Like other neurons of the central nervous system, retinal ganglion cells (RGCs)?the projection neurons of the retina?fail to regenerate after injury. In glaucoma, a leading cause of blindness, degeneration of RGC axons and their subsequent death are two key pathological events that lead to irreversible loss of vision. However, no effective treatments to prevent RGC vulnerability and loss are available. A critical obstacle toward developing novel therapeutics is our insufficient understanding of mechanisms that regulate RGC survival and axon regeneration. Using mouse optic nerve crush (ONC) model, previously, we discovered that removal of phosphatase and tensin homolog (PTEN) protein significantly promotes axon regeneration. More recently, we leveraged ONC model and undertook a large-scale in vivo CRISPR screen to identify key regulators of such mechanisms. Our screen revealed multiple genes whose removal from retinal cells promoted RGC survival and/or axon regeneration. One of the strongest protective phenotypes belonged to the knockout of the c-Jun N- terminal kinases-Interacting Protein 3 (JIP3). However, knockout of JIP3 not only fails to promote axon regeneration in survived RGCs, it abolishes axon regeneration induced by PTEN deletion. Here, I propose performing transcriptomic analysis of RGCs with or without JIP3 and/or PTEN at different time points after optic nerve injury to further investigate molecular programs underlying JIP3-dependent RGC survival, and PTEN- dependent axon regeneration. Furthermore, I will test the neuroprotective effect of JIP3 in a mouse glaucoma model in which elevation of intraocular pressure causes RGC loss.
Glaucoma is the second leading cause of irreversible blindness affecting more than 3 million Americans and ~60 million more people around the globe. Projection neurons of the retina which are responsible for the transfer of light signals to the brain die in glaucomatous condition, rendering retina and brain disconnected. This proposal investigates regulatory gene programs in the retinal projection neurons to identify therapeutic targets for preventing their loss in glaucoma.
