Tuberculosis (TB) is a contagious illness of the respiratory system that is spread through coughing and sneezing. This chronic infectious disease is caused by a bacterial microorganism, Mycobacterium tuberculosis. This bacterium infects one in three people worldwide and claims the lives of two to three million people each year. The incidence of TB is on the rise due to the emergence of multi-drug resistant strains and escalating numbers of HIV-linked deaths. These alarming trends have led the World Health Organization to declare tuberculosis a global health emergency. Pathogenicity of this bacterium is due in part to its unusual ability to survive for long periods of time and to replicate in human immune cells. The mechanisms behind this persistence are poorly understood which is why Katherine Yam is investigating a number of genes essential to pathogenesis of M. tuberculosis. Studies recently revealed that some of these genes are involved in degradation of cholesterol â a source of energy for the bacterium during infection. Yam is studying two of these cholesterol-degrading enzymes, HsaC and HsaD, which help the bacterium survive in the human body. By designing inhibitors for these enzymes, the cholesterol-degrading pathway of M. tuberculosis can be blocked, which will reduce the bacteriumâs ability to cause disease. These enzymes are excellent new targets for TB drug treatments as they are not targets of current drugs and thus will circumvent the problem of drug resistance in TB.
Research Pillar: Biomedical
PTEN Regulates Alternative Splicing
Prostate cancer is the most common non-skin cancer among Canadian men and the second leading cause of cancer death. Prostate cancer starts in the prostate gland, part of the male reproductive system. Frequently, men with early prostate cancer have no warning symptoms. PTEN is a tumour suppressor gene that has been linked to prostate cancer. PTEN helps promote apoptosis (cell death), which helps regulate the uncontrolled cell growth that occurs in cancer; unfortunately, PTEN is often mutated in advanced stages of prostate cancer. Alternative splicing is an integral part of normal cell function, and is important for generating protein diversity and controlling protein function. Tien Yin Yauâs study investigates whether PTEN plays a role in regulating alternative splicing. Yau is studying whether changes in normal mRNA splicing increase susceptibility to prostate cancer by affecting genes implicated in tumor progression. The findings of Yauâs study will increase our knowledge of the molecular mechanisms that regulate alternative splicing. Understanding what changes occur and their effects may result in the development of more effective cancer treatments.
Palmitoylation in the Pathogenesis of Huntington Disease
Huntington disease (HD) is a devastating inherited neurological disease characterized by loss of motor control, cognitive decline and psychiatric disturbances, resulting in eventual death 15 to 20 years after symptoms first appear. In Canada, one in 10,000 people have Huntington disease, and have a 50 per cent risk of passing on the disease to their children. The underlying genetic cause of HD is an expansion of a specific portion of the HD gene, known as the CAG trinucleotide repeat, which results in an expanded stretch of an amino acids in the huntingtin protein. This expansion leads to cell death in specific parts of the brain through mechanisms that are the subject of intense investigation. When the HD gene is translated into huntingtin, the protein undergoes alterations at many sites. Palmitoylation is an example of such an alteration, which involves the addition of a small fatty-acid chain to a protein. Palmitoylation enhances the ability of a protein to associate with membranes (e.g. cell walls), and influences that proteinâs trafficking and function. Most notably, palmitoylation is a reversible protein modification. Decreased palmitoylation may play a role in the cellular events underlying the development of HD. Fiona Young is investigating the role of palmitoylation in the development of Huntington Disease as well as in the context of the normal function of the huntingtin protein. The research could lead to new therapeutic approaches for Huntington disease that involve increasing palmitoylation of the huntingtin protein.
