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Molecular approaches to axonal regeneration.

Hunt, D.; (2004) Molecular approaches to axonal regeneration. Doctoral thesis , University of London. Green open access

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The presence of inhibitory molecules is believed to contribute to the failure of axonal regeneration in the adult mammalian CNS. This thesis is focussed on the role of the Nogo-66 receptor (NgR), and its ligands, in preventing axonal regeneration, and the use of genetically modified herpes simplex virus type-1 (HSV-1) for the disruption of these interactions. The expression of ngr, nogo-66 (i.e. pan-nogo), nogo-a and omgp mRNA in the intact and injured adult rodent nervous system has been examined by in situ hybridisation. Nogo-A expression was investigated by immunohistochemistry. The most significant findings were that, although cerebral cortical neurons strongly express ngr, many other neurons do not express ngr mRNA; indeed, ngr transcripts were absent from the corpus striatum and weakly expressed, if at all, by most spinal cord neurons and most primary sensory neurons. In contrast, nogo isoforms were expressed by many types of neuron in the CNS and PNS. Nogo-A protein was found to be prominently expressed in growing and regenerating axons. It is therefore unlikely that NgR/Nogo interactions can explain the general failure of axonal regeneration in the CNS. Several genetically modified HSV-1 vectors were constructed for the disruption of the NgR-ligand interactions. The first of these was constructed for the expression of a tagged-secreted form of the NgR antagonist peptide (NEP1-40); but, this was found to express poorly both in vitro and in vivo. Additionally, a system for the expression of functional shRNA from HSV-1 is reported. As a proof of principle, eGFP expression was successfully targeted in a cell line in vitro. Similarly, NgR was also targeted in primary cultures of cerebellar granule cells in vitro, but with less effect.

Type: Thesis (Doctoral)
Title: Molecular approaches to axonal regeneration.
Identifier: PQ ETD:602829
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by Proquest
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
URI: https://discovery.ucl.ac.uk/id/eprint/1446887
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