Gene Therapy for Spinal Cord Injury. After an injury, the adult spinal cord fails to regenerate and damage at cervical levels are particularly devastating as they may result in quadriplegia. One aspect of my research is to use adenoviral vectors carrying the gene sequence for brain-derived neurotrophic factor (BDNF) to up-regulate levels of BDNF into spinal cord motor neurons.We have developed a rat model of rubrospinal tract (RST) transection. While retaining the ability to reach, these rats are no longer capable to rotate the paw during the grasping action, a motor sequence called the arpeggio movement. The loss of arpeggio movement in our rat model is a unique behavioural read-out that we aim to reverse by BDNF gene therapy.
The neural basis of skilled reaching. Rats are trained to reach for sugar pellets, a paradigm called "Skilled Reaching". Reaching is filmed when performance has reached an asymptote and the rats are then subjected to selective lesions along the motor pathways. After recovery from the surgical procedure, the rats are tested and filmed again. Performance before and after the surgery is compared using a frame-by-frame analysis of the movies to see the effects of such lesions to their reaching performance.
Muscle-motor neuron topography. My team is also currently investigating the relationship between the muscles of the hind- and forelimb and the spinal cord motor neuron columns that innervate them in rats and mice using retrograde neuronal tracers.
Nerve excitability. We have recently developed a new research project that focuses on the changes in excitability that occur over time after small spinal cord injury. Changes in nerve excitability in RST rats are measured with threshold tracking techniques. These techniques provide information on axonal biophysical properties, specifically regarding the behaviour of various ion channels, pumps and exchangers that are involved in impulse conduction. The aim of this project is also to measure the benefits of BDNF gene therapy on axon conductance after an injury.
The fate of motor neurons below a spinal cord injury. Whether motor neurons die after a spinal cord injury is still a matter of debate. Furthermore, the process by which spinal cord motor neurons could die, i.e. whether they go down the apoptotic or the necrotic pathway, or perhaps both, is undefined. The aim of this project is to explore the possibility that RST lesions trigger apoptotic or necrotic motor neuron death and to measure the benefits of AdBDNF gene therapy on the viability of these motor neurons.
Changes in mRNA levels of BDNF and TrkB receptor after RST transection. Are endogenous levels of BDNF and TrkB (the receptor for BDNF) down-regulated by a RST transection? Can we restore levels of BDNF and TrkB mRNA? After a RST transection, motor neurons are collected with a laser capture microdissection (LMD) system and mRNA for BDNF is isolated with state-of-the-art techniques.
Broad Research Areas:
Neuroscience, Neurotrauma, Disease Modelling
BSc (Psych), MSc (Neuropsych), PhD (Neuroscience)
Specific Research Keywords:
Spinal Cord Injury and Repair, Motor control, Gene therapy, Adenovirus, Neurotrophins, BDNF