| Summary: | Multiple sclerosis (MS) is the predominant cause of persistent, non-traumatic neurological disability in young adults of the western world. The disease is defined by inflammation and neurodegeneration, however, the precise mechanisms underlying immunopathogenesis and neurodegeneration remain to be fully comprehended. Pathological mechanisms implicated in MS include, for example: (i) hypoxia-like tissue injury, (ii) impaired neuronal transport, and (iii) cytokine-mediated immunopathogenesis and these were therefore investigated in this thesis. Hypoxia-like tissue injury has been associated with MS, and the action of hypoxia inducible factor (HIF)-1 has been suggested to protect against such injury. To investigate a potential beneficial effect of the HIF-1 pathway in MS, HIF-1 was pharmacologically stabilised in a murine model of MS. However, no effect on disease development or progression was observed, suggesting that a general induction of H1F 1-dependent pathways may not be a viable therapeutic avenue for MS A molecular motor protein termed kinesin family member 21 B (K1F21 B) that has a suggested function in neuronal transport has recently been implicated in MS as a potential disease-associated candidate gene. A histopathological analysis demonstrated the expression of KIF21B in the neuronal compartment of human post mortem brain tissue. Intriguingly, however, differential expression of KIF21B was only detected in the immunological compartment and was associated with increasing demyelinating lesion activity. This observation is striking as it implies an immunological rather than neuronal role of K1F21 B in MS. Whilst interleukin (I L)-9 and its receptor (IL-9R) have been implicated in a murine model of MS, this cytokine pathway has not been previously characterised in the human disease. Histopathological examination demonstrated a low frequency of lL-9/1L -9 1~ expressing immune cells in MS lesions, suggesting a minor role of the immunological arm of this pathway in the central nervous system. However, in the neuronal compartment there was a notable inverse correlation between IL-9R levels and white matter lesion activity that implicates IL-9R signalling in the modulation of neurona1 responses in MS pathology. Collectively this work provides new insight into several different aspects of MS pathogenesis.
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