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An integrated human stem cell model for elucidating NOTCH signaling in myocardial-endocardial interactions in cardiac development and disease

Award Number: R01HL155282
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/15/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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An integrated human stem cell model for elucidating NOTCH signaling in myocardial-endocardial interactions in cardiac development and disease - Hypoplastic left heart syndrome (HLHS) is a severe type of congenital heart defects, which is characterized by the underdevelopment of left side of the heart. The clinical presentation of HLHS includes hypoplasia of the left ventricle and structural defects in mitral valves, aortic valve, and ascending aorta. HLHS newborns usually die within a week without surgical treatment. We and others have linked the pathogenic NOTCH1 mutations to HLHS and calcific aortic valve disease. It appears that abnormal NOTCH signaling interrupts the communication between myocardium and endocardium thus leads to incomplete growth of ventricular chamber. However, the mechanisms by which NOTCH1 mutations results in hypoplasia of the left ventricle are largely unknown due to limited models for studying HLHS. Genetically engineered animals are not capable of reproducing the clinical phenotypes in HLHS patients. Previous studies have focused on the structural and electrophysiological defects in cardiomyocytes from HLHS patient-derived induced pluripotent stem cells (iPSCs), which may not recapitulate the underlying non-cell autonomous scenarios in the hypoplastic ventricles. In this proposal, we hypothesize that NOTCH1-mediated myocardial-endocardial crosstalk is required for normal human ventricular cardiomyocyte differentiation, and NOTCH1 mutations leads to abnormal myocardial-endocardial interactions which cause the hypoplasia of ventricular cardiomyocytes in HLHS. We will employ an integrated stem cell model using HLHS and CRISPR genome-edited iPSCs to investigate how NOTCH1 mutations lead to abnormal myocardial- endocardial interactions in HLHS. We will design a novel co-culture platform using human iPSC-derived cardiomyocytes (iPSC-CMs) and endothelial cells (iPSC-ECs) with distinct NOTCH1 genetic composition to study the intercellular communication between endocardium and myocardium in both healthy and diseased conditions. In Specific Aim 1, we will investigate the cellular and molecular mechanisms by which endothelial NOTCH1 deficiency suppresses human ventricular cardiomyocyte differentiation and proliferation. In Specific Aim 2, we will determine how the crosstalk between myocardium and endocardium affects ventricular cardiomyocyte differentiation and proliferation by co-culture of human iPSC-CMs and iPSC-ECs. In Specific Aim 3, we will decipher the mechanisms by which NOTCH1 mutations results in the dysfunctional myocardial- endocardial interactions and contribute to hypoplasia of the left ventricle using genome-edited HLHS-iPSCs. The completion of this R01 project will have a major impact on the understanding of HLHS through interactions between endocardium and myocardium using clinically relevant and patient-derived cardiomyocytes and endothelial cells.


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 = $385,000 )
2025	2025	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Cardiovascular Diseases Research	001	5	1/22/2025	NON-COMPETING CONTINUATION	$385,000
2025	2024	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Cardiovascular Diseases Research	000	4	11/29/2024	SUPPLEMENT FOR EXPANSION	$0
2025	2024	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Cardiovascular Diseases Research	002	4	6/5/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $385,000

Issue Date FY: 2024 ( Subtotal = $567,019 )
2024	2024	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Cardiovascular Diseases Research	005	4	9/19/2024	SUPPLEMENT FOR EXPANSION	$67,891
2024	2024	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Cardiovascular Diseases Research	001	4	1/24/2024	SUPPLEMENT FOR EXPANSION	$114,128
2024	2024	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Cardiovascular Diseases Research	002	4	1/25/2024	SUPPLEMENT FOR EXPANSION	$77,578
2024	2024	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Cardiovascular Diseases Research	004	4	8/9/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2024	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Cardiovascular Diseases Research	003	4	2/7/2024	SUPPLEMENT FOR EXPANSION	-$77,578
2024	2024	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Cardiovascular Diseases Research	000	4	1/19/2024	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $567,019

Issue Date FY: 2023 ( Subtotal = $576,706 )
2023	2023	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Cardiovascular Diseases Research	001	3	2/3/2023	SUPPLEMENT FOR EXPANSION	$114,128
2023	2023	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Cardiovascular Diseases Research	002	3	2/6/2023	SUPPLEMENT FOR EXPANSION	$77,578
2023	2023	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Cardiovascular Diseases Research	000	3	1/31/2023	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $576,706

Issue Date FY: 2022 ( Subtotal = $546,982 )
2022	2022	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Cardiovascular Diseases Research	000	2	3/16/2022	NON-COMPETING CONTINUATION	$346,500
2022	2022	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Cardiovascular Diseases Research	004	2	7/28/2022	SUPPLEMENT FOR EXPANSION	$480
2022	2022	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Cardiovascular Diseases Research	001	2	6/17/2022	NON-COMPETING CONTINUATION	$38,500
2022	2022	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Cardiovascular Diseases Research	002	2	7/5/2022	SUPPLEMENT FOR EXPANSION	$114,128
2022	2022	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Cardiovascular Diseases Research	003	2	7/18/2022	SUPPLEMENT FOR EXPANSION	$47,374
														Subtotal = $546,982

Issue Date FY: 2021 ( Subtotal = $385,000 )
2021	2021	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Cardiovascular Diseases Research	002	1	7/30/2021	NEW	$38,500
2021	2021	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Cardiovascular Diseases Research	001	1	3/5/2021	NEW	$4,500
2021	2021	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Cardiovascular Diseases Research	000	1	2/15/2021	NEW	$342,000
														Subtotal = $385,000

Grand Total All Awards = $2,460,707

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An integrated human stem cell model for elucidating NOTCH signaling in myocardial-endocardial interactions in cardiac development and disease

Award Number: R01HL155282

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/15/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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