A novel approach to improve the repair of injured peripheral nerves

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Peripheral nerves connect our tissues and organs to the Central Nervous System (CNS) and are important for movement, our senses and much of the unconscious control of many of our organs. Unlike, the CNS, the Peripheral Nervous System (PNS) is capable of regeneration following injury. This is why movement can be re-established in a reconnected amputated limb, whereas injuries affecting the CNS, such as spinal damage are much less likely to repair. Despite the intrinsic ability of peripheral nerves to repair, the process is not perfect. Following severe injuries, grafts are needed to bridge the region of damage but these have limitations and there is a huge impetus to develop improved artificial grafts. Moreover, following even minor nerve damage, aberrant regeneration can occur which often fails to resolve and can result in the development of pain. Understanding the physiological mechanisms by which peripheral nerves can regenerate following injury should enable improvements in the treatment of severe nerve injuries, provide strategies for the treatment of neuropathic pain and perhaps provide insight into how to improve repair of the CNS.Following the breakage of a nerve, the nerve cells degenerate downstream of the injury separating the nerve cells from their target tissues. The regeneration process therefore requires the regrowth of the nerve cells back to their targets. We have shown that at the site of injury this process is enabled by another cell type, Schwann cells, which are the major glial cell type of the PNS. These cells migrate as cords across the injury site and take the regrowing nerve cells along with them on their surface. Inflammatory cells accumulate at the injury site and we have discovered that these cells secrete a factor that stimulates Schwann cell migration. The identification of this previously unknown Schwann cell chemotactic factor has important implications as it may be beneficial in stimulating Schwann cell migration and hence nerve cell regrowth in artificial grafts. Moreover, inhibition of this factor may attenuate the aberrant nerve regeneration associated with pain. The aim of this proposal is to test, using in vivo models, whether the identification of a potent Schwann cell chemotactic factor will result in therapeutic benefits. To test this we will do the following:1. Test the ability of this factor to improve nerve regeneration in artificial grafts.2. Test the effects of inhibiting the chemotactic factor to determine its potential as a therapeutic target for the treatment of aberrant regeneration.3. To characterise the inflammatory cells responsible for the secretion of the Schwann cell chemotactic factor.The completion of this study should determine the therapeutic potential of using this Schwann cell chemotactic factor to improve nerve repair and/or as a novel drug target to resolve the aberrant nerve regeneration associated with pain. If successful, partners will be sought to take these findings towards the clinic.