Regulation of gene expression by microRNAs during nerve regeneration

Injury to the nerves that transmit information in the body causes a loss of communication between the brain, the control centre, and the rest of body. The failure of these nerves to regenerate, as in the case of spinal cord injuries, frequently results in paralysis and the loss of sensation which can have devastating effects on the patients? lives. The major contributing factors to the failure of injured nerves to regrow are the lack of trophic support and the inhibitory environment generated at the site of injury. Current therapeutic approaches include promoting regeneration via delivery of neurotrophic factors or cell transplantation as well as preventing the generation of the inhibitory environment after injury. While these strategies have had some success in animal models, few have been translated to the clinic and therefore there is a need to find new strategies for stimulating nerve repair. We have discovered that a new class of small RNA molecules may be important in regulating the regenerative responses of the damaged nerves. Research into the mechanisms by which these molecules promote nerve regrowth will lead to the identification of new targets that can be developed into innovative therapies to promote repair of injured nerves.

Nerve regeneration in the adult central nervous system (CNS) is severely limited after injury. By contrast, regrowth occurs more readily in the peripheral nervous system and therefore an understanding of the transcriptional changes that occur in damaged peripheral neurons after injury can be exploited to encourage regeneration in the CNS. Following peripheral nerve axotomy, a diverse group of genes and proteins are regulated to generate phenotypic changes in the dorsal root ganglion (DRG) neurons in order to promote survival and enhance axonal regrowth. Here I hypothesise that the coordinate regulation of these genes occurs by microRNAs (miRNAs), a newly discovered class of small endogenous non-coding RNA molecules that play important roles in developmental and physiological processes. Using a combination of lentiviral vector technology and in vitro and in vivo regeneration models, I will investigate the function of miRNAs in axonal regrowth in DRG neurons. Furthermore, I will dissect the mechanisms by which miRNAs mediate neurite outgrowth and explore their use in in vivo CNS regeneration models. The identification of miRNAs that increase regeneration of injured peripheral neurons as well as their targets can lead to the discovery of novel approaches to promote repair of CNS injuries.