Background Diabetes and coronary artery disease (CAD) are main causes of death in Sweden and worldwide. Novel treatment strategies for the primary and secondary prevention of diabetes and CAD and their complications are needed, in part because in some cases (e.g. diabetes, coronary artery disease) existing drugs do not work equally efficiently in all patients and are in some cases accompanied by undesirable side effects; while for other diseases (e.g. non-alcoholic fatty liver disease, kidney failure) no drugs are available at all for prevention or treatment. Genome-wide association studies identified >1000 genetic loci that are robustly associated with these diseases, their risk factors and/or their complications. However, the genes and mechanisms through which most loci act remain uncharacterised. Aims The objective of my research programme is to identify targets that can be translated into efficient therapeutics for prevention and treatment of diabetes and CAD and their complications, without adverse side effects. The specific aims are to: 1) characterise the role of 600 candidate genes; 2) examine if putative causal genes represent promising targets for intervention; 3) examine if drugs exist against those targets and explore if they can be repurposed; 4) identify and scrutinise small molecules targeting promising targets not yet acted on by existing drugs; and 5) explore target engagement for the most promising small molecules. Methods My group developed and validated high-throughput, image-based model systems for dyslipidaemia, early-stage atherosclerosis, diabetes, cardiac rate and rhythm, fatty liver, and kidney failure in zebrafish larvae. Zebrafish orthologues of the most promising candidate genes in genetic loci for these traits and diseases will be targeted using CRISPR/Cas9 and examined for a role in disease-related traits using high-throughput, in vivo imaging. For putative causal genes, we will explore possible side effects using phenome-wide association studies in UK Biobank data, as well as using additional characterisation in zebrafish. Next, we will examine if drugs against promising targets exist, and if so, if they can be repurposed, using data from Swedish registries and characterisation in zebrafish. Finally, small molecules anticipated to engage with targets not yet acted on by existing drugs will be tested in zebrafish and their mechanisms of action will be characterised. Implications Repurposing of existing drugs for other indications would imply the quickest and safest way to the clinic. In addition, this research program will increase our understanding of cardiometabolic pathophysiology, and likely yield new targets and molecules acting on them that can be taken forward on the path towards clinical trials.