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Development of human axon regeneration model using retinal organoids

About the Solution

Glaucoma is the leading of irreversible blindness with an estimated 64 million affected worldwide in 2013 and projected 111 million by 2040. Glaucoma is a neuronal degenerative disease associated with retinal ganglion cell (RGC) apoptosis and optic nerve degeneration. Once RGCs are lost, they cannot regenerate or be replaced in humans or other mammals, and vision loss is irreversible. RGC regeneration and axon reconnection would be approaches to restore vision; however, little is known about which gene or signaling pathway participating in human RGC degeneration/regeneration, neurons’ interactions and axon reconnection. Although studies have been done by using other animals such as mouse or rat, are the same mechanisms working in humans? Many protocols have been reported for RGC generation from induced pluripotent stem cells (iPSCs) or embryonic stem cells (ESCs) (Gill et al., 2016; Tanaka et al., 2015), but two-dimension (2D) culture limits our understanding of neurons’ interactions in the retina. Unfortunately, 3D retinal organoids (RO) studies have largely ignored questions of RGC differentiation and survival. In this proposal, I aim to address both of these unmet needs by analyzing 3D ROs derived from hiPSCs with a specific application of our RGC cell biology expertise. The goal of this project will be to differentiate more organized and retinal specific RO from hiPSCs, and then use this model to study human RGC degeneration after axon injury using laser axotomy technique, applying a variety of innovative imaging and molecular methods. Finally, I will study approaches to promote human RGC survival and regeneration in this organoid model, as a step towards translating molecular manipulations previously studied in rodents now into the human retinal model.

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