Completed PoP Projects

Research Lead:

Dr. Wiktor Adamowicz, University of Alberta

Funding:

$200,000

Project:

“Socio-Economic Implications of Transmissible Spongiform Encephalopothies (TSEs): CWD”

This project examines the economic and social basis of risk from TSEs, focusing on perceptions, behaviour and vulnerability arising from the presence of TSEs and its effects on farming, hunting and wildlife health. Researchers propose to develop a policy process to deal with these diseases based on the science of the diseases as well as scientific findings on actual and potential farm level impacts, community economic and social vulnerability.

Findings:

Dr. Vic Adamowicz and his team conducted an economic and social analysis of community vulnerability and an analysis of individual (consumer/hunter) responses to CWD. They found that on average, the perceived risk of CWD by hunters is low, and has little impact on their behaviour. Support for management of the disease among these groups is dependent on demographic variables (urban/rural, hunting experience). However, there is support from the Aboriginal population for the management of CWD, as it is understood that significant consumption of deer and moose could lead to greater exposure of Aboriginal population to CWD. They also found that controlling CWD produces positive economic benefits to hunters, and reducing the spread of the disease translates into economic benefits of up to $.5M per year.  

Four input-output models of the farmed cervid and cattle sector have been completed. Further analysis of the data will allow for greater understanding of the economic impact on farm and market levels from these two prion diseases. A study of the Alberta general public's response to CWD is near completion.  In a stylized referendum, on average, Albertans said they would be willing to pay up to $138/year in taxes for 10 years to support a program that reduce the spread and prevalence of CWD  Further economic modeling and analysis of the qualitative data will produce more extensive results in the next few months.

Research Lead:

Dr. Janice Braun, University of Calgary

Funding:

$200,000

Project:

“Chaperoning prions: Elucidation of the cellular machinery for prion folding & misfolding”

This project will investigate the cellular mechanism that regulate the three dimensional prion structures folding and misfolding that controls the conformational state of the prion protein. The project also aims to identify the mechanisms that control the folding status of newly forming prion proteins. The ultimate goal is to exploit the biological mechanism used to effect prion misfolding in developing a therapy to treat or prevent prion disease.

Findings:

Dr. Braun's research aimed to identify the mechanisms that control the folding status of newly forming prion proteins.  Chaperones are proteins that help to guide other proteins to their proper places in the cell.  Chaperones keep protein structures intact, and direct them into a disposal system if they assume an improper form.  A group of these chaperone proteins, called J proteins, have been found to interact with the normal cellular form of prion proteins. 

Dr. Janice Braun's research used state-of-the-art biochemistry, molecular biology and microscopy techniques to examine the J protein chaperone family for new clues in the way they work to control the cellular prion protein function.  Dr. Braun's team was able to establish the molecular determinants of the cellular prion protein with three associated J proteins.  The identification of crucial protective J proteins that regulate the cellular prion protein has provided further insight into prion disease processes.  The biotechnology industry and the clinical treatment of neurodegenerative disease will benefit from the outcomes of this research. 

Research Lead:

Dr. Frank Jirik, University of Calgary

Funding:

$186,112

Project:

“Role of prion Cu-binding in the neurological disease caused by expansion of the octapeptide repeat region.”

Each TSE involves the conversion of a normal prion protein into an abnormal protein which lead to the death of brain cells and ultimately fatal outcomes to the individual whether in humans, cattle or cervid population. This project will establish a new type of transgenic mouse testing method giving higher reproducible results and greater sensitivity in detecting minor modifications of the prion gene in TSE experiments. In addition, this new method for producing transgenic mice is likely to facilitate increased understanding of origins and effects of TSEs especially with respect to the role that copper-binding plays on portions of the prion molecule and prion gene sequence variations that might be involved in TSE resistance.

Findings:

Dr. Jirik and his team used genetically modified mice to explore how mutations in the gene for prion protein might affect the normal and disease-causing effects of prions in cells. They replaced normal prion genes in mice with mutant prion genes and used electrophysiological measurements to study the effect of the altered prion protein on brain functions. They also studied the effects of copper binding on prion protein function in brain cells. It has long been known that copper affects prion proteins, but how this happens is not understood.

