Coronary artery disease (CAD) is a complex, maladaptive inflammatory disease of the vessel wall and is the leading cause of death worldwide. Smooth muscle cells (SMCs) are the predominant cell type in the vessel wall and normally have contractile roles. During CAD, SMCs lose their differentiation markers and subsequently proliferate, migrate and secrete extracellular matrix. Recent studies demonstrate SMCs in the plaque transition towards a 'fibromyocyte' phenotype that is atheroprotective and distinguished by high extracellular matrix expression. Extracellular matrix (ECM) constitutes a large proportion of the atherosclerotic plaque and has roles in both early and late (plaque stability) stages of CAD. Genome-wide association studies (GWAS) for CAD have now identified over 160 loci associated with CAD, with most residing in noncoding regions of the genome. Functional variants usually alter the activity of cis-regulatory elements (CREs) in a cell type/state specific manner, highlighting the importance of regulatory sequences in complex disease. Extracellular matrix (ECM) genes such as FN1, FNDC3B, COL4A1, COL4A2, and COL6A3 are all GWAS hits for CAD, however, the causal roles of ECM proteins remain ambiguous in CAD. We hypothesize that cis-acting genetic variation at ECM loci alter SMC CREs that drive ECM gene expression changes underlying CAD risk. Understanding genetic regulatory mechanisms of ECM genes at different stages of CAD will better define the roles of the ECM in CAD pathogenesis. In aim 1, we will reveal novel regulatory mechanisms at CAD-associated ECM loci using systems genetics approaches and CRISPR perturbations in SMCs. In aim 2, we will resolve cis-regulatory architecture of CAD-associated ECM loci at early and late stages of CAD using joint single-cell analyses. By integrating bulk and single-cell ATAC-seq analyses from a unique resource of normal and diseased human coronary artery samples, along with CRISPR perturbations in SMCs, this proposal will elucidate causal cis-regulatory mechanisms at CAD-associated ECM loci. Understanding gene regulation of ECM proteins may inform new approaches to modify ECM levels in the vessel wall to mitigate CAD progression and promote plaque stability.
|Program type||Postdoctoral Fellowship|
|Effective start/end date||01/01/2020 → 12/31/2021|