Intrinsic Axonal factors in Growth and Regeneration

When the brain or spinal cord are damaged nerve fibres are cut. In the case of spinal cord injury this disrupts the connection between the brain and the body via the spinal cord. The result is paralysis and loss of sensation below the level of the injury. In order to bring back function to patients it is necessary to stimulate the cut nerve fibres to regenerate. Regeneration is inhibited by the presence of blocking molecules in the spinal cord, by the scar tissue that forms around the injury site. In addition spinal cord nerve fibres have an intrinsically poor ability to regenerate. Treatments are now available to remove some of the inhibition from scar tissue, but these will only be partly effective if the vigour of regeneration of the nerve fibres remains low. Previous research from the Fawcett and Holt laboratories has identified a new way in which the regenerative vigour of the nerve fibres can be boosted. The grant application investigates ways in which this discovery can be made into a treatment for spinal cord injury.

The success or failure of axon regeneration is determined by the permissive or inhibitory environment through which the axons are growing and by the intrinsic regenerative ability of the axons. We have recently described a new mechanism which is important in determining the intrinsic regenerative ability of axons. Peripheral axons with high regenerative ability contain the machinery for protein synthesis and can make new proteins at the cut axon tip, while CNS axons with low regenerative potential cannot. We plan to extend these studies to address the following issues:-

1. Investigate the importance of local translation in general and of individual mRNAs in particular for axon regeneration
2. Identify mRNAs that are present in sensory and embryonic retinal axons
3. Determine why ribosomes and mRNAs are transported into sensory axons but not CNS axons, and devise methods to manipulate transport.
4. Modify the intrinsic regenerative ability to axons to enable them to regenerate in the damaged CNS.