Parkinson’s disease (PD) is the second most common neurodegenerative disorder, estimated to affect 100,000 Canadians and is characterized by deficiency of the neurotransmitter dopamine (DA) as a consequence of dopaminergic neuronal death. Existing treatments ameliorate the symptoms, but they do not seem to alter disease progression. Furthermore, treatment often induces undesired side-effects such as motor complications and high risk taking behavior such as compulsive gambling. Positron emission tomography (PET) is a non-invasive imaging modality that uses radioactive tracers to obtain information about biological function in-vivo; depending on their chemical form, radiotracers tag different biochemical processes. PET is thus ideally suited to investigate the complex neurochemical changes associated with neurodegeneration. Using PET we have already provided significant insights into the motor aspects of disease-induced complications; an alteration in the pattern of the neuronal release of DA has been identified as being involved in the occurrence of motor complication. The main goal of this research program is to further develop and use novel imaging techniques to gain insights into the impact of different treatment strategies on motor complications and into treatment-induced psychiatric complications. Studies on human volunteers will be performed on a new, state-of-the art human PET brain scanner. This scanner, existing only in 15 PET centers worldwide, while providing and unprecedented amount of information, requires development of accurate data manipulation and interpretation algorithms, which are another part of this research program. A very important aspect in medical research is the ability to develop and investigate animal models of disease to be able to investigate disease in further detail in a more controlled environment. A third important part of this research program will be the in-vivo investigation of rodent models of PD and their relation to other diseases such as, for example, Alzheimer’s, since there is evidence of some clinical and pathological overlap between neurodegenerative diseases. A unique strength of this program is its ability to bridge advancement of knowledge with the advancement of methodological approaches. This aspect will contribute towards the establishment of a more comprehensive imaging environment aimed at the investigation of neurodegenerative and related disease, which is the program long term goal.
Program: Scholar
The MaMS Study. Malignancy and Multiple Sclerosis: incidence and impact of beta-interferon treatment
Multiple sclerosis (MS) is thought to be a chronic autoimmune disease of the central nervous system, which attacks myelin, a protective material that insulates nerve fibers in the brain and spinal cord. Over time, MS can cause loss of balance, impaired speech, extreme fatigue and problems with vision. Currently there is no cure, but treatment with beta-interferons (IFNBs) is available to reduce the frequency of MS attacks. Recent research suggests that the use of IFNBs may increase the risk of cancer. Given the estimated 75,000 Canadians with MS and the increasing popularity of the MS drugs, even a moderate increase in cancer risk could translate into a substantial number of new cancer cases.
Dr. Helen Tremlett is conducting the first study in North America to investigate the effect of IFNB on cancer risk in an MS population. Dr. Tremlett will examine more than two decades of BC data created by linking the BC Multiple Sclerosis Research Groups’ database with the BC Cancer Agency's Registry to determine the overall risk of cancer in the MS population, and the risk among MS patients treated with beta-interferon compared to the general population. Dr. Tremlett’s research will help to determine the background risk of cancer among MS patients, whether widely used treatments are associated with increased risk of cancer, and will also facilitate researchers in evaluating future drugs licensed for MS.
Apolipoproteins and Autoimmunity to Lipid Antigens
The immune system is designed to rid the body of infections and unwanted cells, such as tumor cells or virally infected cells. The decision to target a certain agent for elimination is made by recognizing that a component (antigen) of a bacteria or virally infected cell is «foreign» to the body. Sometimes, however, the immune system can mistakenly target «self» components in healthy tissue, which leads to autoimmune diseases such as multiple sclerosis (MS). White blood cells called T cells are the central players in this decision making and are classically known to target protein components. Recently, however, it has been found that lipid components (ie. fats) can also be targeted by T cells, which is a new paradigm in immune recognition. We have been studying how T cells recognize lipids, and found that a major blood protein, apolipoprotein E (apoE), which was previously known to carry lipids for metabolic purposes, is also playing a role in the immune system to promote the recognition of lipids. ApoE has been known to play a role in many diseases, including MS and atherosclerosis (the disease of blood vessels which leads to heart disease and strokes). These two diseases also share common features in that there is immune system involvement which causes harm, in MS directed against the fatty insulation of nerves (myelin), and in atherosclerosis, immunity against unknown agents, possibly lipids found circulating in the blood. Our findings integrating lipid metabolism by apoE and the immune system thus open up a new area of research of direct relevance to MS and atherosclerosis, and we will set out to demonstrate that lipids are targeted in these diseases, and how apoE is involved to promote this mistaken targeting. Understanding these mechanisms will allow us to better monitor these disease using blood samples from patients, and also point to new strategies to treat disease by dampening or altering the immune response to lipids.
