Wellcome Trust PhD Programme for Clinicians at the University of Cambridge. (360G-Wellcome-106564_Z_14_Z)

Traumatic axonal injury of the brain (TAlB) is a common and devastating type of acquired brain injury. The injury is mediated through direct axonal damage and a cascade of secondary injury factors including local inflammatory response and energy failure. Understanding the response of axons is important in order to try and salvage injured axons from cell death and prevent progressive neurodegeneration. Hypotheses to be tested: - An in vitro primary culture/organotypic injury model can accurately represent the structural and functional changes found in human TAIB. - TAIB impairs Axonal transport, resulting in o axonal varicosities o failure to deliver axon survival factors resulting in Wallerian degeneration o aberrant protein expression - TAIB induced a proinflammatory cascade of signalling that o Contributes to axonal transport defects o mediates persistent neurodegeneration - Altering the inflammatory/microglial response can o promote neuronal survival and salvage injured neurons o mitigate varicosity formation o terminate aberrant protein expression and long-term neurodegeneration - TAlB triggers a progressive neurodegenerative process I will use stretch models of injury and/or addition of pro-inflammatory cytokines and cytokine blockade in variety of culture subtypes, including dispersed cortical cultures, organotypic slices and cortical explants. I will examine live-iimaging markers of transport in various injury states.