The fast-aging killifish as a unique model to screen, identify and validate druggable targets and(re)myelinating compounds.

Neurodegenerative diseases associated with aging have an increasing prevalence in our greying society. As adult mammals lack the robust capacity to regenerate lost or damaged neurons, age-related deterioration of the central nervous system (CNS) seriously constrains life quality. In contrast to mammals, short-lived killifish, which show aging characteristics similar to humans, have the remarkable ability to repair damage in the adult CNS. Upon aging, this neuroregenerative capacity decreases to a mammalian-like situation, making the killifish a unique vertebrate model to identify molecular targets for neuroreparative therapies with a high translational value for humans. Within this project, we will use a retinal injury model to study the neuroregenerative capacity of (aged) Müller glia, the radial glia-like stem/progenitor cells in the retina, and to identify positive and negative candidate regulators of Müller glia reprogramming in an aging environment. Using state-of-the-art molecular and morphometric technologies, in combination with single-cell RNA sequencing and bioinformatic approaches, we aim to decode the cellular and molecular framework that defines CNS aging, and to dissect how gene regulatory networks (dys)regulated during aging affect neuronal repair. We envision this research to result in new druggable targets for future development of reparative strategies, and even rejuvenation, in the aged mammalian CNS.