Fixing a broken heart: Zebrafish as a model for heart regeneration drug discovery

Myocardial infarction (MI) remains a leading cause of mortality, with currently available treatments addressing symptoms rather than promoting heart muscle regeneration. Cardiac regeneration strategies, inspired by regenerative species like zebrafish, offer promising therapeutic potential. This thesis in part investigates the advantages and limitations of using larval zebrafish as a model for heart regeneration drug discovery. A novel screening platform, ZebraReg, was developed for semi-automated, longitudinal analysis of heart regeneration. Results demonstrated that zebrafish larvae recapitulate key molecular regenerative processes observed in adults, validating them as an advantageous model for drug discovery. Combining the platform with CRISPR/Cas9-based gene knockout studies, the role of the primary cilium and mechanosensing in heart regeneration was investigated. Lastly, a novel drug target for heart regeneration was examined in zebrafish larvae in the context of heart development and regeneration. We demonstrated that the protein target localises to the primary cilium in vitro and affects ciliary length and function, suggesting a previously unknown role in the cilium. In conclusion, this thesis aimed to advance our understanding of heart regeneration and novel therapeutic targets, laying the groundwork for future regenerative medicine approaches for MI.