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Cardiogenesis: Molecular Mechanisms

Award Number: R01HL057181
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/10/1997
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Cardiogenesis: Molecular Mechanisms - PROJECT SUMMARY Congenital heart disease is the result of abnormal development of discrete sub-types of cardiogenic cells during early embryogenesis, and is the most common of all human birth defects. The recently developed ability to analyze the transcriptional and epigenetic state of thousands of individual cells at a time makes it tractable to discern the consequences of genetic alterations on small subsets of cells that could lead to congenital heart defects (CHDs). Nearly 30% of all CHDs involve the developing valvuloseptal region, but the mechanisms underlying valvuloseptal development are incompletely understood. Trisomy 21, the cause of Down Syndrome, offers an opportunity to investigate the genetic basis of valvuloseptal defects, as 50% of Down Syndrome children have CHD, and it is the most common known genetic cause of atrioventricular (AV) septal defects and other defects of septation. However, which of the 241 genes on Ch21 are responsible for causing cardiac defects when present in three copies remains unclear. A minimal critical region containing 148 duplicated syntenic genes sufficient for recapitulating cardiac defects in mice has been established (Dp1Tyb). Using our single cell RNAseq atlas of mouse cardiogenesis, we found only 66 of the 148 genes present in the Dp1Tyb region were expressed during cardiac development, and we defined cardiac cell types with greatest transcriptional and epigenetic changes in the Dp1Tyb mouse model. Furthermore, we differentiated a human trisomy 21 iPS cell line and its isogenic disomic iPS control toward the cardiac lineage, and observed substantial single cell transcriptional and epigenetic dysregulation in trisomic AV myocardial cells. We engineered the disomic human iPS cell line with a CRISPR-based gene activation system, introduced guide RNAs to moderately activate the 66 candidate genes on Ch 21, and used a machine learning approach to identify thirteen Ch21 genes that shifted the transcriptional signature in the AV myocardium to be more similar to that observed in trisomy 21 cells. Among these were 5 transcription factors, including BACH1 and HMGN1. In parallel, scATACseq analysis of trisomy 21 AV myocardial cells revealed a dramatic increase in motifs for the transcriptional repressor BACH1 among more closed chromatin regions. Based on these data, we hypothesize that the cardiac defects of Trisomy 21 arise due to the presence of three copies of one or more of the 13 genes identified in our pooled CRISPR screen, and that increased dosage of one or more transcription factors, such as BACH1 or HMGN1, alters AV myocardium to contribute to such defects. To test this, we propose to: 1) identify trisomy 21 gene(s) duplicated in Down Syndrome that are necessary and sufficient for modulation of iPS-derived AV myocardium; 2) determine the mechanism by which transcription factors from our screen affect transcriptional and epigenetic signatures in AV myocardium; and 3) determine the in vivo dose dependency of candidate genes in the mouse Down Syndrome region on cardiogenesis. Execution of this proposal will reveal the critical gene(s) that cause cardiac defects in Trisomy 21, and provide insight into the mechanisms that drive CHD more generally.


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 = $1,606,500 )
2025	2025	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	001	28	2/19/2025	COMPETING CONTINUATION	$803,250
2025	2025	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	002	30	5/27/2025	NON-COMPETING CONTINUATION	$803,250
2025	2023	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	001	28	2/19/2025	COMPETING CONTINUATION	$11,271
2025	2022	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	27	2/19/2025	NON-COMPETING CONTINUATION	-$11,271
														Subtotal = $1,606,500

Issue Date FY: 2024 ( Subtotal = $787,185 )
2024	2024	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	29	6/7/2024	NON-COMPETING CONTINUATION	$787,185
														Subtotal = $787,185

Issue Date FY: 2023 ( Subtotal = $803,250 )
2023	2023	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	28	8/25/2023	COMPETING CONTINUATION	$803,250
														Subtotal = $803,250

Issue Date FY: 2022 ( Subtotal = $661,959 )
2022	2022	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	27	8/24/2022	NON-COMPETING CONTINUATION	$661,959
														Subtotal = $661,959

Issue Date FY: 2021 ( Subtotal = $661,959 )
2021	2021	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	26	8/19/2021	NON-COMPETING CONTINUATION	$661,959
														Subtotal = $661,959

Issue Date FY: 2020 ( Subtotal = $661,959 )
2020	2020	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	001	25	8/20/2020	NON-COMPETING CONTINUATION	$661,959
2020	2018	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	23	3/7/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $661,959

Issue Date FY: 2019 ( Subtotal = $661,959 )
2019	2019	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	001	24	7/13/2019	COMPETING CONTINUATION	$661,959
2019	2018	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	002	23	8/22/2019	NON-COMPETING CONTINUATION	$0
2019	2018	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	23	7/12/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $661,959

Issue Date FY: 2018 ( Subtotal = $473,250 )
2018	2018	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	23	3/28/2018	NON-COMPETING CONTINUATION	$463,785
2018	2018	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	001	23	7/10/2018	NON-COMPETING CONTINUATION	$9,465
														Subtotal = $473,250

