The CNS of adult mammals, as compared to the peripheral nervous system of mammals or the nervous system of other organisms, has extremely limited capacity for axonal regeneration. Specific factors limiting adult mammalian regeneration of axons have been identified, but they provide an incomplete explanation for poor adult mammalian CNS regeneration. We have completed a genome-wide shRNA-based screen for endogenous genes limiting the repair of axons in the mammalian CNS. We have also conducted experiments to identify conserved genes that affect axon regeneration in the model organism C. elegans. Factors common to both experimental systems are expected to identify fundamental mechanisms in regeneration that are likely to affect the equivalent process in human patients.
We aim to study and develop the translational potential of those evolutionarily conserved mechanisms here. From our studies we have selected one evolutionarily conserved pathway identified both in mouse cell culture and in C. elegans axon regeneration. It is bioinformatically the most enriched gene set in the primary mammalian screen data, with multiple family members identified, and also regulates regeneration in C. elegans. The relevance of the pathway will be tested in preclinical models of traumatic spinal cord injury. Multiple steps in the pathway will be assessed in rodent spinal cord injury models. Both gene deletion strains and pharmacological inhibition will be studied to provide a validated pathway for future therapeutic development. While we will focus on one particular pathway regulating membrane traffic in the axon, we will utilize both laser axotomy and mouse spinal cord traumatic injury to explore additional pathways identified in the primary screen. This project builds on genetic screens in the mature mammalian central nervous system and C. elegans to analyze novel mechanisms that promote axon regeneration after mammalian spinal cord injury. The findings will have high relevance for the development of novel therapeutics for neurological disorders.
Many neurological conditions disrupt connections between surviving neurons. The regeneration of axons has the potential to provide functional neurological recovery, without requiring ?new? cells from transplantation or from neurogenesis. Unfortunately, the CNS of adult mammals, as compared to the peripheral nervous system or nervous system of other organisms, has extremely limited capacity for axon regeneration. We have developed screening methods to identify those genes limiting the repair of axons in the mammalian CNS. We will evaluate regeneration-limiting genes using translational models of traumatic spinal cord injury.
