Transmissible spongiform encephalopathies (TSEs) are a group of fatal diseases affecting humans and animals, including Creutzfeldt-Jakob disease (CJD) in humans, scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle and chronic wasting disease (CWD) in cervids. Prions are the infectious agent associated to TSEs, which appears to be composed exclusively by a misfolded version of the normal prion protein (termed PrPSc), and the disease is transmitted by propagation of the misfolding from the disease associated isoform to the normal host protein (termed PrPc). We have recently described a procedure to induce the conversion of PrPc into PrPSc in vitro starting with minute quantities of brain PrPSc. This procedure, named Protein Misfolding Cyclic Amplification (PMCA) mimics the process of prion replication in vivo, but at an accelerated speed resulting in an exponential amplification of the initial amount of PrPSc. The major goals of this project are to study the replication of CWD and BSE prions in vitro, evaluate tissue distributions of infectious protein, enlighten the routes of transmission and develop a diagnostic assay for CWD and BSE infected animals.
In specific aim 1 we will optimize the PMCA technology for efficient high-sensitivity detection of cattle and deer PrPSc;
Specific aim 2 proposes to use the technology to evaluate the tissue distribution of the infectious agent at different times during the incubation period in cattle and deer infected animals;
In specific aim 3 we will to study the routes of transmission of CWD by analyzing source of materials (such as soil and grass) from animals'natural environment and excretory fluids (feces, urine, saliva);Finally specific aim 4 will attempt to develop a sensitive diagnostic test for BSE and CWD using blood or urine samples. This project offers a balanced combination between basic science mechanistic studies aimed to understand the most relevant scientific problems in the field of zoonotic prion disease and applied studies to resolve the main practical problem associated to these diseases, which is the lack of a highly-sensitive pre-symptomatic diagnosis to limit the spreading of these incurable illnesses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI077774-05
Application #
8381060
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$299,755
Indirect Cost
$28,086
Name
University of Texas Health Science Center Houston
Department
Type
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
Hu, Ping Ping; Morales, Rodrigo; Duran-Aniotz, Claudia et al. (2016) Role of Prion Replication in the Strain-dependent Brain Regional Distribution of Prions. J Biol Chem 291:12880-7
Pritzkow, Sandra; Morales, Rodrigo; Moda, Fabio et al. (2015) Grass plants bind, retain, uptake, and transport infectious prions. Cell Rep 11:1168-75
Moda, Fabio; Gambetti, Pierluigi; Notari, Silvio et al. (2014) Prions in the urine of patients with variant Creutzfeldt-Jakob disease. N Engl J Med 371:530-9
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
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
Concha-Marambio, Luis; Diaz-Espinoza, Rodrigo; Soto, Claudio (2014) The extent of protease resistance of misfolded prion protein is highly dependent on the salt concentration. J Biol Chem 289:3073-9
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
Morales, Rodrigo; Pritzkow, Sandra; Hu, Ping Ping et al. (2013) Lack of prion transmission by sexual or parental routes in experimentally infected hamsters. Prion 7:412-9
Saijo, Eri; Kang, Hae-Eun; Bian, Jifeng et al. (2013) Epigenetic dominance of prion conformers. PLoS Pathog 9:e1003692
Telling, Glenn C (2013) The importance of prions. PLoS Pathog 9:e1003090

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