Reprogramming Retinal Ganglion Cells for Axon Regeneration
The proposed study aims to investigate two novel approaches for promoting long distance (ie, eye to brain) optic nerve regeneration. First based on our completed genetic study we will test if pharmacological inhibition of an identified protein via direct eye injection can promote long distance optic nerve regeneration or whether, based on strong preliminary data, manipulation of another novel gene can induce such regeneration. The project will identify a potential translational approach for promoting optic nerve regeneration, and also open a new avenue for identifying novel gene targets that can be manipulated to enhance optic nerve regeneration.
One major cellular event in glaucoma is optic nerve injury leading to disconnection of retinal nerve fibers from the brain. Long distance optic nerve regeneration is the most basic step for reconnecting optic nerve cells with their original innervating targets in the brain and regaining visual function.
The retina is made of several layers of cells that sequentially transmit the received light signal to the brain for visual processing. Retinal ganglion cells (RGCs) are the final nerve cells (called neurons) that link the retina to the brain through cellular signaling over long nerve fibers called axons that extend from the optic nerve to the brain. In glaucoma, injury to the optic nerve injury disrupts the transmission of these visual signals to the brain. Therefore, the overall goal of our study is to identify novel and effective approaches for promoting long distance optic nerve regeneration.
In the mammalian central nervous system (CNS), mature neurons are unable to regenerate axon after they become injured. This diminished intrinsic axon regeneration ability of mature CNS neurons is regulated by gene expression. Recent studies targeting gene expression and its regulation of intrinsic regenerative ability have produced very promising results in optic nerve regeneration. However, the number of genes/pathways that can be targeted to promote optic nerve regeneration is still very limited, greatly diminishing the translational potential into therapeutic treatments. An important way that gene expression is regulated is through epigenetic modifications without changes in DNA sequences. Based on our preliminary study, we hypothesize that mammalian CNS neurons undergo an epigenetic transition during maturation that leads to silencing of axon growth-promoting genes and upregulation of axon growth-inhibitory genes. Thus, it is possible to reprogram the mature CNS neurons into a regenerating state via remodeling their epigenetic landscape through reprogramming factors or chromatin modulators. In this project, we will first test if a chemical reagent targeting a specific epigenetic molecule can be used to promote optic nerve regeneration. We will then determine if a family of new genes and their associated pathways can be targeted to induce long distance optic nerve regeneration.
Our investigation is very innovative because the chemical reagent we are testing has been safely used in animal models for treating various cancers, thus providing a potential novel and safe translational approach for enhancing optic nerve regeneration. Moreover, our study will show for the first time that a specific pathway involved in induced pluripotent stem cell (iPSCs) techniques also play important roles in promoting optic nerve regeneration.
The proposed study will open a new avenue for identifying novel genes and pathways that can be manipulated to promote optic nerve regeneration. Because many epigenetic regulators can be manipulated with pharmacological reagents, the study may help identify and develop potential therapeutic approaches for glaucoma-induced optic nerve injury.