Transmissible spongiform encephalopathies (TSEs or prion disease) are fatal neurodegenerative diseases such as scrapie, Creutzfeldt-Jakob disease (CJD), BSE and chronic wasting disease (CWD). Our project is aimed at understanding and thwarting the accumulation of PrP-res, the abnormal form of prion protein (PrP) that appears to underlie TSE transmission and pathogenesis. Using cell culture and cell-free systems we have 1) identified lysosomotropic amines, cysteine protease inhibitors and certain new PrP peptide fragments as potentially therapeutic new inhibitors of PrP-res formation, 2) described sites of interaction that occur during PrP-res formation, 3) described interactions between normal PrP and PrP-res molecules from different species that may control interspecies transmissibilities of TSEs, 4) determined effects of the membrane attachment of normal PrP on its conversion to PrP-res, 5) assayed the reversibility of PrP-res formation, 6)identified heparan sulfate and serum amyloid P component as stimulators of PrP-res formation, 6) assessed the ability of PrP-res from CWD-infected deer and elk to induce the conversion of normal PrP from humans, cattle and other species to PrP-res and 7) showed that a detergent can induce conformational changes and fibril formation in normal PrP that are reminiscent of PrP-res formation.
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| Caughey, Winslow S; Priola, Suzette A; Kocisko, David A et al. (2007) Cyclic tetrapyrrole sulfonation, metals, and oligomerization in antiprion activity. Antimicrob Agents Chemother 51:3887-94 |
| Lee, Kil Sun; Caughey, Byron (2007) A simplified recipe for prions. Proc Natl Acad Sci U S A 104:9551-2 |
| Kocisko, David A; Bertholet, Nadine; Moore, Roger A et al. (2007) Identification of prion inhibitors by a fluorescence-polarization-based competitive binding assay. Anal Biochem 363:154-6 |
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| 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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