Wagstaff, Marcus James Dermot; (1997) The neuroprotective effect of the heat shock proteins. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The work presented in this thesis investigates the protective effects of the heat shock proteins in neurons against the cytopathic effects of exogenous stress. The heat shock proteins (hsps) are a group of proteins that are overexpressed in cells in response to temperatures above the cells optimum growth temperature. Cerebral ischaemia in vivo increases the levels of heat shock proteins and their mRNAs. A brief 'sub-lethal' ischaemic insult prior to a 'lethal' ischaemic stress has two effects. Firstly, hsps are overexpressed, and secondly, the extent of neuronal damage is significantly reduced as compared with models that undergo the single 'lethal' ischaemic insult. The work in this thesis investigates whether overexpression of hsps is protective against ischaemia in neurons. Initially, the levels of a range of hsp mRNA and protein overexpression are characterised over time during a focal cerebral ischaemic insult in the core region of ischaemia in rats in vivo, achieved by middle cerebral artery occlusion (MCAO). This thesis proceeds to describe the design, construction and characterisation of recombinant HSV-1 vectors that, after delivery, significantly overexpress hsps in a neuron-derived cell line. These vectors were created with the ultimate goal of heat shock gene delivery to the rat brain in vivo. The protective effect of hsp overexpression was subsequently assessed in neurons in response to heat shock, ischaemic stress and apoptosis. The heat shock transcription factor, HSF1, stimulates the transcription of the heat shock genes in response to stress. Using a constitutively active deletion mutant of HSF1, this thesis profiles the expression of the hsps in response to recombinant HSV-1 vector mediated delivery and overexpression of the H-BH gene in neuronal cells, and also characterises the protective effects of overexpression of the mutant in similar conditions as described above.

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