Research Lead:

Dr. Christoph Sensen, University of Calgary

Funding:

$200,000

Project:

“Preliminary characterization of chronic wasting disease in elk”

The project team plans to build a TSE monitoring toolkit for live animals, using nucleic acid screening methods, that enables detection of early stages of disease. In stage one, the team will conduct a proof-of-concept study using elk infected orally with brain homogenate at the Canadian Food Inspection Agency facility in Lethbridge and will analyze results and make statistical assessment on validity of the approach. DNA extracted from blood will be analyzed for patterns, or "fingerprints" associated with various stages of the disease in various tissues. The results will then be compared with those of established post-mortem TSE tests to help pinpoint the origin of controlling genetic elements. These studies will provide insight into the early stages of TSEs, and may lead to the development of sensitive blood-based tests for TSEs of humans and animals.

Findings:

Dr. Sensen's research team used nucleic acid screening methods in an effort to develop an early-stage screening kit for elk infected with chronic wasting disease (CWD). Live test animals were deliberately infected with CWD and DNA extracted from their blood was analyzed for patterns.  Dr. Sensen's team found that DNA sequence patterns indicating the presence of CWD were observable at least three months before clinical signs of the disease were evident. These findings could be the basis for developing a simple, inexpensive blood test to detect BSE and CWD infection in live cattle and elk. At present, these diseases can only be diagnosed by testing brain samples from dead animals.

Research Lead:

Dr. Jack Jhamandas, University of Alberta

Funding:

$181,000

Project:

“Neurophysiology of prion proteins in rat basal forebrain neurons”

Protein folding is an important biological phenomenon, and protein misfolding can result in the formation of the infectious form of prions capable of causing neurodegenerative brain diseases such as BSE in cattle, chronic wasting disease in elk and deer, and Creutzfeldt-Jakob disease in humans. Understanding how different forms of prion proteins affect cell function in the brain is critical to unraveling the mysteries of these diseases. The studies in this application will use state-of-the-art techniques to probe the responses of individual nerve cells in the brain to the application of different forms of prion protein. These studies will also identify the receptor through which prion proteins may exert their harmful effects in the brain. Identifying such a receptor will help develop compounds that may be able to block the toxic effects of prion proteins in the nervous system.

Findings:

Understanding how different forms of prion protein affect cell function in the brain is critical for unfolding the mystery of prion disease. Dr. Jhamandas and his team used state-of-the-art techniques to investigate how individual nerve cells in rat brains respond to different forms of prion protein. They found that prion proteins affect electrical activity in brain cells.  By measuring this electrical activity, the team hopes to identify the receptor through which prion proteins exert harmful effects in the brain. Identifying this receptor will help scientists develop compounds that can block the toxic effects of prion proteins. 

Research Lead:

Dr. Nat Kav, University of Alberta

Funding:

$200,00

Project:

“Recombinant prion-specific antibodies for passive immunization”

The main objective of this proposal is to evaluate the potential for bacterial and plant-based systems to produce functional, recombinant antibody molecules for potential use as passive immunization agents. Recent findings suggest that antibodies against prion proteins may help delay the progression of, and possibly even prevent prion-related diseases. In addition to evaluating the potential of plant-based antibody production, this project will also use bacterial systems to produce and purify significant quantities of antibodies for injection into various mice models to test their effectiveness in preventing disease.

Findings:

Antibodies against prion proteins may help to prevent or delay the progression of prion-related diseases. But since humans and animals have normal prions in their bodies, it is difficult to produce antibodies that only target the misfolded, infectious form. Dr. Kav and his team have access to antibodies-developed in Switzerland by the world-renowned prion biologist Adriano Aguzzi-that are specific to certain parts of the prion protein.  Dr. Kav and his research team are testing the effectiveness of the recombinant (genetically modified) antibodies they are harvesting by injecting mice with laboratory-produced antibodies and studying the effects on mouse prion protein. Their work could have significant implications for the livestock industry. In theory, if the antibodies prove effective, plant crops containing recombinant prion antibodies could be fed to cattle and thereby immunize animals against BSE. 

