Target and drug discovery for cardiovascular genomic medicine using high-throughput cell screening platform

Coronary Artery Disease (CAD) is the first cause of morbidity and mortality in Qatar and across the world. Genome-wide association studies (GWAS) have identified hundreds of suggestive loci for coronary artery disease that could have a potential role on the development of atherosclerosis, which is the underlying pathogenesis of CAD. Yet, the molecular and cellular mechanisms of most identified genes in the pathogenesis of atherosclerotic plaque remain unknown. High throughput functional approaches will allow elucidating the role of GWAS candidate genes in the cellular events of the atherosclerotic plaque progression and eventually to translate this knowledge to novel therapeutics. In this proposal, we aim to develop a robust high throughput phenotypic screening platform that combine siRNA libraries targeting the genes in GWAS-defined risk loci and phenotypic cell-based assays relevant to the critical cellular events involved in the atherosclerotic plaque progression and vulnerability, including monocyte-endothelial adhesion, smooth muscle cell phenotype switch, and intra-plaque angiogenesis. In collaboration with Hamad Medical Corporation and Qatar Computing Research Institute, we will first perform comprehensive bioinformatic analysis to prioritize gene candidates from a GWAS of around 1,000 Qatari CAD patients, for further functional characterization in human cell-based models relevant to the pathogenesis of atherosclerosis. Next, using our high throughput cell screening platform, we will screen siRNA libraries that target the prioritized GWAS gene candidates to define their biological effects on the critical cellular events of atherosclerosis. Finally, we will perform a primary screen of an annotated FDA-approved drug library to identify drugs reversing the phenotypic perturbation caused by the “loss-of-function” of the identified target genes. Setting up the high throughput phenotypic screening platform would build new capacity in Qatar to conduct functional cell analysis and to interrogate disease pathways in the post-GWAS era. The use of this platform aligns very well with the aims of Qatar Genome Project and, most importantly, fills the gap between the genomic discovery studies of cardiovascular diseases and therapeutic targeting for successful translation into clinical application.

Hamad Bin Khalifa University (HBKU)