Characterization of Salmonella Type III effector: Host protein interactions and their contribution to immune evasion
Salmonella bacteria cause severe intestinal infection and diarrhea in humans. Millions of cases of Salmonella infection occur every year, predominantly in developing countries. However, salmonellosis is still a persistent problem in developed nations; young children, the elderly, and people with compromised immune systems are the most likely to have severe infections. Salmonella bacteria infect human cells and somehow manage to avoid activating the immune system from attacking them, allowing the bacteria to replicate. How these bacteria evade the host immune system response is poorly understood. Salmonella bacteria secrete proteins, called effectors, directly into the host cell through a needle-like channel. Dr. Amit Bhavsar is researching how these effectors bind to other host proteins in human cells; how the host proteinsâ ability to function is affected; and how this enables Salmonella to evade the immune system. This research will result in a better understanding of how Salmonella bacteria evade the host immune system. It could also lead to new ways of restoring the immune system to fight infection, providing an alternative to conventional antibiotics, which have become less effective in the face of antibiotic resistance.
Imaging the Remodeling of Individual Synapses and Vessels in the Living Brain after Stroke
Stroke is the leading cause of adult disability, often rendering its victims with profound impairments in sensory, motor or cognitive function. Fortunately, many individuals experience some partial form of recovery over the ensuing weeks, months and years after stroke. This recovery of function is thought to be dependent on how well surviving brain cells (called neurons) and their connections adapt and form new circuits. However, the nature by which these neurons change in a living organism and the factors that regulate these changes, has not been determined. Craig Brownâs research is aimed at determining how the parts of the neuron that receive information (dendrites) and those that transmit information to other cells (axons) reorganize after stroke. Given that neurons are critically dependent on sufficient levels of blood flow to survive and flourish after stroke, he is also examining structural changes in brain blood vessels and their delivery of blood to vulnerable regions of the brain. He will then examine how therapeutic interventions, such as movement-induced therapies or sensory/electrical stimulation, influence brain reorganization. A better understanding of how the brain adapts to injury and the factors that regulate these process will pave the way for future therapies to optimize recovery of function after stroke.
The role of Integrin-Linked Kinase in Modulation of Vascular Smooth Muscle Migration and Atherosclerotic Intimal Thickening in Type II Diabetes
Incidence of coronary artery disease, which involves narrowing or blocking of the arteries and vessels that provide oxygen and nutrients to the heart, has increased two to four times among people with diabetes. Almost 70 to 80 per cent of diabetes patients die from heart failure. Smooth muscle cells form tissue that contracts without voluntary control. These cells significantly contribute to narrowing or blocking of the arteries in diabetes patients. However, the cellular mechanisms underlying the accelerated rate of smooth muscle cell migration in diabetes are not well understood. Dr. Mitra Esfandiarei is investigating these mechanisms and also assessing the role of integrin signaling â cell communication that involves connecting the cell interior to its exterior or one cell to another. Integrin signaling may help regulate the internal framework of cells that affects muscle contraction and smooth muscle cell migration in diabetes. The research could contribute to development of therapies that prevent or delay accumulation of atherosclerotic plaque and blocking of arteries in diabetes type 2 patients. She ultimately aims to reduce the frequency of disease and mortality due to the cardiovascular complications, and improve the health of patients with type 2 diabetes. In 2001, Mitra Esfandiarei was also funded by MSFHR to study how heart muscle cells can survive infection by coxsackievirus B3 during the course of enteroviral myocarditis, an inflammatory heart disease.
Elucidation of the nature and biological importance of a novel calcofluor white-reactive surface polysaccharide of Campylobacter jejuni important in stress responses and in biofilm formation
Campylobacter jejuni (C. jejuni) is the leading cause of bacterial food poisoning. Infection with the bacteria leads to Campylobacteriosis, which causes diarrhea, fever, and vomiting. The disease can also result in more serious complications, including arthritis, inflammatory bowel disease, and paralysis. C. jejuni is transmitted from animals and birds to humans, where it causes infection. The exact mechanism of how it colonizes in humans and causes disease is unknown. C. jejuni is capable of surviving for long periods of time outside of a host, indicating that it must have several ways of dealing with the stresses associated with a less than ideal environment. Carbohydrate structures covering the surface of C. jejuni play an important role in interactions between the bacteria and its surroundings and may be involved in environmental survival, as well as in the host infection process. Dr. Emilisa Frirdich contributed to a study that identified a new C. jejuni cell surface carbohydrate (polysaccharide), which was found to be involved in C. jejuni stress survival and formation of biofilms (the layer of microorganisms that enables bacteria to adhere to a surface). Many bacteria produce biofilms to increase their ability to survive stress inside and outside of a host. Frirdich is investigating this cell surface carbohydrate to determine its nature, identify the gene products involved in making it, and characterize its biological importance. The research may lead to a better understanding of how C. jejuni causes disease, and ultimately contribute to development of an effective vaccine.
