Acute and chronic spinal cord injury: novel studies of synaptogenesis, plasticity and mechanisms of repair

Spinal cord injury (SCI) leads to severe disability, but in nearly all cases there is some recovery in function over the first year following injury. We intend to find out more about these spontaneous recovery processes in order to try and develop therapies to increase the extent of recovery. For example, using special recording techniques we will study changes in nerve fibre conduction at early and late stages following SCI to see when conduction is compromised and how this changes over time. We have an enzyme therapy which can dissolve molecules that are present in SCI scar tissue. We need to optimise ways of delivering large amounts of this enzyme to the spinal cord while minimising the trauma of repeated administration. We have a new way of delivering the enzyme so that it gets into cells at the spinal cord scar, where it is most needed, and we will test whether this can improve function. We will also use novel techniques to show whether new fibres that have sprouted following this therapy can transmit signals to other nerve cells by studying nerve cell connectivity using special fluorescent probes that light up only when there is activity between cells. Finally we will use techniques to show the molecular signals that change in injured cells when treated with this therapy so that we can target them directly with new drugs. This research will be important for developing therapeutic strategies for treating spinal injured patients.

There have been rapid and significant advances in the area of neurorestoration over the last decade or so, much of which has focussed on neuroprotection, neuroregeneration and adaptive plasticity. There is now a considerable optimism about translating this work into effective clinical therapies, particularly in the area of spinal cord injury where no restorative treatments are available. However, this drive towards therapy cannot proceed before some critical questions are addressed. These are: which of the strategies identified from basic neurobiological studies will be the most effective in the clinic? What mechanism can promote the greatest functional repair? How can a therapy best be applied in a clinical context?

This proposal seeks to undertake a series of linked and mutually interdependent studies in the field of spinal cord injury which will:

1) Characterise processes underlying spontaneous changes in conduction, recovery and remyelination in a clinically relevant chronic spinal cord injury.
2) Optimise delivery of one of the leading experimental strategies, the use of chondroitinase ABC, by developing novel lentriviral vectors.
3) Develop novel techniques to assess structural and functional remodelling of synapses after spinal cord injury. I will use these to quantitatively examine synaptic rearrangements that occur spontaneously after spnal cord injury and driven by interventions targeting chondroitin sulphate proteoglycans. I believe these techniques will find widespread application in this field.
4) Identify molecular mechanisms involved in chondroitinase ABC-mediated repair.