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Oxygen derivation to the brain is a feature of both acute (ischemic stroke) and chronic neurodegenerative diseases such a vascular dementia. My research interests focus on changes at the neurovascular unit under hypoxic conditions, specifically looking at glia/endothelial interactions, CNS inflammation and cellular mechanisms which culminate in the loss of blood-brain integrity. I am using an in vivo model of global cerebral hypoxia and various functional/imaging end points to demonstrate a size selective change in blood-brain barrier integrity in various neuroanatomical brain regions. To explain this regional vulnerability I am using confocal microscopy and SDS-PAGE/Western blot analysis to unravel a cascade of intracellular events, including VEGF receptor activation, oxidative stress, protein kinase C activation and raised levels of pro-inflammatory cytokines which ultimately result in modification of tight junction protein expression (occludin, claudin-5 and ZO-1) on the vascular endothelial cells. These studies have identified several potential sites of pharmacological intervention which I am testing to determine whether I can attenuate blood-brain barrier integrity changes during and following hypoxic stress. For example inhibition of iNOS by L-NAME, attenuates hypoxia-induced loss of hippocampal blood-brain barrier integrity. Further, preliminary results from these studies suggest that there is also attenuation pro-inflammatory cytokines levels which are raised by hypoxic stress. By identification of novel targets of therapy this research has important translational implications for drug development and delivery and therapy of stroke and cerebral ischemia
McCaffrey G, Willis CL, Staatz WD, Nametz N, Quigley C, Hom S, Lochhead J, Davis TP. Occludin oligomeric assemblies at tight junctions of the blood-brain barrier dynamically respond to hypoxia and reoxygenation with changes in structural integrity and isoform composition. J Neurochem (in press).
Willis CL, Davis TP. Chronic inflammatory pain and the neurovascular unit: A central role for glia in maintaining BBB integrity. Current Pharmaceutical Design 14 (2008) 1625-1643. (selected for cover)
Willis CL, Garwood CJ, Ray DE. A size selective vascular barrier in the rat area postrema formed by perivascular macrophages and the extracellular matrix. Neurosci 150 (2007) 498-509
Willis CL, Taylor GL, Ray DE. Microvascular P-glycoprotein expression at the blood-brain barrier following focal astrocyte loss and at the fenestrated vasculature of the area postrema. Brain Res 1173 (2007) 126-136.
Willis CL, Ray DE. Antioxidants attenuate MK-801-induced cortical neurotoxicity in the rat. Neurotox 28 (2007) 161-167.
Willis CL, Ray DE, Marshall, Elliot G, Evans JG, Kind CN. Basal forebrain cholinergic lesions reduce heat shock protein72 response but not pathology induced by the NMDA antagonist MK-801 in the rat cingulate cortex. Neurosci Letts 407 (2006) 112-117.
Willis CL, Leach L, Clarke GJ, Nolan CC, Ray DE. Reversible disruption of tight junction complexes in the rat blood-brain barrier, following transitory focal astrocyte loss. Glia 48 (2004) 1-13. (selected for cover)
Willis CL, Nolan CC, Reith SN, Lister T, Guerin CJ, Mavroudis G, Prior MJW, Ray DE. Focal astrocyte loss is followed by microvascular damage, with subsequent repair of the blood-brain barrier in the apparent absence of direct astrocytic contact. Glia 45 (2004) 325-337.