Autophagy is an important mechanism which removes damaged or dysfunctional parts of neurons and glia and recycles other parts for the cell’s repair. It is necessary for normal functioning of the brain and spinal cord. Following injury (e.g. spinal cord trauma) or neurodegeneration (e.g. Parkinson’s disease) the matrix surrounding the neurons and glia of the CNS changes composition. There is an increase in chondroitin sulfate proteoglycans (CSPGs) which inhibit neuronal growth, preventing functional, neuronal recovery from occurring. We believe that one of the methods CSPGs use to prevent neuronal recovery is through decreasing autophagy in the neurons and glia.
This project will use in vitro and in vivo pre-clinical models to determine: 1) how CSPGs affect autophagic flux, 2) whether the inhibitory CSPG-autophagy interaction affects particular types of neurons or glia, 3) which currently available drugs may be repurposed to reverse this impaired autophagy inhibitory effect and enable neuronal growth to occur in models of neurological injury and neurodegeneration.
The student will be trained in cutting edge cell culture, live cell imaging, animal surgery, SPLiT-seq, Electron microscopy, molecular biology, informatics and drug repurposing. The overarching key objectives of the project are:
Year 1: Characterise the molecular and cellular link between CSPGs and impaired autophagy within neurons and glia through molecular biology, cell culture, and EM .
Year 2: Investigate which neurons and glia are most affected by the CSPG-autophagy interaction using single-cell mRNA profiling and genetic knockdowns.
Year 3: Determine which repurposed drugs might reverse the dampening of restore autophagy and assess the most promising in animal models of spinal cord injury and Parkinson’s disease to see if they facilitate neuronal growth.
The Duty and Warren labs have a great track record in generating high impact results and publications while providing expert training, supervision, and support for PhD students.