Transmissible spongiform encephalopathies (TSEs) are a group of fatal diseases affecting humans andanimals, including Creutzfeldt-Jakob disease (CJD) in humans, scrapie in sheep, bovine spongiformencephalopathy (BSE) in cattle and chronic wasting disease (CWD) in cervids. Prions are the infectiousagent associated to TSEs, which appears to be composed exclusively by a misfolded version of the normalprion protein (termed PrPSc), and the disease is transmitted by propagation of the misfolding from thedisease associated isoform to the normal host protein (termed PrPc). We have recently described aprocedure 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 prionreplication in vivo, but at an accelerated speed resulting in an exponential amplification of the initial amountof 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 adiagnostic assay for CWD and BSE infected animals.
In specific aim 1 we will optimize the PMCAtechnology for efficient high-sensitivity detection of cattle and deer PrPSc;
Specific aim 2 proposes to use thetechnology to evaluate the tissue distribution of the infectious agent at different times during the incubationperiod in cattle and deer infected animals;
In specific aim 3 we will to study the routes of transmission ofCWD by analyzing source of materials (such as soil and grass) from animals' natural environment andexcretory fluids (feces, urine, saliva); Finally specific aim 4 will attempt to develop a sensitive diagnostic testfor BSE and CWD using blood or urine samples. This project offers a balanced combination between basicscience mechanistic studies aimed to understand the most relevant scientific problems in the field ofzoonotic prion disease and applied studies to resolve the main practical problem associated to thesediseases, which is the lack of a highly-sensitive pre-symptomatic diagnosis to limit the spreading of theseincurable illnesses.
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