Research Lead:

Dr. Luis Schang, University of Alberta

Project:

“Protein kinases in the pathobiology of prion diseases”

TSEs are atypical infectious diseases that produce irreversible loss of neurons and cause brain damage. Although the risk of human transmission of these diseases is relatively low, the general perception of this risk is very high mostly due to the limited understanding of the processes by which the agents of these diseases induce neuronal loss and brain damage, as well as to the lack of effective treatments. This proposal is focused on understanding the roles of a large family of proteins in neuronal loss and irreversible brain damage resulting from TSEs. The proposal is also focused on identifying potential targets for the development of novel drugs to slow down or block the progression of TSEs.

Funding:

$97,043  (discontinued)

Research Lead:

Dr. Charles Holmes, University of Alberta

Funding:

$200,000

Project:

“Molecular characterization of a novel prion protein signal transduction pathway”

Identifying the signalling pathways and control systems within prion-infected cells that lead to disease symptoms in infected animals will be crucial to developing effective therapies to intervene in the disease's progression. This project will shed light on the function of the “healthy” prion protein expressed in normal cells, leading to a better understanding of what happens if that protein's function is impaired.

Findings:

Understanding the function of a healthy prion protein is the first step in understanding what happens when that protein's normal function is impaired. Dr. Holmes's research team hypothesized that a normal prion protein is involved in transferring information from the outside to the inside of cells. This information transfer, or signalling, controls activities in the cell. Identifying the signalling pathways and control systems within prion-infected cells is crucial for developing therapies that can effectively treat prion diseases.  Dr. Holmes's project demonstrated that components of the signalling mechanism do in fact interact with one another and with prion protein. Future studies will probe the interaction points and define the role of prion proteins in signal transfer pathways.

Research Lead:

Dr. Brian Sykes University of Alberta

Funding:

$188,850

Project:

“NMR studies of folding and misfolding of fibril-forming proteins in the liquid and solid states”

When some proteins become misfolded, they can collect in infected cells and form protein fibrils. The structure of these fibrils, found in prion diseases as well as Alzheimer's and Parkinson's, differs depending on which misfolded protein is involved in their formation. This project will analyze the structure of the fibrils found in BSE-infected animals, with the potential to use this information to design methods for destroying these fibrils in infected mammals.

Findings:

Some misfolded proteins collect in BSE-infected cells and form threadlike clusters called fibrils. Understanding how normal, stable bovine prion proteins convert to fibrils could lead to methods for destroying these fibrils in mammals with prion disease.  Dr. Sykes's research team successfully inserted bovine prion DNA into bacterial systems that could be stimulated to make large amounts of the protein rapidly and inexpensively. Using nuclear magnetic resonance (NMR) spectrometry, they were able to characterize the fibril form and map the transition of the prion protein from its normal state to the fibril structure.

Research Lead:

Dr. Howard Young, University of Alberta

Funding:

$191,236

Project:

“Molecular basis for the species barrier in prion protein disease transmission”

Recent research suggests that smaller collections of misfolded prion proteins are active infectious agents and may have greater biological impact than fully-formed fibrils themselves. Fibrils of different species have different structures, related to the particular version of prion infecting that species. These structural differences contribute to a “species barrier,” preventing easy transmission of prion disease from one species to another in some cases but not in others. This project will identify key protein structures differences underlying the species barrier in order to treat or prevent BSE transmission.

Findings:

Misfolded prion proteins clump together and eventually form long strands or fibrils. Since fibrils from different species have different structures, they are not easily transmitted from one species to another. Identifying the differences in protein structure that underlie this species barrier could be useful for the treatment or prevention of bovine spongiform encephalopathy (BSE).  Dr. Young's research team developed detailed characterizations of prion proteins from four different species and detected distinct, species-dependent behaviour. The team saw evidence that bovine prions behave differently than prions in other species, which may suggest that cattle are more susceptible to prion-related diseases. The team also confirmed that fibrils can be disrupted, analyzed and screened to test the effectiveness of specific antibodies.  In the next phase of their research, Dr. Young's team will use electron tomography-which makes it possible to see extremely small structures-to characterize brain samples from animals with prion disease.