	COMPETING CONTINUATION	$360,570
2013	2013	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Cardiovascular Diseases Research	004	10	8/20/2013	COMPETING CONTINUATION	$360,570
2013	2011	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Cardiovascular Diseases Research	002	8	2/10/2013	NON-COMPETING CONTINUATION	-$3,030
2013	2011	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Cardiovascular Diseases Research	001	9	2/10/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$3,030
2013	2011	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Cardiovascular Diseases Research	000	8	10/26/2012	NON-COMPETING CONTINUATION	$0
2013	2011	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Cardiovascular Diseases Research	003	9	8/19/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $360,570

Issue Date FY: 2011 ( Subtotal = $419,388 )
2011	2011	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Cardiovascular Diseases Research	000	8	3/4/2011	NON-COMPETING CONTINUATION	$419,388
														Subtotal = $419,388

Issue Date FY: 2010 ( Subtotal = $419,388 )
2010	2010	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Cardiovascular Diseases Research	000	7	4/5/2010	NON-COMPETING CONTINUATION	$419,388
														Subtotal = $419,388

Issue Date FY: 2009 ( Subtotal = $419,388 )
2009	2009	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Cardiovascular Diseases Research	000	6	3/20/2009	NON-COMPETING CONTINUATION	$419,388
														Subtotal = $419,388

Issue Date FY: 2008 ( Subtotal = $432,390 )
2008	2008	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Cardiovascular Diseases Research	000	5	3/20/2008	COMPETING CONTINUATION	$432,390
														Subtotal = $432,390

Grand Total All Awards = $8,527,920

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Integrative Approach to Divergent Remodeling in Thin Filament Cardiomyopathies

Award Number: R01HL075619

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2003

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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