Integrin engineering to promote axon regeneration and Schwann cell migration

After damage to the spinal cord or brain many nerve fibres are cut. In spinal cord injury this means that motor commands from the brain cannot reach muscles, and sensory information from the skin cannot reach the brain. In order to produce a cure the nerve fibres have to be made to regenerate from the injury point back into the spinal cord and up towards the brain. At present nerve fibre regeneration after spinal cord damage does not succeed, due to many factors such as the scar tissue at the injury site that blocks nerve fibre growth. In the scar tissue there is a molecule called tenascin which nerve fibres could use to grow on, but they lack the receptor molecules to interact with tenascin. The project will put the necessary type of receptor molecules (integrins) on the cut nerve fibres, and will make further modifications to the integrins to prevent them being turned off by inhibitory factors in the scar tissue. A second part of the project is to take a cell type called Schwann cells, which can promote nerve fibre growth, and implant them into spinal cord injuries as a bridge over which the regenerating nerve fibres can grow. In order to make it possible for these cells to integrate into the spinal cord they will also have modifications to their surface integrins.

The aim of the grant is to develop a new set of tools for structural repair of the damaged spinal cord, base on the manipulation of integrins. By engineering integrin expression, trafficking, activation and signalling we aim to promote axon regeneration, and to increase the ability of Schwann cells to migrate and integrate into the CNS environment. Tenascin-C is upregulated in the damage spinal cord, so we have identified an integran that interacts with it. Proof of principle that expression of a tenascin-binding integrin can promote axon regeneration has already been obtained. However we believe that in the adult CNS inhibitory mechanisms may interfere with integrin activation, trafficking and signalling. We have interventions to counteract these potential influences, and will apply them one by one until we have a successful integrin strategy for promoting CNS repair. This builds on previous work in the applicant?s laboratories on axon regeneration, Schwann cell migration and integrins. It also builds on work by our collaborators on integrin trafficking and activation. The tools for the work are mostly already made, but they have not previously been applied to axon regeneration or Schwann cell migration. The project also builds on spinal cord injury models and methods for behavioural assessment developed in the Fawcett laboratory. Repair of CNS damage will require the integration of several treatments; integrin engineering will probably be an important part of these treatments.