Mechanisms of X-linked Dyskeratosis congenita
Dyskeratosis congenita (DC) is an inherited premature-aging syndrome that typically results in bone-marrow failure. Symptoms include abnormal skin pigmentation, abnormal or absent nails and white, pre-cancerous areas on the lips and in the eyes, mouth and other body openings. More than 80% of patients with DC develop bone-marrow failure, which leads to decreased production of all types of blood cells. Premature death is usually the result of bone marrow failure. Most cases of DC are caused by changes in the DKC1 gene on the X chromosome. DKC1 encodes a protein called dyskerin, which helps maintains chromosomes, in addition to its essential function of manufacturing protein synthesis machinery. A symptom-free mother carrying a DKC1 mutation has a 50% chance of transmitting it to a son who will develop the disease.
Using genetic and biochemical techniques, Dr. Judy Wong is working to determine the mechanisms of X-linked DC. There are more than thirty amino acid mutations of the dyskerin protein that are known to be associated with X-linked DC. Understanding the molecular events that give rise to X-linked DC will help predict how patients will be affected and assist in the development of genetic therapies. Dr. Wong plans to test the effectiveness of dyskerin gene replacement techniques in restoring normal activity in X-linked DC cells. Her work will also improve our understanding of how other physiological factors can compromise normal aging.
The Genetics of Asthma, Atopy and Allergic Diseases
My research focuses on trying to identify why some children get asthma and others do not. By identifing specific environmental and genetic risk factors and determining how they work together to predispose children to developing asthma and other allergic diseases we can design better treatments. Studies have found a 1-in-5 risk of developing asthma if one parent has asthma. The odds rise to 2 out of 3 if both parents have asthma. However, in itself, a genetic predisposition does not ensure that asthma will develop. Asthma and allergic disease are the result of both genetics and the environment. The interaction between a genetic disposition and environmental factors is key in the development of – or in protecting against- asthma. I will use information from 250 French Canadian Asthma Families and two additional birth cohorts, and information from the town of Busselton Australia in my research. Home visits were conducted for all the families and children to collect information on environmental factors such as family history, number of children, parental occupations, daycare, pets, dust samples, infections, hospitalizations and medication usage. After reviewing the literature we have found 162 genes which may predispose children to developing asthma and we will be looking at these genes in conjuction with other environmental factors to try and better understand why some children develop asthma and others do not. Using statistical models we will look at what genetic and environment factors best explain why some children develop asthma and others do not. We will then do further laboratory experiments to try and identify these factors work together.
Optimal, evidence-based use of vaccines
Immunization is one of the most powerful tools available in medicine. The number of available vaccines expands each year, reducing infection and disease. Optimal use of these new products can be hampered by gaps in understanding the disease epidemiology, vaccine effectiveness or longevity of protection provided. These gaps also affect decision-making related to resource allocation and prioritization of immunization programs. Dr. Jan Ochnio is working to close these gaps by gathering missing evidence to facilitate vaccine use in several viral and bacterial infections. As a MSFHR Scholar, Ochnio investigated the risk of hepatitis A for children in specific areas of the province. Now, his research is focusing on two areas: investigations of hepatitis A virus infections using population-based assays and saliva/mail-based surveys, and optimizing prevention of meningococcal infections by measuring the levels and duration of protection offered by the various meningococcal immunization schedules in Canada. A better understanding of the most efficient strategies for using vaccines could lead to substantial savings in health care by omitting unnecessary doses and the related costs of providing these doses. Ochnioâs findings will be shared with public health policy experts to be used in finely-tuned vaccination programs and policies that will provide optimal protection for Canadians.
