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4 YEAR PhD IN NEUROSCIENCE

Kenneth Smith


Understanding the causes and consequences of hypoxia in the inflamed CNS

Our recent findings reveal that the inflamed CNS can be severely hypoxic, to the extent that oxygen availability cannot sustain normal function or structure, resulting in degeneration. Hypoxia occurs in different types of experimental inflammatory lesions, and histological and MRI evidence indicate that it also occurs in multiple sclerosis (MS). Although severe hypoxia is transient, persisting at the onset of inflammation for only 1-3 days, our evidence is that it can have a permanent legacy, causing demyelination and probably degeneration by exacerbating an energy crisis in neurons and oligodendrocytes. Hypoxia therefore emerges as an important (but currently largely unrecognised) component of the inflamed CNS, which is likely to contribute not only to the pathology of MS, but also to the pathology of the neurodegenerative diseases, including Alzheimer’s, Parkinson’s and motor neuron disease because all of these disorders have an inflammatory component. We aim to understand lesion hypoxia, and to develop novel therapies based on the new findings.

We offer two PhD projects to explore the role of hypoxia in neuroinflammatory disease. One project will employ confocal imaging to explore the effects of hypoxia on mitochondrial function, and the other will explore a range of imaging methods used in the clinic to determine the reasons why the CNS becomes hypoxic. Both projects will incorporate the examination of novel therapeutic approaches to protect the CNS from hypoxia and its consequences.

Publications:

C. Marik, P.A. Felts, J. Bauer, H. Lassmann, K.J. Smith. Lesion genesis in a subset of patients with multiple sclerosis: a role for innate immunity? Brain, 2007;130:2800-2815. PM: 17956913

R.J.M. Franklin, C. ffrench-Constant, J.M. Edgar, K.J. Smith. Neuroprotection and repair in multiple sclerosis. Nature Reviews Neurology, 2012;8:624-634. PM:23026979

D. Morsali, D. Bechtold, W. Lee, S. Chauhdry, U. Palchaudhuri, P. Hassoon, D. Snell, K. Malpass, T. Piers, J. Pocock, A. Roach, K.J. Smith. Safinamide and flecainide protect axons and reduce microglial activation in models of multiple sclerosis. Brain, 2013 (In press).

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