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Multimodal genetic regulatory architecture of coronary artery disease

Award Number: R01HL148239
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Multimodal genetic regulatory architecture of coronary artery disease - PROJECT SUMMARY Coronary artery disease (CAD) remains a global public health burden despite advances in risk factor targeted therapies. Meta-analyses across ancestrally diverse populations have identified >300 genetic loci associated with CAD risk. We and others have investigated candidate genes that are dysregulated in the coronary vascular wall; however, the causal genes and regulatory mechanisms remain mostly unknown. Recent advances in single-cell genomics profiling have begun to unravel the cellular diversity during atherosclerosis. Molecular quantitative trait (QTL) mapping and gene regulatory network approaches in disease-relevant tissues have refined some of the regulatory mechanisms, however the specific cell types and phenotypic states driving these changes remain unclear. We have leveraged a large biobank of coronary artery tissues from ancestrally diverse individuals to perform bulk and single-cell profiling of genetic variation and cell states. Using single-nucleus profiling of chromatin accessibility in healthy and subclinical atherosclerotic coronary arteries we identified cis-regulatory elements to explain transitions of smooth muscle cells (SMC) to fibroblast-like cell types. By meta-analyzing single-cell gene expression data in atherosclerosis, we have also identified etiologic SMC phenotypic states underlying CAD as well as coronary artery calcification (CAC). Here we propose to extend our previous efforts to apply multimodal single-cell profiling to capture QTLs and gene regulatory mechanisms in both subclinical and advanced atherosclerotic coronary segments. Building on our holistic framework and resources, this proposal will generate unprecedented insights into the hierarchical regulatory networks that influence dysregulated vascular wall processes. By enriching these high-resolution data with large-scale population genetics, clinical imaging, and genomic and histologic cardiometabolic tissue biobanks we will provide context for translating these findings to patients at various stages of disease. We have already identified several disease stage and cell state-specific markers for atherosclerosis. We will validate and discover new candidate causal genes and functional regulatory elements using perturbation assays coupled to high-throughput phenotyping in SMC, along with spatial imaging in intact tissues across the disease trajectory. Together with our interdisciplinary and experienced collaborators and unique established resources, we are well-positioned to carry out this work and discover fine-grained molecular features and hallmarks of CAD initiation and progression in the coronary vessel wall. Ultimately, these studies will enable the next generation of multimodal treatment strategies for risk stratification and eradication of this debilitating disease.


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 = $682,043 )
2026	2026	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	8	7/3/2026	NON-COMPETING CONTINUATION	$682,043
														Subtotal = $682,043

Issue Date FY: 2025 ( Subtotal = $695,962 )
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	001	7	8/6/2025	NON-COMPETING CONTINUATION	$695,962
2025	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	5	4/2/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $695,962

Issue Date FY: 2024 ( Subtotal = $742,087 )
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	001	6	6/21/2024	COMPETING CONTINUATION	$742,087
2024	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	5	6/21/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $742,087

Issue Date FY: 2023 ( Subtotal = $405,258 )
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	5	4/28/2023	NON-COMPETING CONTINUATION	$405,258
														Subtotal = $405,258

Issue Date FY: 2022 ( Subtotal = $405,258 )
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	4	4/12/2022	NON-COMPETING CONTINUATION	$364,732
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	001	4	6/29/2022	NON-COMPETING CONTINUATION	$40,526
														Subtotal = $405,258

Issue Date FY: 2021 ( Subtotal = $405,258 )
2021	2021	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	3	4/20/2021	NON-COMPETING CONTINUATION	$405,258
														Subtotal = $405,258

Issue Date FY: 2020 ( Subtotal = $405,258 )
2020	2020	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	2	4/3/2020	NON-COMPETING CONTINUATION	$405,258
														Subtotal = $405,258

Issue Date FY: 2019 ( Subtotal = $420,633 )
2019	2019	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cardiovascular Diseases Research	000	1	5/31/2019	NEW	$420,633
														Subtotal = $420,633

Grand Total All Awards = $4,161,757

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Multimodal genetic regulatory architecture of coronary artery disease

Award Number: R01HL148239

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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