Issue Date FY: 2017 ( Subtotal = $559,710 )
2017	2017	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	22	3/29/2017	NON-COMPETING CONTINUATION	$554,023
2017	2015	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Cardiovascular Diseases Research	001	20	6/28/2017	COMPETING CONTINUATION	$5,687
														Subtotal = $559,710

Issue Date FY: 2016 ( Subtotal = $585,049 )
2016	2016	J DAVID GLADSTONE INSTITUTES	P.O. BOX 419100	SAN FRANCISCO	CA	94141	SAN FRANCISCO	USA	Cardiovascular Diseases Research	002	21	3/31/2016	NON-COMPETING CONTINUATION	$554,023
2016	2016	J DAVID GLADSTONE INSTITUTES	P.O. BOX 419100	SAN FRANCISCO	CA	94141	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	20	12/24/2015	SUPPLEMENT FOR EXPANSION	$22,195
2016	2016	J DAVID GLADSTONE INSTITUTES	P.O. BOX 419100	SAN FRANCISCO	CA	94141	SAN FRANCISCO	USA	Cardiovascular Diseases Research	001	20	1/15/2016	SUPPLEMENT FOR EXPANSION	$8,831
														Subtotal = $585,049

Issue Date FY: 2015 ( Subtotal = $473,250 )
2015	2015	J DAVID GLADSTONE INSTITUTES	P.O. BOX 419100	SAN FRANCISCO	CA	94141	SAN FRANCISCO	USA	Cardiovascular Diseases Research	001	20	4/9/2015	COMPETING CONTINUATION	$473,250
2015	2014	J DAVID GLADSTONE INSTITUTES	POST OFFICE BOX 419100	SAN FRANCISCO	CA	94141	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	19	3/23/2015	NON-COMPETING CONTINUATION	$0
														Subtotal = $473,250

Issue Date FY: 2014 ( Subtotal = $472,910 )
2014	2014	J DAVID GLADSTONE INSTITUTES	P.O. BOX 419100	SAN FRANCISCO	CA	94141	SAN FRANCISCO	USA	Cardiovascular Diseases Research	001	19	3/19/2014	NON-COMPETING CONTINUATION	$38,604
2014	2014	J DAVID GLADSTONE INSTITUTES	P.O. BOX 419100	SAN FRANCISCO	CA	94141	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	19	12/2/2013	NON-COMPETING CONTINUATION	$434,306
														Subtotal = $472,910

Issue Date FY: 2013 ( Subtotal = $459,400 )
2013	2013	J DAVID GLADSTONE INSTITUTES	P.O. BOX 419100	SAN FRANCISCO	CA	94141	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	18	11/30/2012	NON-COMPETING CONTINUATION	$434,306
2013	2013	J DAVID GLADSTONE INSTITUTES	P.O. BOX 419100	SAN FRANCISCO	CA	94141	SAN FRANCISCO	USA	Cardiovascular Diseases Research	001	18	7/2/2013	NON-COMPETING CONTINUATION	$25,094
														Subtotal = $459,400

Issue Date FY: 2012 ( Subtotal = $482,562 )
2012	2012	J DAVID GLADSTONE INSTITUTES	P.O. BOX 419100	SAN FRANCISCO	CA	94141	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	17	11/25/2011	NON-COMPETING CONTINUATION	$442,076
2012	2012	J DAVID GLADSTONE INSTITUTES	P.O. BOX 419100	SAN FRANCISCO	CA	94141	SAN FRANCISCO	USA	Cardiovascular Diseases Research	001	17	3/21/2012	NON-COMPETING CONTINUATION	$40,486
														Subtotal = $482,562

Issue Date FY: 2011 ( Subtotal = $482,562 )
2011	2011	J DAVID GLADSTONE INSTITUTES	P.O. BOX 419100	SAN FRANCISCO	CA	94141	SAN FRANCISCO	USA	Cardiovascular Diseases Research	001	16	3/1/2011	COMPETING CONTINUATION	$482,562
2011	2010	J DAVID GLADSTONE INSTITUTES	POST OFFICE BOX 419100	SAN FRANCISCO	CA	94141	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	15	12/7/2010	NON-COMPETING CONTINUATION	$0
														Subtotal = $482,562

Issue Date FY: 2010 ( Subtotal = $466,080 )
2010	2010	J DAVID GLADSTONE INSTITUTES	P.O. BOX 419100	SAN FRANCISCO	CA	94141	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	15	1/29/2010	NON-COMPETING CONTINUATION	$466,080
														Subtotal = $466,080

Issue Date FY: 2009 ( Subtotal = $466,080 )
2009	2009	J DAVID GLADSTONE INSTITUTES	P.O. BOX 419100	SAN FRANCISCO	CA	94141	SAN FRANCISCO	USA	Cardiovascular Diseases Research	000	14	1/30/2009	NON-COMPETING CONTINUATION	$466,080
														Subtotal = $466,080

Issue Date FY: 2008 ( Subtotal = $466,080 ) (Continued on the next page)
Grand Total All Awards = $14,517,719

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Cardiogenesis: Molecular Mechanisms

Award Number: R01HL057181

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/10/1997

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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