Structural analysis of the molecular machinery involved in protein secretion, membrane protein assembly and protein processing
The ability for proteins to travel across cell membranes is critical to the life of all cells, yet research shows that bacterial cells differ from human cells in some of the components necessary for this movement to occur. In previous work supported by an MSFHR Scholar award, Dr. Mark Paetzel uncovered the three-dimensional structure of proteins that make up the molecular machinery involved in this movement in bacterial cells. Now a Senior Scholar, Dr. Paetzel will continue this work with the goal of learning more about these structures in order to determine how to inhibit the movement of proteins across cell membranes in bacteria. He will use X-ray crystallography to investigate the proteins involved in protein targeting, translocation, and membrane protein assembly in bacteria. Dr. Paetzel is also investigating a particular enzyme that functions at the membrane surface â one that causes the cleaving of interior peptide bonds in a protein. Understanding how to inhibit this enzyme and its role in bacterial cell movement could lead to the development of a novel class of antibiotics â a strategy that is required to meet the ever-increasing challenge of antibiotic resistance.
Mechanisms of target-dependent neuronal differentiation in Drosophila
Normal nervous system function requires the generation of an enormous diversity of neurons during development. Differences in the identity and function of neurons depend upon differences in the repertoire of genes that the neuron expresses. Differential expression of these genes is controlled by intrinsic factorsâthe complement of transcription factors that exist within the neuronsâ and by extrinsic factors, signals secreted by other cells. Alterations in either of these factors have been implicated in many developmental, psychiatric and degenerative diseases. Dr. Douglas Allan is investigating how these intrinsic and extrinsic signals interact in neurons to selectively turn on the expression of different repertoires of genes in different neurons, so that the neurons attain their appropriate form and function. He is using the fruit fly, Drosophila melanogaster, as a model organism to study these mechanisms, because of the battery of powerful molecular genetic experimental tools available in this organism. Since the basic mechanisms of neuronal development are shared by fruit flies and humans, his work is relevant to understanding how human neurons develop and how disruption of these signals can cause disease.
Examination of the role of cadherin/beta-catenin adhesion complexes in the development and maintenance of synaptic junctions
Synapses of the central nervous systemâjunctions across which a nerve impulse passes from neuron to neuronâare highly-specialized regions of cell-to-cell contact. Deficiencies in synaptic function are central in many psychiatric and neurodegenerative diseases such as schizophrenia, Alzheimerâs, Parkinsonâs and Huntingtonâs disease. Cell adhesion molecules, localized at synapses, are believed to have an important role in the regulation of synapse formation, maintenance and function. Dr. Shernaz Bamji has previously shown that cadherin and beta-catenin adhesion complexes act to recruit and tether synaptic vesicles to presynaptic compartments, and that transient disruptions of these adhesion complexes are important for the sprouting of new synapses. She is now further investigating the cellular and molecular mechanisms by which synaptic cell adhesion molecules regulate the formation, stability, and elimination of CNS synapses. . Understanding the underpinnings of these mechanisms may lead to the identification of new targets for therapeutic intervention in psychiatric and neurodegenerative diseases.
Structural and functional characterization of the vibrio cholerae toxin-coregulated pilus
Vibrio cholerae is a bacteria that infects the human small intestine to cause the potentially fatal diarrheal disease cholera. This disease, which is spread through contaminated drinking water, represents a major health threat in developing countries, with young children being most vulnerable. The toxin co-regulated pili (TCP) on the surface of V. cholerae are important components in the bacteriaâs ability to cause disease in the host. TCP are hairlike filaments that hold the bacteria together in aggregates or microcolonies, protecting them from the host immune response and concentrating the toxin they secrete. The TCP are also the route through which the V. cholerae bacteria is itself infected by a virus called CTX-phi, which enables V. cholerae to produce cholera toxin. Dr. Lisa Craig is determining the molecular structure of the TCP and delineating the regions of this filament that are involved in microcolony formation and in binding to CTX-phi. The information obtained from her studies may lead to vaccines, therapeutics and diagnostics for combating this deadly disease.