Many microorganisms reside in our bodies as part of normal living. For example, bacteria in the gastrointestinal system outnumber our own cells and form a stable connection with the body that persists for life. These resident bacteria are needed for parts of the digestive tract to develop and function properly. In addition, beneficial bacteria attach to the walls of the intestinal tract, preventing harmful bacteria from occupying these surfaces, and protect us from infectious diseases as a result. A lot of research has focused on disease-causing bacteria like E. coli and Salmonella, which are among the leading causes of gastrointestinal illness and death worldwide. Yet little is known about the role of beneficial bacteria in battling these microbes, which is the focus of Inna Sekirov’s research. She is examining what role resident bacteria play during the response of the intestinal immune system to infection and how these bacteria respond to antibiotics used to treat gastrointestinal illnesses. Findings from her research will help to establish whether drugs are likely to have a positive or adverse impact on a patient’s beneficial bacteria, and could also help inform new therapies or dietary regimes that complement or strengthen the ability of these bacteria to help the body fight infection.
Research Pillar: Biomedical
The role of O-Glycosylation in a mouse model of amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the loss of motor neurons (specialized nerve cells) in the spinal cord, brain, and descending motor tracts. ALS leads to muscle weakness and paralysis, and is often fatal. Numerous biochemical processes have been linked to the progression of ALS, including increased levels of protein modification (phosphate units). Xiaoyang Shan is researching the role of modified sugar units, known as O-GlcNAc, in maintaining the proper functioning of neurofilaments (structural proteins) that give neurons support and shape but become damaged in ALS patients. He is also investigating the role of O-GlcNAc in maintaining healthy motor function. The findings could help increase understanding of the causes of ALS, and contribute to development of a potential treatment to slow or halt the progression of the disease.
Systems biology analysis of dynamic cellular pathways
Many diseases, including cancers and autoimmune disorders, arise from malfunctions of complex cellular processes. These processes regulate such things as the cell’s ability to grow, change cell type, and even die. Complex biomolecular networks, consisting of interacting genes and proteins, create the sophisticated information processing circuits within cells that control these biomolecular events. Inherited genetic defects, genetic mutations and some environmental cues can alter these networks to create abnormal cellular functioning leading to disease. Medicines treat and cure disease by controlling malfunctioning biomolecular networks. This requires a deep understanding of how cellular networks function and why malfunctioning networks fail. James Taylor’s research focuses on cellular signaling, the mechanism for processing external information that is the basis for a cell’s ability to sense the environment and communicate with other cells. He is studying how information signals flow through, and are processed by, signaling networks. The research is being conducted with baker’s yeast, a single cell organism that is commonly used for research involving fundamental cellular processes. Using computational, engineering and advanced experimental methods, Taylor is exploring how these networks create normal cell functionality and how changes in these networks lead to disease. By contributing to our knowledge of cellular signaling in yeast cells, this research will shed light on malfunctions of cellular processes in humans.
Testosterone-Dependent Regulation of Arachidonic Acid Metabolism Influences the Development of Hypertension Following Insulin Resistance
Resistance to insulin — the hormone that converts sugar into energy — leads to diabetes and high blood pressure (hypertension). Chronic hypertension can lead to cardiovascular complications like heart disease and stroke — two leading causes of death. This is a cause for concern since two million Canadians have diabetes, and this number is expected to rise to three million by the end of the decade. Consuming a diet high in fructose, a sugar used to sweeten soft drinks and other foods, causes insulin resistance and increases blood pressure. Harish Vasudevan has found that differences in gender and sex hormones play a role in the development of high blood pressure. For example, pre-menopausal women are less likely to develop hypertension than men or post-menopausal women. The female sex hormone, estrogen, protects these women against developing insulin resistance and high blood pressure. But the male sex hormone, testosterone, is required for blood pressure to elevate following insulin resistance. Fructose also disturbs the normal relaxation in blood vessels, but requires testosterone to do so. Vasudevan is examining how changes in the blood vessels depend on testosterone and estrogen. This research will further clarify the role of sex hormones in the development of insulin resistance and hypertension, which should, in turn, lead to new treatments for these chronic diseases.
Volume and Shape of the Caudate Nucleus and Putamen as Biomarkers for Parkinson's Disease Progression
Parkinson’s disease is a degenerative disorder of the central nervous system. Symptoms include shaking, muscle stiffness, speech problems, memory loss and vision problems. The disease involves the inactivation of dopamine-producing cells in a part of the brain called the substantia nigra. There is no definitive test to diagnose Parkinson’s disease, making it difficult to diagnose in its early stages. By the time a patient is diagnosed, up to 80 per cent of the dopamine-producing cells may have already stopped working. There is therefore a need for a more reliable test for diagnosis of Parkinson’s disease. There is reason to believe that Parkinson’s disease can be detected by measuring the size and shape of two anatomic structures within the brain that are both connected to the substantia nigra: the caudate nuclei and the putamen. When the cells in the substantia nigra become inactive, less dopamine is sent to the caudate nuclei and putamen. Aaron Ward is studying whether a decrease in dopamine results in changes to the size or shape of the caudate nuclei or putamen. Using magnetic resonance imaging, Ward is computing a 3-D representation for each patient’s caudate nuclei and putamen. The ultimate goal is to discover aspects of the shape of these structures that could serve as indicators of Parkinson’s disease. This would allow earlier and more reliable diagnosis, and facilitate the tracking of patient response to therapy.
