Induction and characterization of RGC axon regeneration in models of glaucoma

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Induction and characterization of RGC axon regeneration in a mouse model of glaucoma Glaucoma is a large and heterogeneous group of optic neuropathies characterized by optic nerve degeneration that results in irreversible vision loss. Primary open-angle glaucoma (POAG) is the most common form of glaucoma, accounting for the majority of all cases. Elevated intraocular pressure (IOP) is the most important and only known modifiable risk factor associated with POAG. Despite therapeutic reduction of IOP, vision loss still continues to progress in most glaucoma patients. Retinal ganglion cells (RGCs) are the only neurons that relay visual information from the retina to the brain. Like other neurons in the central nervous system, RGCs do not spontaneously regenerate their axons after damage. These neurons, which collectively form the optic nerve, are also highly vulnerable when their axons are damaged. While the molecular pathways that damage RGCs in glaucoma are not fully understood, several studies using the animal models of glaucoma have described the presence of local insult in the optic nerve at the level of lamina, where the RGC axons exit the eye. Furthermore, in a mouse model of glaucoma (i.e. dexamethasone-induced ocular hypertension (OHT)), it was demonstrated that optic nerve degeneration precedes structural and functional loss of RGCs, and that the axonal damage and transport deficits initiate at the optic nerve head. Importantly, insults to the RGC axons under these circumstances result in Wallerian degeneration distal to the site of damage, ultimately causing disconnection between the retina and the brain. Using optic nerve crush in mice, we and others have demonstrated that genetic manipulation of different genes in the RGCs promotes long distance axon regeneration. However, while traumatic optic nerve crush is a useful technique for investigating the mechanisms of RGC axon regeneration, it does not faithfully reproduce glaucomatous optic nerve damage which axonal injury is partial and progresses gradually over time. In this proposal, we will use a combination of axon tracing techniques, mouse genetics and 3D imaging to examine the extent to which RGC axon regeneration and axon remodeling takes place after OHT. The results obtained from this study will create a paradigm shift in how we investigate optic nerve regeneration, and provide foundation for future investigations into developing reparative therapy for treating advanced glaucoma patients.