Prion diseases are a group of emerging transmissible neurodegenerative diseases of humans and animals. Prion diseases of humans can be caused by interspecies transmission, for example, variant Creutzfeldt- Jacob disease is caused by transmission of bovine spongiform encephalopathy to humans. Following interspecies transmission, adaptation of prions to a new host species can involve competition between prion strains until one prion strain predominates. The long-term goal of this laboratory is to describe the mechanism(s) of prion adaptation to a new host species. In a step to achieve this goal, we plan to investigate the molecular basis of prion strain selection. We have developed a prion strain selection model where hamsters are first infected in the sciatic nerve (i.n.) with the drowsy (DY) strain of transmissible mink encephalopathy (TME), then i.n.superinfected with the hyper (HY) strain of TME. Using this model, we have localized the site of prion strain selection to the lumbar spinal cord, most likely within ventral motor neurons (VMNs). We hypothesize that alterations in prion agent transport and/or prion agent replication are responsible for prion strain selection within the central nervous system. To investigate this hypothesis we will i) establishing the degree to which DY TME infection alters axonal transport of a retrograde tracer or epitope or fluorescently labeled PrPSc from the sciatic nerve to VMNs in the lumbar spinal cord ii) determine the effect of DY TME replication in VMNs has on subsequent HY TME replication in VMNs by Western blot analysis and/or animal bioassay of microdisseced VMNs and iii)assess the effect of DY TME infection on the viability of VMNs which are the first cell type infected by HY TME following sciatic nerve inoculation by quantifying VMN populations using unbiased stereology. Results from the aims in this proposal will define the mechanism(s) of prion selection, begin to address the factor(s) that prions compete for, and advance our understanding of how prions adapt to a new host species following interspecies transmission.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS052609-05
Application #
7795725
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Wong, May
Project Start
2006-04-01
Project End
2011-05-31
Budget Start
2010-04-01
Budget End
2011-05-31
Support Year
5
Fiscal Year
2010
Total Cost
$279,340
Indirect Cost
Name
Creighton University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
053309332
City
Omaha
State
NE
Country
United States
Zip Code
68178
Shikiya, Ronald A; Eckland, Thomas E; Young, Alan J et al. (2014) Prion formation, but not clearance, is supported by protein misfolding cyclic amplification. Prion 8:415-20
Saunders, Samuel E; Bartelt-Hunt, Shannon L; Bartz, Jason C (2012) Occurrence, transmission, and zoonotic potential of chronic wasting disease. Emerg Infect Dis 18:369-76
Saunders, Samuel E; Bartz, Jason C; Bartelt-Hunt, Shannon L (2012) Soil-mediated prion transmission: is local soil-type a key determinant of prion disease incidence? Chemosphere 87:661-7
Saunders, Samuel E; Bartz, Jason C; Shikiya, Ronald A (2012) Protein misfolding cyclic amplification of prions. J Vis Exp :
Sigurdson, Christina J; Bartz, Jason C; Nilsson, K Peter R (2011) Tracking protein aggregate interactions. Prion 5:52-5
Ayers, Jacob I; Schutt, Charles R; Shikiya, Ronald A et al. (2011) The strain-encoded relationship between PrP replication, stability and processing in neurons is predictive of the incubation period of disease. PLoS Pathog 7:e1001317
Saunders, Samuel E; Shikiya, Ronald A; Langenfeld, Katie et al. (2011) Replication efficiency of soil-bound prions varies with soil type. J Virol 85:5476-82
Shikiya, Ronald A; Bartz, Jason C (2011) In vitro generation of high-titer prions. J Virol 85:13439-42
Shikiya, Ronald A; Ayers, Jacob I; Schutt, Charles R et al. (2010) Coinfecting prion strains compete for a limiting cellular resource. J Virol 84:5706-14
Ayers, Jacob I; Kincaid, Anthony E; Bartz, Jason C (2009) Prion strain targeting independent of strain-specific neuronal tropism. J Virol 83:81-7

Showing the most recent 10 out of 13 publications