The error-free duplication of a multicelled organism’s genetic material is critical to its survival. Even small changes in the genetic code during duplication can lead to diseases such as cancer. Equally important to cell division is the error-free transmission of chromosomes to each of the two daughter cells, which depends on the proper regulation of sister chromatid cohesion (the attachment of both strands of newly-replicated DNA to the area of the chromosome called the centromere). When the mechanisms involved in chromatid cohesion are defective, there may be uneven segregation of chromosomes to daughter cells. This results in abnormal chromosome numbers (aneuploidy), a characteristic of many cancers. Ben Montpetit is studying the components responsible for regulating cohesion of sister chromatids. Ben’s research is aimed at providing a better understanding of what happens when the cohesion process is flawed, and to help identify therapeutic targets in cells with defects due to altered chromatid cohesion.
Research Pillar: Biomedical
Identification of new targets for the treatment of androgen-independent Prostate Cancer
Current treatments for advanced prostate cancer eliminate the growth-promoting effects of androgens such as testosterone. Unfortunately, while this treatment is initially effective in reducing prostate growth, the usual outcome is an untreatable form of prostate cancer where the cancer becomes androgen-independent (grows without androgens). Steven Quayle is working to isolate the different genes that are expressed (activated) at different hormonal stages of prostate cancer. He is using a technique where prostate cancer cells grown in hollow fibres progress to androgen-independence in a controlled, reproducible manner. This will allow Steven to confirm the changes in gene expression that consistently occur with disease progression, and study in more detail the role of particular genes. These genes may be useful as indicators of disease progression, as well as potential targets for treatment.
The role of the tumor suppressor ING in cell growth and death in a frog model system
Mary Wagner is interested in the fundamental mechanisms that govern a cell’s decision to divide, mature or die. Armed with this information, she says, we can gain greater insight into many different diseases where these basic functions are altered. For example, cancer is characterized by uncontrolled cell division, and inappropriate cell death is the hallmark of degenerative diseases such as Alzheimer’s and muscular dystrophy. Mary is studying the role of ING (INhibitor of Growth), a protein that helps regulate these basic cell functions. While ING is also found in the cells of humans, mice, rats and yeast, Mary is studying the protein’s role in the metamorphosis of tadpoles into frogs—a drastic and rapid transformation involving tail death, leg growth and brain remodeling. She is also investigating how environmental pollutants can act as hormones to disrupt normal cell development and function.
Structural characterization of bacterial type III secretion system components
Bacterial resistance to antibiotics is on the rise and poses increasing threats to susceptible individuals, including the elderly, children and immunocompromised patients. To develop new and effective therapeutics against these microbial enemies, a thorough understanding of their pathogenic (disease-causing) mechanisms is required. Calvin Yip’s research focuses on characterizing the structural components of the bacterial type III secretion system (TTSS). Found in many pathogenic bacteria-including Enteropathogenic E. coli and Salmonella strains-these secretion devices are essential to the bacteria’s ability to cause disease. These systems allow pathogenic bacteria to deliver effector molecules into human cells, where they disrupt normal cellular function. Calvin is investigating how the TTSS structures are assembled and how they deliver effector molecules into cells. In conjunction with other biophysical studies, this work will result in a deeper understanding of the assembly and function of TTSS and may provide the basis to design new drugs.
Transcriptional regulation of HIV LTR and mechanism of HIV latency and reactivation
Anti-retroviral therapy for HIV typically suppresses the virus in patients’ blood to undetectable levels, enabling people with the infection to live symptom-free. However, some T cells are latently infected by HIV and remain unaffected even by prolonged treatment. These latently infected cells and other lymphocytes pose the major barrier to eliminating HIV infection, and provide a latent reservoir for the virus to reactivate. Long-term anti-retroviral treatment can also cause HIV resistance to therapy in some patients. An alternate strategy is therefore needed to target the latently infected virus and ultimately cure AIDS. Dr. Jiguo Chen is researching how HIV-1 establishes latency and how it reactivates. He and other colleagues in the Sadowski lab have isolated and identified a complex of several transcription factors termed RBF-2 (Ras-responsive element binding factor), which binds to HIV long terminal repeat (HIV-1 LTR) and represses HIV-1 transcription during latency. He believes that this complex plays a role in establishing and maintaining latency. He is using several different experimental strategies to determine the role of RBF-2 and to learn how it works during latency and reactivation, so new drug therapies can be designed to clear HIV from patients’ immune systems.
