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MicroRNA Control of Dilated Cardiomyopathy

Award Number: R01HL130840
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/12/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2027
AWARD TERMINATION DATE: 03/10/2026

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MicroRNA Control of Dilated Cardiomyopathy - Dilated cardiomyopathy (DCM)-associated heart failure is a leading cause of mortality worldwide. About a third of DCM is due to gene variants in a broad range of cardiac muscle proteins. Although this information has improved patient management, it has not yet led to new therapeutics that target the underlying mechanisms of disease. A major roadblock is that the consequences of the DCM-causing mutations are not understood in sufficient detail to identify points of therapeutic intervention. During the first funding cycle of this project, we used large-scale screening of synthetic microRNAs as an entry point to discover genes that, when inhibited, restored contractility of induced pluripotent stem cells (hiPSC-CMs) carrying DCM-causing mutations. We identified two synthetic microRNAs that normalized contractility of DCM cardiomyocytes comparable to CRISPR-correction of the underlying mutation. Neither microRNA affected isogenic, control hiPSC-CMs, indicating that they act on disease-related processes. We biochemically identified their targets, identifying 203 genes, of which individual siRNA-mediated inhibition of 117 restored contractility of TNNT2 mutant DCM mutant hiPSC-CMs from different patient donors. While some of the candidate genes have been tested as therapeutic targets in heart failure, the vast majority represent new therapeutic target space for inherited DCM. This is multi-PI renewal application is to determine the mechanisms of action of these genes and to establish evidence of disease modifying activity using human genetics and a mouse DCM model. The multi-PI and co-I team unites expertise in iPSC and animal models, systems biology, and human genetics that will have a synergistic impact on our long-term goal of defining therapeutic mechanisms for DCM that would not be possible through separate proposals. Given the diverse genetics and clinical presentations of inherited DCM, our overarching hypothesis is that subsets of the candidate genes, and the physiological processes they affect, will revert contractile dysfunction in a DCM mutation-specific manner. Thus, Aim 1 is to define mechanisms that restore contractile function in DCM caused by different gene variants, and associate beneficial molecular genetic and metabolic pathways with particular DCM-causing mutations, Aim 2 is to investigate whether genetic variants linked to each of the miR- target genes associate with human cardiovascular diseases or quantitative traits using existing GWAS studies, and Aim 3 is to test whether targets of a microRNA that selectively ameliorates contractility in TNNT2-mutant hiPSC-CMs converge on ER stress using a mouse knock-in model engineered with the same Tnnt2 mutation as in the patient hiPSCs.


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: 2026 ( Subtotal = $591,214 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	002	7	3/13/2026	NON-COMPETING CONTINUATION	-$60,454
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	7	2/20/2026	NON-COMPETING CONTINUATION	$651,668
2026	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	001	6	3/10/2026	TERMINATION	$0
														Subtotal = $591,214

Issue Date FY: 2025 ( Subtotal = $750,962 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	6	11/20/2024	NON-COMPETING CONTINUATION	$586,921
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	002	6	8/5/2025	NON-COMPETING CONTINUATION	$65,213
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	001	6	1/14/2025	SUPPLEMENT FOR EXPANSION	$98,828
														Subtotal = $750,962

Issue Date FY: 2024 ( Subtotal = $701,768 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	002	5	9/20/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	001	5	8/28/2024	SUPPLEMENT FOR EXPANSION	$36,031
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	5	12/12/2023	COMPETING CONTINUATION	$665,737
														Subtotal = $701,768

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	4	11/11/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $733,369 )
2019	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	001	4	5/13/2019	NON-COMPETING CONTINUATION	$733,369
2019	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	3	12/18/2018	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $733,369

Issue Date FY: 2018 ( Subtotal = $685,158 )
2018	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	001	3	9/19/2018	SUPPLEMENT FOR EXPANSION	$129,525
2018	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	3	5/14/2018	NON-COMPETING CONTINUATION	$555,633
														Subtotal = $685,158

Issue Date FY: 2017 ( Subtotal = $550,913 )
2017	2017	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	2	5/29/2017	NON-COMPETING CONTINUATION	$550,913
														Subtotal = $550,913

Issue Date FY: 2016 ( Subtotal = $608,395 )
2016	2016	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	1	5/24/2016	NEW	$608,395
														Subtotal = $608,395

Grand Total All Awards = $4,621,779

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MicroRNA Control of Dilated Cardiomyopathy

Award Number: R01HL130840

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/12/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2027

AWARD TERMINATION DATE: 03/10/2026

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