Transmissible spongiform encephalopathy (TSE) or prion diseases are rare fatal neurodegenerative illnesses of humans and other animals. The recent awareness of TSE diseases has accelerated due to the appearance of bovine encephalopathy or mad cow disease in Europe, especially the United Kingdom, and its potential for transmission via the food chain to humans and the awareness that the majority of deer and elk on farms as well as 10 to 20% of wild deer and about 1 % of elk develop TSE disease (CWD). The transmission of CWD to humans is unknown and although there is currently no evidence of passage of TSE via blood products in humans exposed to BSE, the reported transmission by blood in ruminants is of concern. Our hypothesis is that uniquely designed and developed transgenic (tg) models offer the opportunity to address important but as yet unknown or unresolved issues in TSE diseases. Towards that end we have successfully developed a tg model using PrP ko mice as a host in which expression of PrPsen can be induced in a rev tet system with administration of doxycycline, and a tg model in which GP1 anchorless PrPsen is also expressed in other PrP ko mice. The former will allow data on the turnover of PrPres in vivo and provide information as to its removal, information of value to determine the potential efficacy of anti-PrP therapy during different timed stages of disease. The latter GP1-/- model should provide data on glycosylation, spread or failure to spread PrPres from the inoculated site, the ability of GP1 anchorless PrPsen to be converted to PrPres to cause disease, as well as analysis of potential differences in incubation time/disease incidence among different strains of mouse scrapie. The third tg model is the expression of white tail deer (WTD) prion under control of the mouse PrP promoter in PrP ko mice, This model should be useful to study pathophysiology of CWD as well as probing CWD strain differences. These studies will be complimented by providing the appropriate PrP ko and PrP reconstituted mice for studies by Jose Criado and mouse models to test efficacy of both antibody and small molecules that mimic antibody in treatment of TSE.
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