The prion diseases are a group of neurodegenerative disorders of animals and humans which may be both transmissible and inherited. They are associated with an abnormal form, designated PrPsc (scrapie form of the prion protein), of a normal cellular protein designated PrPc. Prions are unique in that, as an infectious pathogen, PrPcs is a protein devoid of nucleic acid. The nature of the structural difference between PrPc and PrPsc is clearly fundamental to understanding the modus operandi of the prion. One approach to elucidating this difference involves raising antibodies that are capable of distinguishing the isoforms.
The aim of this project is to exploit combinatorial antibody library technology to generate monoclonal Fab fragments against scrapie, cellular and mutant forms of prion proteins. The advantages of this new technology over conventional hybridoma technology are that many more antibodies can be examined, that one is not restricted to immunizing rodents, that strategies can be designed to select antibodies of narrowly designed specificity and that antibody specificity can be readily manipulated genetically. The antibodies generated will be used to study the conformational changes associated with conversion of the cellular to the infective scrapie form of the prion protein, to compare mutant and native prion proteins and as immunohistochemical probes for prion proteins. Combinatorial libraries will be generated from mice and rabbits immunized with selected prion antigens including Syrian hamster, mouse and human PrPsc and PrPc. Semi-synthetic libraries will also be used. The libraries will be panned against diverse prion antigens including peptides and cryostat sections of scrapie brain. Judicious combination of immunogen and panning agent should allow selection of antibodies with the desired properties e.g. the ability to distinguish scrapie and cellular or mutant and wild type forms of PrP.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG002132-17
Application #
6233948
Study Section
Project Start
1997-04-01
Project End
1997-12-31
Budget Start
1996-10-01
Budget End
1997-09-30
Support Year
17
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
O'Brien, Connor J; Droege, Daniel G; Jiu, Alexander Y et al. (2018) Photoredox Cyanomethylation of Indoles: Catalyst Modification and Mechanism. J Org Chem 83:8926-8935
Condello, Carlo; Lemmin, Thomas; Stöhr, Jan et al. (2018) Structural heterogeneity and intersubject variability of A? in familial and sporadic Alzheimer's disease. Proc Natl Acad Sci U S A 115:E782-E791
Woerman, Amanda L; Kazmi, Sabeen A; Patel, Smita et al. (2018) MSA prions exhibit remarkable stability and resistance to inactivation. Acta Neuropathol 135:49-63
Yang, Bing; Wu, Haifan; Schnier, Paul D et al. (2018) Proximity-enhanced SuFEx chemical cross-linker for specific and multitargeting cross-linking mass spectrometry. Proc Natl Acad Sci U S A 115:11162-11167
Irimata, Katherine E; Dugger, Brittany N; Wilson, Jeffrey R (2018) Impact of the Presence of Select Cardiovascular Risk Factors on Cognitive Changes among Dementia Subtypes. Curr Alzheimer Res 15:1032-1044
Nick, Mimi; Wu, Yibing; Schmidt, Nathan W et al. (2018) A long-lived A? oligomer resistant to fibrillization. Biopolymers 109:e23096
Woerman, Amanda L; Watts, Joel C; Aoyagi, Atsushi et al. (2018) ?-Synuclein: Multiple System Atrophy Prions. Cold Spring Harb Perspect Med 8:
Woerman, Amanda L; Kazmi, Sabeen A; Patel, Smita et al. (2018) Familial Parkinson's point mutation abolishes multiple system atrophy prion replication. Proc Natl Acad Sci U S A 115:409-414
Wang, Tuo; Jo, Hyunil; DeGrado, William F et al. (2017) Water Distribution, Dynamics, and Interactions with Alzheimer's ?-Amyloid Fibrils Investigated by Solid-State NMR. J Am Chem Soc 139:6242-6252
Giles, Kurt; Woerman, Amanda L; Berry, David B et al. (2017) Bioassays and Inactivation of Prions. Cold Spring Harb Perspect Biol 9:

Showing the most recent 10 out of 363 publications