The long-term objective of the research is to define the role of the prion protein in the neuropathogenesis of strain diversity for the transmissible spongiform encephalopathies (TSEs). Specifically, Dr. Bessen will test the hypothesis that the pathogenicity of TSE strains is determined, in part, by the properties of the prion protein that comprises each strain.
In Aim #1, the applicant will develop a fluorometric cell-free conversion assay for PrP-res formation using thioflavin T.
In Aim #2, the applicant will utilize an in situ PrP conversion assay to determine the brain distribution and rate of conversion of PrPC to strain-specific PrP-res isoforms. This assay will also be used to define the role of anti-TSE drugs in the conversion reaction, to probe the mechanism of drug inhibition, and to rapidly screen for new inhibitors or accelerators of PrP-res formation. Finally, in Aim #3 the applicant will develop PrP-res fibril extension assays that utilize electron microscopy and high-definition photomicroscopy to examine the kinetics and polarity of PrP-res fibril formation. For each of the aims, the hyper (HY) and drowsy (DY) strains of transmissible mink encephalopathy (TME) will be examined in order to determine the role of strain-specific PrP-res in the neuropathogenesis of strain diversity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29NS037914-04
Application #
6393999
Study Section
Special Emphasis Panel (ZRG1-NLS-3 (01))
Program Officer
Kerza-Kwiatecki, a P
Project Start
1998-07-02
Project End
2003-05-31
Budget Start
2001-06-01
Budget End
2002-05-31
Support Year
4
Fiscal Year
2001
Total Cost
$99,029
Indirect Cost
Name
Creighton University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Omaha
State
NE
Country
United States
Zip Code
68178
Saunders, Samuel E; Bartz, Jason C; Bartelt-Hunt, Shannon L (2009) Influence of prion strain on prion protein adsorption to soil in a competitive matrix. Environ Sci Technol 43:5242-8
Mulcahy, Ellyn R; Bessen, Richard A (2004) Strain-specific kinetics of prion protein formation in vitro and in vivo. J Biol Chem 279:1643-9
Bartz, Jason C; Kincaid, Anthony E; Bessen, Richard A (2002) Retrograde transport of transmissible mink encephalopathy within descending motor tracts. J Virol 76:5759-68
Bartz, J C; Bessen, R A; McKenzie, D et al. (2000) Adaptation and selection of prion protein strain conformations following interspecies transmission of transmissible mink encephalopathy. J Virol 74:5542-7