Cerebral ischemia (stroke) and spinal cord injury (SCI) cause disability due to axonal damage and loss of neurons and glia. Axons regenerate following injury to the peripheral nervous system but there is only limited axon sprouting after stroke or SCI. Factors within and surrounding CNS neurons limit regrowth of their axons. Extrinsic factors include a paucity of positive influences in the environment (e.g. growth factors) and the presence of cavities and inhibitory cues (e.g. myelin inhibitors, proteoglycans).

Intrinsically, mammalian CNS neurons downregulate many growth-promoting genes on maturation and consequently extend axons poorly after injury. CNS axon regeneration remains extremely limited in most experimental paradigms and effective restorative therapies remain to be developed.

My research has two main threads. First, my work (and that of others) shows that CNS axon growth can be promoted by degrading growth-inhibitory molecules within CNS injury sites using an enzyme known as chondroitinase ABC. Ongoing studies aim to determine whether this treatment has benefits in clinically relevant models of stroke and SCI.

Second, I have recently identified a set of growth-associated genes that are regulated during regeneration of injured spinal cord axons into a growth permissive transplant in the spinal cord. To do this, I combined several cutting-edge technologies including laser microdissection, amplification of mRNA, microarray analysis and real time RT PCR. Ongoing work aims to determine which of these growth-associated genes are necessary or sufficient to promote growth of injured axons. We use medium throughput screening using primary neurons and a 96 well electroporator to identify genes that promote CNS axon growth. We also use viral vectors to overexpress and knock down candidate genes in vitro and in vivo.

In conclusion, my long-term research goal is to identify and test novel strategies for promoting CNS axon growth and recovery after CNS injury.

Stroke; spinal cord injury; viral vectors; RNAi; gene therapy; in vivo and in vitro