WP6 objectives: we aim to identify novel targets for DCM, understand the direction of effect for therapeutic intervention and define the ideal modality. We aim to validate three of these identified targets in vivo using mouse models of DCM.
As a first step in target identification, we will annotate variants and loci derived from GWAS and WGS to identify potential effector genes and derive information on functional consequences. Differentially expressed genes will be used as input for pathway analyses to identify markers for biological functions and processes. Clinical parameters will be associated with the transcriptomic clusters to identify biologically relevant pathways, narrowed down to specific molecular targets. We will integrate our genetic evidence with supporting non-genetic data to systematically generate a prioritized list of putative DCM drug targets for validation. We will study whether first candidate drugs targeting the identified genes/gene products/pathways engage the target and improve cardiac remodelling, function, and arrhythmias at a predefined and quantitative level in animal DCM models without toxicity. We aim to first validate 3 targets in genetic DCM with the prospect of more during and after the project.