Research has confirmed that an inherited mutation in the huntingtin protein causes Huntington disease, a progressive and ultimately fatal neurological disorder that usually starts in mid-life. There is much more to be learned about the onset and course of the disease and there is no effective treatment. Dr. Edmond Chan is addressing those gaps by profiling gene expression in mice with Huntington disease. His research aims to identify altered patterns of gene expression that link with early, mid and late stages of the disease. The profile may identify genes involved in initiating the process that leads to progressive damage and death of brain cells. Chan will formulate and test specific theories that connect gene expression patterns with the molecular development of Huntington disease. Ultimately, genes identified in the research could suggest treatment strategies to improve quality of life for patients with the disorder.
Research Pillar: Biomedical
Early events of infection and genome adaptation to parasitism in Microsporidia
Microsporidia are a group of parasites composed of just a single cell, but are found to infect all known animals – including humans – and can be fatal to people with compromised immune systems, such as AIDS or transplant patients. Microsporidia grow and multiply inside their host cells, but they exist outside of their hosts as spores that can infect nearby cells. Dr. Naomi Fast is striving to understand the cellular signals that the parasite uses to infect cells. She is examining and comparing what genes are expressed before and after spores infect their hosts, to identify genes that are specifically activated during infection. Identifying these genes could point to potential targets for drug treatments.
Characterization of the Ctf3/Mcm22/Mcm16 outer kinetochore complex; a link to the yeast spindle pole body
In order for cells to grow properly, chromosomes must accurately separate to opposite poles of the dividing cell. Mistakes in this process can lead to cancer due to instability of the chromosomes. Dr. Vivien Measday is using a yeast model to study chromosome segregation. She has a particular interest in the centromere, the region of the chromosome required for proper segregation, and the kinetochore, which consists of centromere DNA and its associated proteins. Using genetic screens, Measday is identifying and characterizing kinetochore proteins. Studying these proteins will increase understanding of why chromosomal instability occurs in cancer cells and in other disorders such as Down’s syndrome.
Structure-function relationship of the GTP-exchange factor smgGDS and its role in breast cancer
Ras proteins act as molecular switches that control functions including growth and movement of all cells. They also play a role in causing almost one-third of human cancers. Several families of proteins, including smgGDS, regulate Ras activity. Genetic changes leading to the production of an abnormal form of smgGDS are a characteristic of certain leukeumias. As well, too much smgGDS in cells leads to their transformation into cancer cells. Dr. Peter Schubert is determining the detailed structure of smgGDS and identifying parts of the protein that activate Ras proteins. The research should provide basic information necessary for designing drugs to block the action of smgGDS in leukemia.
Mechanisms and functions of activin/nodal signaling in early embryogenesis
We all start as a single cell, which divides and eventually forms the body. A great deal of cell communication goes into making decisions about this body plan. My research examines how cells communicate with one another during embryonic development. The body plan is set up by organizing centres, or groups of cells that dictate signals to other parts of the early embryo. Two centres have been identified in mammals: the anterior visceral endoderm (AVE) coordinates the development of the head, and the node arranges the trunk into front, back, left and right. The way these organizing centres control growth of the embryo, and the cell-to-cell signalling involved in the process, are poorly understood. The same signalling systems used in creating an embryo break down during cancer. Ultimately, if we can identify what happens under normal circumstances, we can better understand what goes wrong with signalling pathways during the development of cancer or congenital defects. The results of my research also have implications for stem cell research. Stem cells have the potential to differentiate into various types of cells. If we can determine the signals that cause particular cells to become liver, brain or kidney cells during embryonic development, researchers should be able to cue stem cells to differentiate into specific cell types.
Prevention of falls and hip fractures in the elderly through biomechanics
Falls are the number one cause of injury-related deaths and hospitalizations in Canada. Among the elderly, falls account for 84 per cent of all injuries and about 23,000 hip fractures annually. Reducing the frequency and severity of these injuries is a critical national health priority, and one that my research team is approaching from several angles. In one approach, we are using laboratory experiments and mathematical modeling to study age-related changes in posture and balance along with strategies for avoiding injury in the event of a fall. In another approach, we are determining how movement patterns and risk for falls are affected by physiological factors, such as muscle strength and vision, and by behavioural factors, such as risk-taking tendencies. On the applied side, the team is working to develop devices such as hip pads, compliant floors and exercise programs to help prevent fractures. This combination of basic and applied efforts should lead to the development of innovative and effective techniques to prevent falls and fall-related fractures in the elderly.
