Cellular Protection Strategies in Diffuse Axonal Injury (DAI)

Dr. Alexis Joannides

Diffuse axonal injury (DAI) is recognised as one of the key pathological features which most closely correlates with clinical phenotype in traumatic brain injury (TBI). Early pathological studies have demonstrated that mechanical trauma can lead to axonal damage in the absence of direct mechanical tearing. The recognition of secondary axonal injury over a period of hours and its potential evolution into a chronic neurodegenerative process creates a window of opportunity for disease-modifying therapies aimed at axonal protection and preservation. Investigating the molecular basis of axonal degeneration and protection in the context of TBI is dependent on the presence of appropriate cellular models. Axonal stretch in vitro has been shown to replicate many of the structural consequences of DAI, and both organotypic and single cell-based models have been developed. Recent reports utilising such models are beginning to provide insight into potential disease mechanisms. On this background the project proposes to develop a human stem cell-based axonal stretch model to investigate the role of injury-induced axonal degeneration, and explore its modulation by both genetic and environmental means. The program of work will build on our previous experience with ex vivo modelling using human stem cell populations and will ultimately provide a platform for the development of novel disease-modifying and neuroprotective therapies in TBI.