Thursday, December 26, 2024 12/26/2024

Identifying the organotypic and disease-specific vascular cell populations by integrating single cell data with polygenic risk

Award Number: U01HL166060
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Vascular cells are present throughout the human body and contribute to risk of multiple diseases. Vascular dysfunction directly affects risk for arterial diseases (e.g. coronary artery disease and stroke) as well as manifestations of other diseases such as dementia, cancer, and diabetes. Single cell analysis of the human vasculature has already begun to identify the basic mechanisms of vascular dysfunction in the large number of associated diseases. Our group, and several other labs, have used single cell RNA-sequencing (scRNA-seq) to identify vascular cell heterogeneity. We performed scRNA-seq of the aorta to identify functionally distinct endothelial cell (EC) subpopulations, and multiple groups have identified activated myofibroblasts in diseased mouse and human vascular tissue. These studies prove heterogenous cell populations exist in the arterial wall, but it remains undetermined which populations play a causal role in early vascular dysfunction and disease risk. The Human BioMolecular Atlas Program (HuBMAP) provides a rich source of data to begin to establish a causal link for specific vascular cell subpopulations with disease. In HuBMAP data, ECs and vascular smooth muscle cells (VSMCs) comprise a large portion of the single cells identified from each organ. However, to establish the cell types and transcriptional pathways associated with disease it will be necessary to incorporate the new datasets and computational methods we propose in this application. We aim to use new computational methods to integrate data from diseased vascular tissue with normal HuBMAP data, to identify the disease- relevant features of vascular cells. New methods to integrate disease associated genes from GWAS will also help investigators prioritize causal cells for multiple common diseases. To achieve this, we will: 1) Use new software to identify organotypic features of vascular cells in HUBMAP reference data; 2) Identify disease-specific vascular cell signature by comparing HUBMAP reference data with samples from vascular disease; and 3) Build and share a computational program to identify disease-relevant cell populations and gene modules through integration with genetic association data. These analyses make use of existing vascular disease snRNA-seq data from a rich collection of diseased subjects we can share with the HuBMAP. All data from vascular disease subjects is available for open data sharing, and has been collected to include a diverse collection of subjects with respect to sex and ancestry. Our methods and statistical software to perform this integration of multiple single cell datasets with genetic associations will establish a generalizable methodology to rapidly discover the disease-relevant cells and processes of the vasculature, and all other cell-types, for any diseases with genetic risk and available GWAS. Our team is immediately ready to undertake the proposed studies and share the software with the HuBMAP community. We have a track record of rapidly sharing single cell RNA-seq data, and have a diverse team with expertise in vascular biology, statistical genetics, and computational biology.


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 = $56,244 )
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	3	12/4/2024	SUPPLEMENT FOR EXPANSION	$56,244
														Subtotal = $56,244

Issue Date FY: 2024 ( Subtotal = $519,340 )
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	3	5/17/2024	NON-COMPETING CONTINUATION	$526,267
2024	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	001	2	6/11/2024	SUPPLEMENT FOR EXPANSION	-$6,927
														Subtotal = $519,340

Issue Date FY: 2023 ( Subtotal = $601,120 )
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	001	2	9/21/2023	SUPPLEMENT FOR EXPANSION	$89,625
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Trans-NIH Research Support	000	2	5/24/2023	NON-COMPETING CONTINUATION	$511,495
														Subtotal = $601,120

Issue Date FY: 2022 ( Subtotal = $546,730 )
2022	2022	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Trans-NIH Research Support	000	1	6/23/2022	NEW	$546,730
														Subtotal = $546,730

Grand Total All Awards = $1,723,434

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Identifying the organotypic and disease-specific vascular cell populations by integrating single cell data with polygenic risk

Award Number: U01HL166060

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

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