Scrapie of sheep is the prototype of a group of diseases collectively designated the transmissible spongiform encephalopathies (TSE). TSE diseases affect a wide range of species including sheep, cattle, mink, humans and others. The newest member of the group, bovine spongiform encephalopathy (BSE) or """"""""mad cow disease"""""""" is believed to have been derived from scrapie infected sheep. There is no evidence that sheep scrapie infects humans. However, passage of sheep scrapie through cattle may have altered its biological characteristics possibly making BSE transmissible to humans. Interspecies transmission of TSE diseases is difficult to predict but probably involves complex interactions between specific protein molecules of the species considered and in particular a protein designated prion protein (PrP). The overall objective of this project is to determine how PrP and other factors and conditions govern transmission from one species to another. Strategies to interfere with the transmission or disease process will be developed based on these findings. Interspecies transmission of TSE diseases between and among various species is now known to involve interactions between the prion proteins (PrP) of the species involved. For example, the TSE agent which causes disease in mice can in a few circumstances cause disease in hamsters but the hamster agent does not cause clinical disease in mice. To determine how PrP influences transmission from hamsters to mice we have developed transgenic mice which express hamster prion protein (HPrP). The HPrP has been expressed using a variety of promoters including the neuron-specific enolase promoter (NSE) which targets expression to neurons, the GFAP specific promoter to target expression to astrocytes and natural promoters which result in expression in many tissues. Each of these types of mice has been bred to PrP null mice which do not express mouse PrP. Thus, we have available several types of mice which we have used to investigate how expression of PrP in specific cell types influences susceptibility to scrapie and how HPrP and mouse PrP (MoPrP) interact. Mice which express HPrP under the control of natural or NSE promoters are completely susceptible to hamster scrapie agent following intracerebral inoculation. This result showed that PrP is critical to transmission and that expression restricted to neurons is sufficient for transmission to occur. If NSE/HPrP was expressed in mice which lacked functional MoPrP expression, the incubation period was reduced indicating that the presence of MoPrP in some way competed with HPrP to delay the onset of disease. The effect was protective for the mice in that disease was delayed. Mice which express HPrP under the control of the GFAP promoter (GFAP/HPrP) did not become clinically sick after inoculation of hamster scrapie agent. However, if GFAP/HPrP was expressed in mice which lacked MoPrP, expression they did become sick following hamster agent inoculation. This result suggested that astrocyte specific expression of HPrP was also sufficient for transmission to occur though much less efficiently than was true if expression was limited to neurons. Furthermore, this result demonstrated very strong interference between MoPrP and HPrP in the mice which expressed both.
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| Meade-White, Kimberly; Race, Brent; Trifilo, Matthew et al. (2007) Resistance to chronic wasting disease in transgenic mice expressing a naturally occurring allelic variant of deer prion protein. J Virol 81:4533-9 |
| Raymond, Gregory J; Raymond, Lynne D; Meade-White, Kimberly D et al. (2007) Transmission and adaptation of chronic wasting disease to hamsters and transgenic mice: evidence for strains. J Virol 81:4305-14 |
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| Kocisko, David A; Vaillant, Andrew; Lee, Kil Sun et al. (2006) Potent antiscrapie activities of degenerate phosphorothioate oligonucleotides. Antimicrob Agents Chemother 50:1034-44 |
| Kocisko, David A; Caughey, Winslow S; Race, Richard E et al. (2006) A porphyrin increases survival time of mice after intracerebral prion infection. Antimicrob Agents Chemother 50:759-61 |
| Criado, Jose R; Sanchez-Alavez, Manuel; Conti, Bruno et al. (2005) Mice devoid of prion protein have cognitive deficits that are rescued by reconstitution of PrP in neurons. Neurobiol Dis 19:255-65 |
| Chesebro, Bruce; Trifilo, Matthew; Race, Richard et al. (2005) Anchorless prion protein results in infectious amyloid disease without clinical scrapie. Science 308:1435-9 |
| Silveira, Jay R; Raymond, Gregory J; Hughson, Andrew G et al. (2005) The most infectious prion protein particles. Nature 437:257-61 |
| Kocisko, David A; Morrey, John D; Race, Richard E et al. (2004) Evaluation of new cell culture inhibitors of protease-resistant prion protein against scrapie infection in mice. J Gen Virol 85:2479-83 |
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