Systems genetics of vascular smooth muscle phenotypes

Ended Project Grant Awarded Last action

Award ID
R01HL166428
Recipient
Awarding agency
Obligated
$10,256,077

Award facts

Assistance listing
93.837 Cardiovascular Diseases Research
Completion date
Place of performance
Virginia, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Coronary artery disease (CAD) remains the leading cause of death in the western world despite significant advances in early detection and extensive use of lipid-lowering and anti-hypertensive drugs. To date, no single drug has been developed to target the primary disease process in the vessel wall. A complete understanding of the disease susceptibility is urgently needed to develop additional therapies. Common forms of atherosclerosis involve environmental factors, hundreds of genetic variations, and their interactions, each of which exert a relatively small effect on disease susceptibility. The most recent genome-wide association study (GWAS) in nearly six hundred fifty thousand individuals identified 175 independent variants associated with increased risk for CAD. However, most of the underlying genes and the related mechanisms of how these variants contribute to the disease process remain unknown. This proposal outlines an integrative genetics study in a unique resource of human aortic smooth muscle cells (SMCS) isolated from 151 genotyped multi- ethnic heart transplant donors to discover the CAD-associated variants that perturb SMC gene expression and their downstream functional consequences. In recent studies, we measured gene expression in quiescent and proliferative culture conditions representing the transdifferentiation of SMCS from a healthy to an atherogenic phenotype. We identified 84 genes whose expression was associated with CAD variants in GWAS loci. However, the causal genetic variants in these loci remain to be elucidated. Therefore, as part of the proposed studies, we will first perform massively parallel reporter assays to identify the variants that modulate gene expression in SMCS. We will also take advantage of the natural variation in gene expression to construct CO- expression and bayesian networks to understand how the predicted candidate causal genes function in SMCS. We will refine these networks by mapping regulatory elements to nascent RNA transcripts in response to pro- inflammatory cytokines. We will then validate our predictions in gain and loss-of-function experiments in cultured SMCS. We will also validate our predictions in well-phenotyped coronary artery specimens from cases of unexpected sudden death by performing immunohistochemical analysis of proteins encoded by genes that are predicted to play a key role in atherosclerosis-relevant SMC phenotypes. The overall goal of the proposed studies is to integrate systems genetics and computational biology leading to mechanistic predictions of the gene networks that are perturbed by CAD. Besides understanding CAD loci, these integrative genetics studies will provide a useful window into the flow of biological information from genetic variants to SMC gene expression and atherosclerosis-relevant phenotypes.

Transactions

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Subawards

Subrecipient Amount Awarded
Cvpath Institute Inc. To perform immunohistochemical and/or RNAish analysis to assess the protein and/or transcript levels of candidate genes predicted to be associated with coronary… $53,750
Cvpath Institute Inc. Work performed through this subcontract will select 20-24 stable or unstable plaques per year with progressive coronary plaques, including the type of lesions… $114,453

Quick answers

Who received award R01HL166428?

R01HL166428 was awarded to Rector & Visitors Of The University Of Virginia by National Heart Lung and Blood Institute (National Institutes of Health) on December 15, 2022.

How much is award R01HL166428 worth?

$10,256,077 has been obligated on R01HL166428.

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