Our broad long-term objective is to address the mechanisms by which species barriers and strain specificities control the pathogenesis and transmission of chronic wasting disease (CWD), a contagious disease of deer and elk belonging to a group of fatal, transmissible neurodegenerative disorders of animals and humans caused by prions. Our major objectives are to use proven transgenic (Tg) approaches to study the means by which primary structure elements of the prion protein (PrP) and prion strain properties influence CWD transmission barriers, to address the origins of CWD and the prevalence of CWD strains, and to determine the mechanism of prion transmission among cervids.
Three Specific Aims are proposed: (1) To use Tg mice expressing cervid (Cer) PrP [Tg(CerPrP)] that simulate disease in deer and elk to study the mechanisms of CWD transmission among cervids and sub-clinical CWD replication in the absence of accumulation of conventional forms of pathogenic PrP;(2) To use Tg approaches to assess the influence of CWD strain variation and CerPrP polymorphisms on CWD pathogenesis and to address the disease-causing potential of CWD strains in other species;and, (3) To probe the molecular basis of species-dependent CWD transmission barriers using novel chimeric murine/CerPrP constructs and an innovative combination of Tg approaches and in vitro PrP amplification. Addressing the mechanism of CWD transmission will lead to better CWD control in cervid populations and allow more accurate assessments of the risks posed to humans and livestock from exposure to CWD. The proposed studies will also further our understanding of the general molecular events underlying prion propagation, species barriers and prion strains that will ultimately result in rational therapeutic and diagnostic approaches for human and animal prion diseases and will provide important information about the molecular nature of the infectious agent in the contexts of clinical and sub-clinical prion disease.
| Bian, Jifeng; Khaychuk, Vadim; Angers, Rachel C et al. (2017) Prion replication without host adaptation during interspecies transmissions. Proc Natl Acad Sci U S A 114:1141-1146 |
| Mays, Charles E; Kim, Chae; Haldiman, Tracy et al. (2014) Prion disease tempo determined by host-dependent substrate reduction. J Clin Invest 124:847-58 |
| Angers, Rachel; Christiansen, Jeffrey; Nalls, Amy V et al. (2014) Structural effects of PrP polymorphisms on intra- and interspecies prion transmission. Proc Natl Acad Sci U S A 111:11169-74 |
| Bian, Jifeng; Kang, Hae-Eun; Telling, Glenn C (2014) Quinacrine promotes replication and conformational mutation of chronic wasting disease prions. Proc Natl Acad Sci U S A 111:6028-33 |
| Vickery, Christopher M; Lockey, Richard; Holder, Thomas M et al. (2014) Assessing the susceptibility of transgenic mice overexpressing deer prion protein to bovine spongiform encephalopathy. J Virol 88:1830-3 |
| Saijo, Eri; Kang, Hae-Eun; Bian, Jifeng et al. (2013) Epigenetic dominance of prion conformers. PLoS Pathog 9:e1003692 |
| Haldiman, Tracy; Kim, Chae; Cohen, Yvonne et al. (2013) Co-existence of distinct prion types enables conformational evolution of human PrPSc by competitive selection. J Biol Chem 288:29846-61 |
| Michel, Brady; Ferguson, Adam; Johnson, Theodore et al. (2013) Complement protein C3 exacerbates prion disease in a mouse model of chronic wasting disease. Int Immunol 25:697-702 |
| Piccardo, Pedro; King, Declan; Telling, Glenn et al. (2013) Dissociation of prion protein amyloid seeding from transmission of a spongiform encephalopathy. J Virol 87:12349-56 |
| Telling, Glenn C (2013) The importance of prions. PLoS Pathog 9:e1003090 |
Showing the most recent 10 out of 24 publications
