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A genetic approach to identify the common mechanisms of vascular disease

Award Number: DP2HL152423
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2019
PERIOD OF PERFORMANCE END DATE: 08/06/2022

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A genetic approach to identify the common mechanisms of vascular disease - Project Summary In my clinical training, I repeatedly saw the devastating effects of vascular disease on patients in the prime of their lives. Vascular diseases such as coronary artery disease (CAD), stroke, arterial dissection, and migraine headache combine to cause over half the death and disability in the United States1. To eradicate vascular disease it will be important to develop new treatments that target the arterial cells where the disease begins. The disease-causing pathways in these cells may be common to all vascular diseases, and their shared genetic risk can be a window into this pathophysiology. The loci associated with multiple vascular diseases have recently been identified through genome-wide association studies (GWAS). These loci represent new therapeutic targets, but their biological mechanisms remain largely unexplored. There are multiple challenges that exist for identifying these disease-causing biological mechanisms. First, each association often involves multiple variants. Second, most causal variants occur in non- coding regions, where the associated gene is unclear. Third, the relevant cell type is often critical for determining the function of a variant. I have identified new opportunities to address each of these challenges by integrating methods in GWAS analysis, single cell RNA-sequencing, and genome-editing of vascular cells. I utilized this approach to study the regulatory effect of the 6p24 locus on endothelin-1 expression, and aim to extend this unique combination of methods to the full set of pleiotropic vascular loci. This New Innovator Award application seeks to understand the intersecting mechanisms of multiple vascular diseases from the functional analysis of human genetic variation. The analytic pipeline I propose will prioritize loci with pleiotropic effects on three vascular diseases, and interrogate their combined effects on vascular cell function. I will establish an analytic pipeline to identify common vascular disease-associated loci and functionally characterize their biological effects. This will establish a new approach to the prioritization and functional characterization of vascular disease-causing variants, and identify new biological pathways for the treatment of multiple vascular diseases.


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: 2024 ( Subtotal = -$33,251 )
2024	2022	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	001	1	8/21/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2022	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	1	10/16/2023	SUPPLEMENT FOR EXPANSION	-$33,251
														Subtotal = -$33,251

Issue Date FY: 2022 ( Subtotal = $101,600 )
2022	2022	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	001	1	12/20/2021	SUPPLEMENT FOR EXPANSION	$101,600
2022	2019	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	1	10/15/2021	NEW	$0
														Subtotal = $101,600

Issue Date FY: 2019 ( Subtotal = $2,685,000 )
2019	2019	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	1	8/29/2019	NEW	$2,685,000
														Subtotal = $2,685,000

Grand Total All Awards = $2,753,349

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A genetic approach to identify the common mechanisms of vascular disease

Award Number: DP2HL152423

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2019

PERIOD OF PERFORMANCE END DATE: 08/06/2022

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