Identifying Drivers of Retinal Ganglion Cell Differentiation from Endogenous Stem Cells

About This Grant

SUMMARY The optic nerve is comprised of Retinal Ganglion Cells (RGCs), which are the only neurons capable of relaying visual information from the retina to the brain. A variety of conditions contribute to ganglion cell loss, which can result in total blindness. Many therapies have been designed to protect the optic nerve, but to date no therapy has been developed that reverses damage that has already occurred. While regeneration of the optic nerve may seem ambitious, there are several species such as zebrafish that can completely regrow a damaged optic nerve, or replace lost RGCs, providing a roadmap to how this process could be reconstituted in humans. Significant progress has been made towards this goal across various mammalian systems, with particular mutations or transgenic overexpression paradigms leading to partial reconstitution of the regenerative process. These preliminary findings provide strong support that thorough characterization of the regenerative process has the potential to translate into effective therapies. However, several methodological barriers have hampered thorough understanding of RGC regeneration in zebrafish. Firstly, multiple stem cell pools are capable of producing RGCs in zebrafish, which has made it difficult to define the precise sequence of events underlying RGC production. Further, it is unclear what signals tune this regenerative response to ensure that the appropriate number and types of cells are replaced. We have generated the hypothesis that the regenerative response must be initiated by a damage signal derived from dying RGCs. We have designed a series of aims to (1) characterize the process of RGC regeneration in zebrafish with unprecedented detail, (2) identify the origins of the cues that regulate RGC regeneration, and (3) identify factors that drive RGC regeneration even in the absence of RGC loss. Together, these findings will highlight a collection of biomolecules that instruct MG to regenerate the optic nerve, which will have important translational ramifications for the treatment of Glaucoma.