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Experimental and Computational Studies in Genetic Cardiomyopathies

Award Number: R01HL157169
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Experimental and Computational Studies in Genetic Cardiomyopathies - Experimental and Computational Studies in Genetic Cardiomyopathies PI: Farid Moussavi-Harami Abstract Cardiomyopathies, including hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM), are an ideal venue for implementing precision medicine strategies. This is due to more routine use of genetic testing and the vast amount of knowledge regarding underlying biophysical mechanisms of sarcomeric variants, which contribute to both DCM and HCM. While the mechanisms of how sarcomeric variants cause cardiomyopathies is an active area of investigation, it is clear that they disrupt the finely tuned force-generation properties of cardiomyocytes. Many investigators have used a variety of biophysical and biochemical assays to study mechanism of sarcomeric variants and then scale these studies up to cells, tissues and animal models. These approaches are informative, but incremental and unable to asses many variants at once. Success in this area requires robust high-throughput assays with the ability for analysis of thousands of divergent variants at once. Our proposal will directly overcome limitations in the field by applying data analytics to biophysical simulations and experimental cardiac twitches. The fundamental hypothesis is that the principal features of cardiac twitches summarize the complex intra and inter-filament interactions of sarcomeric variants. Moreover, we can utilize these features for variant classification, predicting therapeutic response and identification of new therapeutics targets. Testing these hypotheses requires 1) large datasets of variants, 2) models that account for variant location and abundance in sarcomeres and 3) development and validation of data analytic methods. Biophysical simulations of sarcomeric variants can provide such datasets, but require validation in experimental systems. We will use a spatially explicit computational model of the sarcomere that can simulate how perturbations in sarcomere mechanochemistry change myocyte force generation. Simulated twitches will be generated, validated and used for predicting targeted therapeutics.


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 = $674,216 )
2025	2025	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cardiovascular Diseases Research	001	4	6/4/2025	NON-COMPETING CONTINUATION	$67,422
2025	2025	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cardiovascular Diseases Research	000	4	4/24/2025	NON-COMPETING CONTINUATION	$606,794
														Subtotal = $674,216

Issue Date FY: 2024 ( Subtotal = $660,731 )
2024	2024	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cardiovascular Diseases Research	001	3	6/21/2024	NON-COMPETING CONTINUATION	$53,937
2024	2024	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cardiovascular Diseases Research	000	3	4/4/2024	NON-COMPETING CONTINUATION	$606,794
														Subtotal = $660,731

Issue Date FY: 2023 ( Subtotal = $669,803 )
2023	2023	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cardiovascular Diseases Research	000	2	4/5/2023	NON-COMPETING CONTINUATION	$669,803
														Subtotal = $669,803

Issue Date FY: 2022 ( Subtotal = $669,803 )
2022	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cardiovascular Diseases Research	000	1	4/27/2022	NEW	$669,803
														Subtotal = $669,803

Grand Total All Awards = $2,674,553

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Experimental and Computational Studies in Genetic Cardiomyopathies

Award Number: R01HL157169

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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