The role of the DOG-1 helicase in repair of DNA interstrand cross-links in the model organism Caenorhabditis elegans
DNA damage repair pathways prevent cancer by recognizing and repairing DNA damage. If DNA damage is not constantly and consistently repaired in this way, it can lead to mutations in the DNA, which accumulate over time. Without normal DNA repair pathways in action, cancer will eventually develop. Jillian Youds’ research focuses on the DNA repair pathway involved in the hereditary cancer susceptibility syndrome Fanconi anemia. Patients with Fanconi anemia have unstable chromosomes and commonly develop cancer at a young age. It is thought that these patients are unable to repair cross-links in their DNA, which can prevent essential cell processes from occurring. As these DNA repair pathways are common to many organisms, Youds is using the nematode C. elegans to conduct her studies. Using molecular biology, genetic and biochemistry techniques, Youds will study how DNA cross-links are repaired by the cell under normal circumstances. This research is relevant to patients with Fanconi anemia, and it will contribute to the development of the best possible chemotherapeutics to optimize cancer treatments. Since the loss of functional repair pathways is a contributing cause of cancer and also a means to target cancer cells for elimination during treatment, an understanding of how the DNA cross-link repair pathway works will bring us closer to the ultimate goals of prevention and successful treatment of cancer.
Signaling Pathways Underlying Spreading Depression and Ischemic Depolarization
The visual aura some people experience with migraine headaches is caused by “spreading depression,” a wave that begins in the outer portion of the brain and spreads throughout the gray matter. During the wave, nerve cell activity lessens and brain tissue swells. A similar wave, called ischemic depolarization (ID), occurs during a stroke. Ischemic strokes cause the sudden death of brain cells when blood flow to the brain is blocked. Although spreading depression was first reported more than 60 years ago, researchers are still unclear about how the wave is generated. Ning Zhou is using a new imaging technique, called two-photon laser scanning microscopy, to examine detailed changes in individual cells when brain tissue suffers from spreading depression or ischemia (insufficient blood supply). Although these two events are similar, brain cells do not die during the wave of spreading depression. Zhou will examine the differences to discover why nerve cells undergo unusual swelling during spreading depression, and how this contributes to cell death during stroke. This research could provide insight into how to prevent tissue damage induced by strokes.
Carbohydrate recognition and metabolism in streptococcus pneumoniae: Structural and functional dissection of unique virulence factors
Pneumonia is an acute respiratory disease, the major cause of which is the bacterium Streptococcus pneumoniae. This bacterium is the leading cause of death from infectious disease in North America and a leading cause of death worldwide, particularly in children and the elderly. This bacterium can also cause meningitis, septicemia, and otitis media (middle ear infection). Reports indicate that 40 per cent of pneumonia cases caused by S. pneumoniae are resistant to penicillin and new multidrug resistant strains are beginning to emerge. To reduce increasing rates of antibiotic resistance and augment judicious use of the pneumococcal vaccine, alternative methods for treating S. pneumoniae infections must be found. Several proteins have been found in S. pneumoniae that are believed to contribute to its virulence. It is suspected some of these proteins destroy sugars such as glycogen in specific lung cells that normally serve to protect the lungs against infection. These damaging proteins are potential targets for preventing or slowing the infection. Dr. Alisdair Boraston will focus on two aspects of these S. pneumoniae proteins: if and how these proteins are destroying sugars and how to inhibit this activity. Biochemical studies will provide understanding about how these enzymes degrade sugars and whether any inhibitor molecules can interfere with this. Structural studies using X-ray crystallography will show structural features of the proteins that contribute to their activity and aid in the design of new inhibitors. Taken together, this information will lead to new approaches and agents to target pneumonia caused by S. pneumoniae.
Defining the structural basis of surface antigen glycoprotein mediated virulence in Toxoplasma gondii
Toxoplasmosis is a serious human pathogen carried by about one-third of the population. People develop toxoplasmosis either after ingesting undercooked meat that contains T. gondii cysts, or by coming into contact with cat feces from an infected animal. Once infected, healthy adults initially show a range of temporary flu-like symptoms; however, while these symptoms pass, the parasite Toxoplasma gondii remains in the body for life, with limited drug treatment available. Infection during pregnancy can cause miscarriage, neonatal death and a variety of fetal abnormalities, including developmental delays. It is also harmful to those whose immune systems are compromised, such as those with HIV/AIDS, cancer or who have had an organ transplant. Very little is known about how T. gondii causes disease. Dr. Martin Boulanger is studying the structure of host-pathogen interactions to determine the activities that allow T. gondii to attach to and invade human cells. With this information, treatments can be developed to prevent or manage Toxoplasmosis. This work will also apply to better understanding of other parasite-caused disease such as malaria and cryptosporidiosis.
Development and application of data standards for flow cytometry
Flow cytometry is a method of identifying and sorting cells and their components by staining with a fluorescent dye and detecting the resulting fluorescence (usually by laser beam illumination). Flow cytometry is widely used in health research (e.g. for stem cell identification and vaccine development), and in the diagnosis, monitoring and treatment of a variety of diseases, including cancers and HIV/AIDS.
Recent advances in high-throughput flow cytometry allows for the analysis of thousands of samples per day, creating detailed descriptions about millions of individual cells. Managing and analyzing this volume of data is a challenge that Dr. Ryan Brinkman is addressing through the development of data standards, algorithms, and bioinformatics tools. Dr. Brinkman is also applying these methodologies to the analysis of several large clinical flow cytometry datasets in an effort to identify biomarkers for lymphoma, neonatal auto-immunity, and graft versus host disease.