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Long-term expression of mutant PrP in the murine nervous system using a viral vector

Reference	BS308132
Principal Investigator / Supervisor	Professor Tony Minson
Co-Investigators / Co-Supervisors	Professor William Blakemore, Professor Stacey Efstathiou
Institution	University of Cambridge
Department	Pathology
Funding type	Research
Value (£)	238,246
Status	Completed
Type	Research Grant
Start date	01/10/1997
End date	01/10/2000
Duration	36 months

Abstract

We seek to demonstrate that delivery and expression of mutant PrP genes to the murine nervous system, using a replication-defective herpes simplex virus (HSV) vector, will induce neuropathology and prion associated infectivity. To this end wild type and one of three mutant MoPrP genes will be cloned downstream of the neuronal-specific HSV latency associated promoter. We will establish whether pathology/infectivity can be generated following vector administration to either wild type PrP +/+ or Tg (MoPrP-P101L) mice. Such studies will demonstrate the feasibility of using HSV as a vector for `agent delivery' and confirm that Tg (MoPrP- P101L) mice are more susceptible than wild type mice to vector driven expression of mutant MoPrP P101L. Our second aim is to use HSV vectors to establish transgenic target tissue in a PrP null background. HSV vectors encoding human PrP either met or val at codon 129 or bovine PrP will be injected into the CNS of Tg (Prn-p0/0) mice. At various times after delivery of the relevant HSV vectors, an inoculum of BSE-infected cattle brain homogenate will be administered to HSV-transduced brain tissue and animals will be sampled. CNS material will be examined for (a) histopathological changes and (b) the generation of proteinase K resistant PrPsc and associated infectivity. Should this experimental approach prove successful in generating pathology and/or propagation of infectivity it will facilitate a systematic study of PrP gene mutations involved in PrP conversion and hence propagation of prion infectivity.

Summary

unavailable

Committee	Closed Committee - Agri-food (AF)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	Biology of Spongiform Encephalopathies - Phase 3 (BS3) [1996-1997]
Funding Scheme	X – not Funded via a specific Funding Scheme

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