Susceptibility genes and environmental risk factors in Alzheimer's Disease
Dr. Robin Hsiung is researching the genetic and environmental origins of Alzheimer’s disease. The disease is the most common type of dementia, affecting five per cent of seniors aged 65 and older, and 40 per cent of people over 80. People suffering from Alzheimer’s often need costly treatments and placement in care facilities. Recent advances in molecular genetics have led to the discovery of at least four genes involved in the development of Alzheimer’s disease. However, a number of genes that are believed to be connected to the disease have yet to be confirmed. Robin will examine samples and data from two large Canadian studies of people with Alzheimer’s and other cognitive impairments. His research will identify the genes and environmental risk factors that indicate susceptibility for Alzheimer’s disease. Understanding how these risks can be modified will enable the development of new educational programs and therapies that may decrease the incidence and financial burden of this disease.
Identification of critical gene regulatory domains using bioinformatics and comparative genomics
Over the last ten years, researchers have identified all the genes in our species—approximately 40,000 genes—called the human genome. The mouse genome will be completed soon. It’s estimated that mice and humans shared a common ancestor 70-100 million years ago, and we still share many of the same genes. Dr. Mia Klannemark is using specialized computer programs to compare data on mouse and human genes. She hopes to gain insight into regulatory regions adjacent to genes, which control the production of proteins. Mia is examining how genes make proteins, and identifying which regulatory regions have remained the same between mice and humans, because these genes indicate important functions that have not changed over the period of evolution. She is also identifying genes that have changed, which may contribute to the differences between species. This knowledge will help us understand how genetic variation influences the development of disease, and could lead to more effective treatments.
Role of Notch4 in angiogenesis
New blood vessels can grow from existing blood vessels in a process called angiogenesis. Limiting new blood vessel growth is a promising approach to treating cancer because tumours require a blood vessel supply to grow larger than two to three millimetres or to metastasize (spread) to other sites. But much remains to be learned about the molecular mechanisms of angiogenesis in tumours. In earlier research, Dr. Michela Noseda and colleagues have shown that a protein called Notch4 can inhibit angiogenesis. Notch arrests growth in the endothelial cells that line the inside of blood vessels, but it’s not known how this process occurs. In her current research project, Michela will investigate how the Notch protein prevents endothelial cells from proliferating. Ultimately, she wants to discover whether manipulating Notch activity in tumour blood vessels can induce tumour regression and limit metastasis.
Role of lipid rafts in AMPA receptor trafficking and synaptic plasticity
Brain cells communicate with one another by releasing chemical transmitters, which bind to receptors on the surface of neighbouring cells and cause them to become excited (switched on). One of the most important transmitters is glutamate, which plays a key role in learning and memory. However, the presence of too much glutamate in the brain (such as during a stroke) can lead to brain cell death. Dr. Changiz Taghibiglou is studying how lipid structures on the surface of brain cells – known as rafts – affect how glutamate is transmitted between cells. Floating on the cell membrane, lipid rafts contain channels and receptors that transmit brain cell signals. By conducting experiments that alter the composition of lipid rafts, Changiz hopes to better understand the role of lipid rafts in glutamate transmission and suggest possible ways to modulate the function of glutamate receptors and prevent cell death.
Molecular characterization of the virulence protein secretion machinery of Enteropathogenic E. coli
Enteropathogenic and Enterohemorrhagic Escherichia coli are disease-causing bacteria that cause severe diarrhoeal illness and death in young children and susceptible individuals. Often associated with hamburger disease, these bacteria are extremely dangerous when consumed, secreting proteins that cause cell disruption and damage to the human digestive tract. The resurgence of these bacteria in regional and rural water supplies also poses a considerable threat to the health of populations. Dr. Nikhil Thomas is working to improve the understanding of the mechanisms these bacteria use to cause disease. He aims to identify bacterial proteins that interact with each other to cause infection in the digestive tract. By understanding the mechanisms and strategies these disease-causing bacteria use, antimicrobials and treatments can be tested, with the ultimate goal of a vaccine to prevent disease.