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Causal variant association mechanisms in TCF21 binding coronary disease loci

Award Number: R01HL134817
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2017
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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Causal variant association mechanisms in TCF21 binding coronary disease loci - Building on the extensive genome wide association studies (GWAS) of coronary artery disease (CAD), and single cell characterization of atherosclerosis, we have shown that the smooth muscle cell (SMC) lineage harbors much of the risk for vascular disease. Further, these data indicate that SMC can assume two disease- related transition states linked to disease risk. We identified TCF21 as a protective CAD GWAS gene and showed that it regulates a disease-related transition of medial SMC to a fibroblast-like phenotype, producing cells we term “fibromyocytes” (FMC). Further, we and others have found that SMC can also transition to a second phenotype, characterized by expression of genes known for their role in endochondral bone formation and intimal vascular calcification. Mouse genetic models have indicated that this chondrogenic process, which gives rise to cells we term “chondromyocytes” (CMC), is promoted by CAD GWAS causal factors Pdgfd and Twist1, and actively inhibited by protective TCF21 target CAD GWAS signaling molecules ZEB2 and SMAD3. Further, recent transcriptomic and epigenomic (multi-ome) single cell studies indicate that FMC and CMC are the end products of independent trajectories that SMC can differentially traverse in the disease setting. We thus hypothesize that CAD protective GWAS genes TCF21 and ZEB2 promote disease protective FMC and inhibit disease promoting CMC trajectories through regulation of critical enhancers and their regulatory transcription factors (TFs) that underlie the fundamental mechanisms of CAD genetic risk in the SMC lineage. Algorithms that link disease variation and disease transcriptomic data at the whole genome level show that disease genetic risk resides in the cell state changes from SMC to FMC and SMC to CMC. We now propose to investigate the enhancers, related TFs and their target genes (regulons) that mediate these phenotype transitions, through the following Aims. In Aim 1, we will perform time-course studies with mouse disease models targeted for disease inhibiting CAD associated genes Tcf21 and Zeb2 to map the cis- and trans-acting factors and disease-related regulons that determine the disease trajectories and directionality of disease risk. Findings from these studies will be mapped onto multi-omic single cell assay data of human coronary lesions to establish that orthologous enhancers and molecular SMC mechanisms mediate phenotype transitions in human disease. In Aim 2, we will address the hypothesis that over-expression of Tcf21 in medial SMC will promote increased transition to the FMC phenotype, as indicated by epigenetic and gene regulatory network modules, as well as increased fibrous cap formation and additional risk protective features. In Aim 3, CRISPRi PerturbSeq experiments in human coronary artery smooth muscle cells will validate the results from previous Aims, and further characterize downstream enhancers, related TFs, and regulatory networks. The proposed studies will identify cellular and molecular mechanisms that mediate SMC transitions to FMC and CMC, and the relationship of these transitions to vascular calcification and disease risk.


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 = $685,144 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	001	10	3/27/2026	NON-COMPETING CONTINUATION	$20,975
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	10	2/16/2026	NON-COMPETING CONTINUATION	$664,169
														Subtotal = $685,144

Issue Date FY: 2025 ( Subtotal = $717,444 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	001	9	12/9/2024	COMPETING CONTINUATION	$717,444
2025	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	8	12/9/2024	NON-COMPETING CONTINUATION	$0
2025	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	002	8	5/21/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $717,444

Issue Date FY: 2024 ( Subtotal = $553,417 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	001	8	6/12/2024	NON-COMPETING CONTINUATION	$45,177
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	8	12/18/2023	NON-COMPETING CONTINUATION	$508,240
														Subtotal = $553,417

Issue Date FY: 2023 ( Subtotal = $584,533 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	001	7	3/6/2023	NON-COMPETING CONTINUATION	$58,451
2023	2023	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	7	12/22/2022	NON-COMPETING CONTINUATION	$526,082
														Subtotal = $584,533

Issue Date FY: 2022 ( Subtotal = $599,949 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	002	6	12/17/2021	NON-COMPETING CONTINUATION	$539,955
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	003	6	6/8/2022	NON-COMPETING CONTINUATION	$59,994
2022	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	001	5	11/26/2021	COMPETING CONTINUATION	$75
2022	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	4	11/26/2021	NON-COMPETING CONTINUATION	-$75
														Subtotal = $599,949

Issue Date FY: 2021 ( Subtotal = $598,669 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	003	5	6/28/2021	COMPETING CONTINUATION	$173,950
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	001	5	6/19/2021	COMPETING CONTINUATION	$59,866
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	5	12/21/2020	COMPETING CONTINUATION	$538,803
2021	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	002	4	6/28/2021	NON-COMPETING CONTINUATION	-$173,950
														Subtotal = $598,669

Issue Date FY: 2020 ( Subtotal = $618,063 )
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	4	12/20/2019	NON-COMPETING CONTINUATION	$587,161
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	001	4	1/28/2020	NON-COMPETING CONTINUATION	$30,902
														Subtotal = $618,063

Issue Date FY: 2019 ( Subtotal = $618,063 )
2019	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	001	3	8/29/2019	NON-COMPETING CONTINUATION	$0
2019	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	3	1/16/2019	NON-COMPETING CONTINUATION	$618,063
														Subtotal = $618,063

Issue Date FY: 2018 ( Subtotal = $618,063 )
2018	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	2	1/10/2018	NON-COMPETING CONTINUATION	$605,701
2018	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	001	2	6/23/2018	NON-COMPETING CONTINUATION	$12,362
														Subtotal = $618,063

Issue Date FY: 2017 ( Subtotal = $618,063 )
2017	2017	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Cardiovascular Diseases Research	000	1	12/20/2016	NEW	$618,063
														Subtotal = $618,063

Grand Total All Awards = $6,211,408

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Causal variant association mechanisms in TCF21 binding coronary disease loci

Award Number: R01HL134817

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2017

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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