Background: Recovery of neuronal functions is one of the most common challenges in the healthcare of patients after different types of brain injuries, yet without therapies to functionally replace degenerated neurons.
Hypothesis: Cxcr3 and Tlr2 signalling pathways, as the key molecular checkpoints in regulating the glial scar formation and the understanding of these pathways, will allow us to specifically interfere with scar formation to improve tissue regeneration.
Strategy: We will use translational trans-species approaches to dissect the mechanisms of scar formation in animal models (zebrafish and mouse).
After different types of brain injury, the recovery of neuronal functions is one of the most common healthcare challenges. However, therapies to functionally replace degenerated neurons are still lacking. Regenerative therapies face two major challenges: a) how to improve the connectivity of spared neurons or replace lost neurons to improve functional recovery (restorative neurogenesis) and b) how to prevent or limit glial scar formation. A scar is non-functional tissue that not only interferes with the function of the brain area at the site of its deposition but also influences the integration of new neurons. In contrast to mammals, zebrafish are able to restrict glial scar formation, replace lost neurons and regenerate neural tissue in a scarless manner. Therefore, we will pursue a novel trans-species comparison (zebrafish and mouse) to identify the regulatory checkpoints restricting glial scar formation, with the goal of eliminating its detrimental effects, while at the same time not hampering the initial beneficial role of glial cells in wound healing. This approach should enable the mechanisms of scar formation to be deciphered, given that we have succeeded in identifying key pathways (Cxcr3 and Tlr2) active in oligodendrocyte progenitors during scar formation. Pharmacological interference with these pathways blocks scar formation and improves functional recovery after injury. We aim to use translational trans-species approaches to dissect the mechanisms of scar formation in animal models (zebrafish and mice), to identify predictive biomarkers and therapeutic targets applicable to human brain injury.