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.
|Moreno, Julie A; Telling, Glenn C (2017) Molecular Mechanisms of Chronic Wasting Disease Prion Propagation. Cold Spring Harb Perspect Med :|
|Bian, Jifeng; Khaychuk, Vadim; Angers, Rachel C et al. (2017) Prion replication without host adaptation during interspecies transmissions. Proc Natl Acad Sci U S A 114:1141-1146|
|Waqas, Muhammad; Lee, Hye-Mi; Kim, Jeeyoung et al. (2017) Effect of poly-L-arginine in inhibiting scrapie prion protein of cultured cells. Mol Cell Biochem 428:57-66|
|Morales, Rodrigo; Hu, Ping Ping; Duran-Aniotz, Claudia et al. (2016) Strain-dependent profile of misfolded prion protein aggregates. Sci Rep 6:20526|
|Wyckoff, A Christy; Kane, Sarah; Lockwood, Krista et al. (2016) Clay Components in Soil Dictate Environmental Stability and Bioavailability of Cervid Prions in Mice. Front Microbiol 7:1885|
|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|
|Yuan, Qi; Eckland, Thomas; Telling, Glenn et al. (2015) Mitigation of prion infectivity and conversion capacity by a simulated natural process--repeated cycles of drying and wetting. PLoS Pathog 11:e1004638|
|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|
|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|
Showing the most recent 10 out of 42 publications