Role for postsynaptic protein complex assembly in synapse development
Neurons (nerve cells) in the brain and central nervous system transmit signals to each other across connections called synapses. Glutamate is the primary neurotransmitter (messenger) that nerve cells use to send signals across these synapses to induce action in the brain. Glutamate enables the brain to develop and language to be learned. Without synapses that allow the chemical signal’s transmission from one nerve cell to the next, nerve cells will not be able to communicate with each other. Other neurotransmitters carry inhibitory signals to reduce activity in the brain. My research has shown that the post-synaptic density protein (PSD-95) stimulates the formation and maturing of the synapses that release glutamate, and increases the release of this neurotransmitter. Members of the PSD-95 family are involved in the development and organization of receptors that are clustered on the receiving side of the synapse. I am investigating how PSD-95 proteins regulate receptor clustering at synapses. This research is important because the number of receptors regulates the strength of the message: the more receptors, the stronger the message. We want to gain a better understanding of how receptors accumulate at synapses, and how changes in this process may underlie long-term changes in synapse structure and function associated with learning and memory. If we can determine how to change the number of receptors, we can permanently enhance the signals received in the brain, which could improve learning and memory function. Also, by understanding how synapses are formed and how neurotransmitter receptor clustering is regulated, we may figure out how to rescue abnormalities in synapse formation and function associated with several neurological diseases such as Alzheimer’s, mental retardation, schizophrenia and epilepsy.
Analysis of prostate cancer progression using functional genomic approaches
In the early stages of prostate cancer, tumour growth is regulated by male sex hormones, called androgens. In treatment, androgens are removed to shrink the prostate tumour. However, the results of this therapy are usually temporary as surviving tumour cells become independent of androgens for growth and survival. I am investigating the genes responsible for this transition. To analyze these genes in a high throughput manner, I have created a Microarray Facility, the second of its kind in Canada. In the Facility, we can put up to tens of thousands of genes at a time on a single microscope slide. With this technology, we can now do experiments in a few days that would have taken years not long ago. We are comparing normal tissue to early and late tumours, and examining which genes are associated with tumour development. This research will identify the genes that cause prostate cancer, and how genes are turned on and off as the cancer progresses. We can use the information to predict when prostate cancer will occur, prevent its onset and develop new treatments that target the cancer-causing genes. In addition, we are investigating the effects environmental contaminants and dietary factors may have on the development and progression of prostate cancer.
Gonadotropin-releasing hormone (GnRH) in reproductive biology and medicine
The long-term goal of my research is to understand the multi-faceted role of gonadotropin-releasing hormone (GnRH), the primary regulator of the reproductive process. Our brains release GnRH to the pituitary gland, where it stimulates the synthesis and release of the gonadotropin hormones that regulate gonads (ovaries and testes). My research has shown that GnRH also affects cell function in the ovaries and placenta and the hormone may play a role in controlling estrogen and progesterone production. GnRH has a role in both normal ovarian physiology and in the development of ovarian cancer. Ovarian cancer is a major cause of death, but little is known about the way it develops. We are seeking new knowledge that will help us understand the role of GnRH in the development of ovarian cancer, which should lead to more effective treatments in future. We also know GnRH affects the successful implanting of an embryo to establish a pregnancy and the formation of placenta, but that process is not well understood. My research will help explain the causes and process of fertility. Synthetic GnRH compounds are often used in different areas of reproductive medicine, such as fertility and sterility, ovulation control and assisted reproduction. This research will provide a better understanding of the cellular and molecular effects of these compounds and should improve clinical applications as a result.
Evolution of microbial virulence
There is currently a poor understanding of how a relatively harmless microbe can evolve into one that causes disease. However, analyzing microbial DNA indicates that these bacteria may exchange their DNA with one another, essentially sharing genes that cause disease. Some microbes have evolved into disease-producing organisms relatively recently, making them good models for examining how bacteria results in disease. That’s because we are more likely to relate genetic changes in bacteria to those that cause virulent disease when the changes are more recent. My team is conducting laboratory and computer research to analyze the role gene exchange plays in the development of disease-causing microbes, and to characterize the evolution of recent disease-causing microbes. Understanding how benign bacteria evolved into virulent disease-causing bacteria will increase knowledge of how bacteria cause disease and lead to genuinely new therapeutics and prophylactics to combat current disease-causing microbes, and hopefully help prevent new ones from emerging in the future.