Abstract

This proposal describes experiments to investigate the molecular mechanism of pathogenesis in prion diseases. It is built upon the hypotheses that the primary pathogenic event involves a specific interaction between the native and disease forms of the protein, and that this interaction destabilizes a particular sub-domain of the native structure. In order to test this hypothesis, in vitro spectroscopic studies will be performed on both the native protein, and mutants designed to inexorably identify the site of interaction.
The specific aims of the proposal include studying the unfolding and conversion of the native recombinant protein, using site-directed mutagenesis to produce the key mutants, and performing the same folding/unfolding studies on each of these mutant proteins. Elucidation of molecular-level details will be afforded by fluorescence circular dichroism, infrared absorption and Ramon spectroscopies. The overall goal of this research is to provide the information necessary to begin rational design of molecular inhibitors of prion assembly. The overall goal of this research is to provide the information necessary to begin rational design of molecular inhibitors of prion assembly.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR015583-02
Application #
6494918
Study Section
Special Emphasis Panel (ZRR1)
Project Start
2001-09-01
Project End
2002-08-31
Budget Start
Budget End
Support Year
2
Fiscal Year
2001
Total Cost
Indirect Cost

  Institution

Name
University of Montana
Department
Type
DUNS #
City
Missoula
State
MT
Country
United States
Zip Code
59812

  Publications

Gates, Christina; Backos, Donald S; Reigan, Philip et al. (2018) Isoxazolo[3,4-d]pyridazinones positively modulate the metabotropic glutamate subtypes 2 and 4. Bioorg Med Chem 26:4797-4803
Bayat Mokhtari, Elham; Lawrence, J Josh; Stone, Emily F (2018) Data Driven Models of Short-Term Synaptic Plasticity. Front Comput Neurosci 12:32
Gupta, Tarun; Morgan, Hannah R; Andrews, Jonathan C et al. (2017) Methyl-CpG binding domain proteins inhibit interspecies courtship and promote aggression in Drosophila. Sci Rep 7:5420
Steiger, Scott A; Li, Chun; Backos, Donald S et al. (2017) Dimeric isoxazolyl-1,4-dihydropyridines have enhanced binding at the multi-drug resistance transporter. Bioorg Med Chem 25:3223-3234
Stine, Jessica M; Ahl, Gabriel J H; Schlenker, Casey et al. (2017) The Interaction between the Third Type III Domain from Fibronectin and Anastellin Involves ?-Strand Exchange. Biochemistry 56:4667-4675
Park, Sunyoung; Nevin, Andrew B C; Cardozo-Pelaez, Fernando et al. (2016) Pb exposure prolongs the time period for postnatal transient uptake of 5-HT by murine LSO neurons. Neurotoxicology 57:258-269
Gábriel, Robert; Erdélyi, Ferenc; Szabó, Gábor et al. (2016) Ectopic transgene expression in the retina of four transgenic mouse lines. Brain Struct Funct 221:3729-41
Gupta, T; Morgan, H R; Bailey, J A et al. (2016) Functional conservation of MBD proteins: MeCP2 and Drosophila MBD proteins alter sleep. Genes Brain Behav 15:757-774
Steiger, Scott A; Li, Chun; Campana, Charles F et al. (2016) Lanthanide and asymmetric catalyzed syntheses of sterically hindered 4-isoxazolyl-1,4-dihydropyridines and 4-isoxazolyl-quinolones. Tetrahedron Lett 57:423-425
Palacios-Moreno, Juan; Foltz, Lauren; Guo, Ailan et al. (2015) Neuroblastoma tyrosine kinase signaling networks involve FYN and LYN in endosomes and lipid rafts. PLoS Comput Biol 11:e1004130

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