PROJECT SUMMARY Injuries of mature central nervous system (CNS) axons result in loss of vital functions due to the failure of CNS axons regeneration. We previously conducted an extensive molecular dissection of the PTEN/PI3K/AKT/mTOR complexes (mTORCs) signaling network, illuminated their cross-regulating mechanisms, and definitively determined the linear and parallel signals that contribute to optic nerve regeneration. However, the specific effectors downstream of PTEN or AKT that proactively regulate axon regeneration are still unknown. This is a proposal to identify regeneration markers and true permissive signals of axon regeneration by comparing regenerating and non-regenerating RGCs with the same genetic modulation. This information will provide an unambiguous pro-regeneration signaling pattern that will guide us to identify novel therapeutic targets and assist in safely translating our findings into innovative neural repair treatments for patients with CNS injuries and neurodegenerative diseases. In addition, it is also extremely important to determine how neuroprotection and regeneration therapies interact, especially whether protecting regenerating axons from degeneration enhances their viability and growth so that they can achieve full-length regeneration with recovery of visual function.