Tuesday, July 1, 2025 7/1/2025

Elucidating Mechanism of Cardiac Fibrosis with Cell Village of Pooled Human iPSCs

Award Number: R01HL130020
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/16/2015
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Elucidating Mechanism of Cardiac Fibrosis with Cell Village of Pooled Human iPSCs - PROJECT SUMMARY Cardiac fibrosis contributes to the progression of heart failure. Currently, there is no FDA-approved drug specifically targeting cardiac fibrosis due to the lack of understanding of the underlying mechanism and a reliable drug discovery platform. Here, we will use a novel multiplexing methodology of creating a cell village by pooling multiple patients' induced pluripotent stem cell (iPSC) lines in a dish to map the genetic basis of interindividual differences in response to a profibrotic cocktail. In Aim 1, we will co-culture 100 iPSC lines from 60 healthy donors and 40 dilated cardiomyopathy (DCM) patients in 10 distinct cell villages, where each cell village contains ten independent patient-specific iPSC lines. Next, we will differentiate each cell village into iPSC-derived cardiomyocytes (iPSC-CMs), endothelial cells (iPSC-ECs), and cardiac fibroblasts (iPSC-CFs), and then generate 3D engineered heart tissues (EHTs). Finally, we will perform a single-cell multiomics sequencing analysis of the cell villages to understand the impact of internal genetic predisposition and external profibrotic stimuli on EHTs. In Aim 2, we will perform high throughput screening to identify novel small molecules for treating cardiac fibrosis using novel iPSC-CF reporter lines. The antifibrotic effects of the drug hits will be validated in primary CFs and EHTs. We will perform RNA- and ATAC- sequencing to determine the downstream signaling pathways of the newly identified compounds. In Aim 3, we will validate the therapeutic effects of antifibrotic compounds in mice models of dilated cardiomyopathy. The cardiac function will be measured by echocardiography, and fibrosis severity will be assessed by histology at multiple time points. We will also perform single-nuclei multiome and spatial transcriptomics to delineate the impact of therapeutic drug treatment in each cell type cluster and cell-cell interactions in the heart based on the 10x Genomics platform. Collectively, we expect to identify new signaling pathways and novel compounds for patients with cardiac fibrosis and heart failure.


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 = $766,771 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	006	10	5/30/2025	NON-COMPETING CONTINUATION	$766,771
2025	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	005	9	5/3/2025	COMPETING CONTINUATION	$0
2025	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	004	9	4/1/2025	COMPETING CONTINUATION	$1,140,983
2025	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	002	8	4/1/2025	NON-COMPETING CONTINUATION	-$601,810
2025	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	003	8	4/1/2025	SUPPLEMENT FOR EXPANSION	-$64,282
2025	2022	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	001	7	4/1/2025	SUPPLEMENT FOR EXPANSION	-$82,708
2025	2022	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	7	4/1/2025	NON-COMPETING CONTINUATION	-$392,183
														Subtotal = $766,771

Issue Date FY: 2024 ( Subtotal = $776,035 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	005	9	5/3/2024	COMPETING CONTINUATION	$776,035
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	006	9	5/15/2024	COMPETING CONTINUATION	$0
2024	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	004	8	5/3/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	003	8	5/3/2024	NON-COMPETING CONTINUATION	$0
2024	2021	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	002	6	5/3/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2021	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	001	6	5/3/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2021	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	6	10/16/2023	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $776,035

Issue Date FY: 2023 ( Subtotal = $666,092 )
2023	2023	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	8	12/9/2022	NON-COMPETING CONTINUATION	$541,629
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	002	8	2/17/2023	NON-COMPETING CONTINUATION	$60,181
2023	2023	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	001	8	12/10/2022	SUPPLEMENT FOR EXPANSION	$64,282
														Subtotal = $666,092

Issue Date FY: 2022 ( Subtotal = $738,201 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	002	7	6/14/2022	NON-COMPETING CONTINUATION	$60,963
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	7	12/2/2021	NON-COMPETING CONTINUATION	$548,672
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	001	7	12/3/2021	SUPPLEMENT FOR EXPANSION	$128,566
2022	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	003	6	6/30/2022	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $738,201

Issue Date FY: 2021 ( Subtotal = $1,398,258 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	001	6	5/24/2021	NON-COMPETING CONTINUATION	$61,824
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	004	6	9/17/2021	SUPPLEMENT FOR EXPANSION	$501,316
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	6	12/13/2020	NON-COMPETING CONTINUATION	$556,418
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	002	6	6/7/2021	SUPPLEMENT FOR EXPANSION	$121,848
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	003	6	8/31/2021	SUPPLEMENT FOR EXPANSION	$156,852
														Subtotal = $1,398,258

Issue Date FY: 2020 ( Subtotal = $625,285 )
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	002	5	3/19/2020	COMPETING CONTINUATION	$0
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	5	12/12/2019	COMPETING CONTINUATION	$625,285
2020	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	001	4	3/19/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $625,285

Issue Date FY: 2019 ( Subtotal = $395,000 )
2019	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	4	12/13/2018	NON-COMPETING CONTINUATION	$395,000
														Subtotal = $395,000

Issue Date FY: 2018 ( Subtotal = $395,000 )
2018	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	001	3	6/23/2018	NON-COMPETING CONTINUATION	$7,900
2018	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	3	12/8/2017	NON-COMPETING CONTINUATION	$387,100
														Subtotal = $395,000

Issue Date FY: 2017 ( Subtotal = $395,000 )
2017	2017	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	2	11/25/2016	NON-COMPETING CONTINUATION	$395,000
														Subtotal = $395,000

Issue Date FY: 2016 ( Subtotal = $395,000 )
2016	2016	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	1	12/16/2015	NEW	$395,000
														Subtotal = $395,000

Grand Total All Awards = $6,550,642

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Elucidating Mechanism of Cardiac Fibrosis with Cell Village of Pooled Human iPSCs

Award Number: R01HL130020

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/16/2015

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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