Elucidating Neuron-Intrinsic Molecular Mechanisms of Optic Nerve Regeneration

PROJECT SUMMARY To understand the neuronal intrinsic control of optic nerve regeneration, we initially conducted an extensive molecular dissection of the PTEN/PI3K/AKT/mTOR complexes signaling network, illuminated their cross- regulating mechanisms, and definitively determined the linear and parallel signals that contribute to optic nerve (ON) regeneration. We then developed a novel Retro-seq platform to label, purify, and single cell sequence regenerating and non-regenerating retinal ganglion cells (RGCs), by which we identified a group of downstream effectors of PTEN deletion that directly promote significant ON regeneration and surprisingly, also produce striking glaucoma neuroprotection. We propose the common target of these pro-regeneration and pro- neuroprotection genes may be the mechanistic nodal point that drives axon regeneration and neuroprotection directly. We will investigate another top gene from the regeneration-associated gene list and its functional related molecules to illustrate the potential new mechanisms of neuronal intrinsic control in adult CNS axon regeneration. Moreover, we will test individual pro-regeneration genes and their combinations in our newly developed acute and chronic mouse SOHU glaucoma models, in hope of identifying the most effective neural repair strategies that promote significant neuroprotection and visual functional recovery. These in-depth focused studies of prominent pro-regeneration and neuroprotection genes and their interactions are likely to illustrate a novel mechanism of axon regeneration, identify the most promising therapeutic targets, and therefore eventually establish translational strategies for safe and effective clinical management of glaucoma and other CNS neurodegeneration patients.