One major reason for the devastating and permanent disabilities after spinal cord and other types of central nervous system (CNS) injuries is the inability of lesioned axons to regenerate and re-build the functional circuits. Thus, a long-standing challenge has been to find ways to promote axon regeneration and restore functions. Among the different types of descending axons, corticospinal tract (CST) axons appear to be the most refractory to regenerate. Because of the CTS’s critical role in controlling voluntary movement, developing a strategy to promote CST regeneration will be paramount for functional recovery after spinal cord injury. Despite considerable efforts over the past decades, from both basic and clinical sides, currently there is no method that enables regeneration of CST axons even in experimental spinal cord injury models in mammals. In our recent studies towards understanding the intrinsic regenerative ability of CNS neurons, we discovered the conditional deletion of PTEN, a negative regulator of the mTOR activity, leads to robust axon regeneration after optic nerve injury in adult mice. Strikingly, our further studies demonstrated similarly robust regeneration of CST axons in two different spinal cord injury models, namely T8 dorsal hemi section and T8 spinal cord complete crush. Importantly, such CST regeneration phenotype has been replicated by the lab of Dr. Binhai Zheng, who failed to observe CST regeneration in Nogo/NgR knockout mice. These exciting results of anatomical regeneration provide an unprecedented opportunity to assess whether these regenerating axons are able to form functional connection and mediate functional recovery after spinal cord injury. The specific aims of this application include:
Specific Aim 1: To assess whether regenerating CST axons elicited by PTEN deletion are able to form functional connections in the spinal cord caudal to the lesi on sites.
Specific Aim 2: To examine whether late-onset PTEN deletion in adult can promote CST regeneration after spinal cord injury.
Specific Aim 3: To assess whether PTEN deletion could promote functional and behavioral recovery after C5 spinal cord injury.