Identifiering av mål för behandling av kranskärlssjukdom via ett zebrafisk-modellsystem
Tidsperiod: 2016-01-01 till 2019-12-31
Projektledare: Marcel den Hoed
Budget: 5 875 226 SEK
The aim of my research programme is to identify novel drug targets and compounds for the therapeutic intervention of coronary heart disease (CHD). To this end, I have identified 93 positional candidate genes in loci identified as being associated with CHD in genome-wide association studies. Two PhD students will target these genes in a zebrafish model system using CRISPR-Cas9, and examine their effect on vascular infiltration by lipids, oxidized LDL cholesterol, macrophages and neutrophils, as well as on endothelial thickness and luminal diameter, before and after feeding on a control or high-cholesterol diet. Promising genes will be taken forward for additional characterization in adult fish, i.e. for RNA sequencing of macrophages, neutrophils, erythrocytes and endothelial cells, and for global metabolomic profiling of vascular plaque tissue from fish fed on a high-cholesterol diet. These experiments are anticipated to identify pathways by which putative causal genes influence atherogenic traits.Mutant models that already induce atherogenic traits at five days post-fertilization will be used for a chemical compound screen, aiming to identify small molecules that prevent or reduce early stage atherosclerosis. Promising compounds will be taken forward for additional experiments in high-cholesterol diet fed larvae.My research programme will: i) provide a framework for novel in vivo model systems to identify drug targets and chemical compounds aimed at decreasing atherosclerosis and CHD; ii) further increase our understanding of atherosclerosis and CHD pathophysiology by integrating results from imaging and -omics approaches; and iii) provide a new set of drug targets and compounds that can be taken forward for pharmacological and pharmacokinetic testing.