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The Role of Yes Associated Protein (YAP) in Hypertrophic Cardiomyopathy

Award Number: F31HL158227
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/01/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2024

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The Role of Yes Associated Protein (YAP) in Hypertrophic Cardiomyopathy - Project Summary/Abstract Hypertrophy Cardiomyopathy (HCM) is the most prevalent hereditary cardiovascular disease – affecting 1 in 500 individuals. Advanced forms of the disease clinically present with hypercontractility, hypertrophy (enlargement of the organ and individual cardiomyocytes) and fibrosis. Several single-point mutations in b- myosin heavy chain (MYH7), Myosin Binding Protein C (MYBPC3), and Troponin (cTn) have been associated with HCM and increased contractility at the organ level. However, the kinetics at the molecular level remain unclear, as different sarcomeric protein mutations can result in increased, decreased, or unchanged force production. A knowledge gap persist in understanding how these altered kinetics at the molecular level lead to the more advanced hypertrophic phenotype of HCM at the cellular level. Interestingly, the Hippo Pathway has been demonstrated to be activated during developmental growth, quiescent during cardiac homeostasis, and reactivated in pathological growth (i.e. HCM). However its involvement in the disease, in particular the initiation of the hypertrophic phenotype, is poorly understood. Here, we aim to understand whether homeostatic mechanical signaling through the canonical growth regulator, Hippo-YAP, is altered 1) by changes in the biomechanics of single HCM mutant cardiomyocytes and 2) by alterations in the mechanical environment. We propose to use human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) genetically edited to harbor point mutations associated with HCM, as a reduce ordered model to study the relationship between mechanical signaling and hypertrophic growth. We will modulate mechanical stresses (i.e. diseased conditions) in healthy and diseased cardiomyocytes by treatment with inotropic drugs and culture in fibrotic-like stiff conditions and track the resulting signaling events by fluorescently labeling the key regulatory protein of the Hippo pathway (YAP). To further elucidate the mechanism by which YAP is contributing to the phenotypes of HCM we have developed a novel optogenetic tool, termed OptoYAP, which provides full temporal and spatial control of the Hippo pathway. Lastly we aim to understand the mechanism behind the reactivation of YAP in pathological conditions by perturbing the mechanical signaling by the nucleus. We hypothesize that 1) changes in force production alter the homeostatic mechano-signaling of the Hippo pathway to initiate cellular hypertrophy and 2) subsequent changes to the extracellular environment (stiffening) compounds this effect leading to a feedforward signal progressing the disease phenotypes. 3) pathological YAP signaling is driven by excessive force transmission by the cytoskeleton resulting in nuclear deformation. Our results will provide insights into HCM progression and provide a testbed for therapeutic options in treating HCM.


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 = -$1,332 )
2025	2024	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Cardiovascular Diseases Research	000	3	1/23/2025	NON-COMPETING CONTINUATION	-$1,332
														Subtotal = -$1,332

Issue Date FY: 2024 ( Subtotal = $8,923 )
2024	2024	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Cardiovascular Diseases Research	002	3	8/29/2024	NON-COMPETING CONTINUATION	$180
2024	2024	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Cardiovascular Diseases Research	001	3	5/31/2024	NON-COMPETING CONTINUATION	-$31,181
2024	2024	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Cardiovascular Diseases Research	000	3	1/19/2024	NON-COMPETING CONTINUATION	$39,924
														Subtotal = $8,923

Issue Date FY: 2023 ( Subtotal = $39,924 )
2023	2023	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Cardiovascular Diseases Research	000	2	2/1/2023	NON-COMPETING CONTINUATION	$38,982
2023	2023	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Cardiovascular Diseases Research	001	2	4/14/2023	NON-COMPETING CONTINUATION	$942
														Subtotal = $39,924

Issue Date FY: 2022 ( Subtotal = $38,982 )
2022	2022	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Cardiovascular Diseases Research	001	1	1/7/2022	NEW	$0
2022	2022	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Cardiovascular Diseases Research	002	1	6/7/2022	NEW	$716
2022	2022	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Cardiovascular Diseases Research	000	1	1/7/2022	NEW	$38,266
														Subtotal = $38,982

Grand Total All Awards = $86,497

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The Role of Yes Associated Protein (YAP) in Hypertrophic Cardiomyopathy

Award Number: F31HL158227

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/01/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2024

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