This project is dedicated to discovering ways to induce regeneration of the corticospinal tract (CST and recovery of motor function after spinal cord injury (SCI). The CST is the pathway that is responsible for the ability to move voluntarily. Damage to the CST as a result of a spinal cord injury is the reason people are paralyzed. The project is based on discoveries that the CST can be induced to regenerate following spinal cord injury by targeting molecular pathways that control cell growth in development, specifically phosphatase and tensin homolog (PTEN). PTEN is responsible for shutting down the type of protein synthesis that is critical for cell growth during development. PTEN acts by blocking the mammalian target of Rapamycin, (mTOR), so deletion of PTEN releases inhibition on mTOR, which in turn allows the cell to synthesize proteins that are critical for cell growth. We have shown that genetic deletion of PTEN in mice and knockdown of PTEN in rats with AAVshRNA allows CST neurons to mount a robust regenerative response, which is accompanied by recovery of motor function. The new project is based on exciting and novel recent discoveries that targeting PTEN in adult nerve cells induces a state of youthful vigor in which there is perpetual growth in addition to an ability to regenerate after injury. The overall goal of the project is to determine the cellular and molecular mechanisms of this growth-enabled state and identify the genes that are turned on or shut off during growth and regeneration. Defining the pattern of gene expression that underlies the growth-enabled state in nerve cells will identify targets for future therapeutic interventions to promote regeneration and repair after injury and potentially protect nerve cells from degeneration in neurodegenerative disorders.
This project will define the cellular and molecular mechanisms underlying successful regeneration of corticospinal tract axons after spinal cord injury. We focus on interventions targeting intrinsic neuronal growth capacity, some of which are already in the early stages of development as candidate therapies. By defining cellular and molecular mechanisms underlying axon regeneration, the project will reveal new targets for other more translatable interventions to promote axon regeneration after injury.