Dietary modulation of mitochondrial function in the prevention of diabetic heart disease
An estimated 150 million people worldwide have diabetes, a metabolic disorder marked by high blood sugar. After anti-diabetic medications were developed, high blood sugar was no longer a primary cause of death for diabetics. Other complications, particularly heart failure, have become a major factor in mortality. Free radicals are unstable and highly reactive atoms. Both type 1 and type 2 diabetes involve increased free radical release in heart cells. Research has suggested that increased accumulation of free radicals irreversibly damages mitochondria, the part of heart cells that helps convert fat into energy for the heart’s pumping action. If the mitochondria are damaged, fat accumulates in the heart. The combination of free radical release, fat accumulation, and lack of energy can kill heart cells, leading to the development of a weak heart in diabetic patients. Dr. Sanjoy Ghosh is studying the benefits of supplementing diet with S-adenosyl methionine and omega-3 polyunsaturated fatty acids. He is researching whether they can lower the release of free radicals, protect mitochondria, decrease fat deposits, and increase energy production in the diabetic heart. His goal: a natural, non-toxic therapy to prevent or delay the onset of diabetic heart disease.
Critical protective role of Toll-like receptor 2 in bacterial induced colitis
Inflammatory bowel diseases (IBD), as well as many forms of infectious gastroenteritis, are thought to occur when the integrity of intestinal barriers is disrupted, allowing luminal bacterial products to cross into the intestinal mucosa, stimulating immune cells and triggering and unmitigated immune response. Unfortunately, there is currently no cure, no prevention and limited therapeutic options for IBD. Current evidence suggests that a genetic defect in people with IBD can affect intestinal homeostasis or the balance between an active inflammatory response to an invading pathogen and tolerance to commensal bacteria In individuals with IBD, inflammation is turned on to protect against offending agents, but it doesnât get turned off once the pathogen has been cleared. Instead, the immune system seems to react to intestinal commensal bacteria that were once tolerated. It is suspected that the usually protective epithelial and mucosal barrier lining the intestine is impaired in patients with IBD, allowing intestinal bacteria to leak across the epithelium and activate immune cells. This prolonged exposure to intestinal bacteria and their products results in exaggerated and chronic inflammation. This causes the symptoms of IBD, which includes diarrhea, severe abdominal pain and other health problems outside the digestive system. Dr. Deanna Gibson is investigating the immune mechanisms involved in IBD by examining how the immune system recognizes and responds to bacteria within the intestine in vivo. She is studying a molecule, Toll-like receptor 2, which has been implicated in IBD and is critical for protecting the intestine from developing severe and lethal colitis. By determining how Toll-like receptor 2 controls susceptibility to bacterial induced colitis, her research could lead to an understanding in intestinal homeostasis which is required to design new therapeutics and discover targets against IBD.
Evaluation of the tumour microenvironment in HER-2 positive breast cancer with non-invasive imaging and molecular techniques: Implications for rational combination therapies
Despite major advances in diagnosis and treatment, one in 25 Canadian women will die of breast cancer. Breast cancer patients whose tumours express (produce) high levels of the protein HER-2, in particular, have poor prognosis. This type of tumour is especially aggressive, metastatic, resistant to treatment, and has individual cells capable of withstanding adverse conditions in the tumour. HerceptinÂź, a drug that specifically targets HER-2, has shown remarkable results in some women with HER-2 overexpression; however, a significant number of women with this type of tumour do not respond to the drug. In order to identify aspects of HER-2 tumours that may have an impact on therapy, Dr. Mihaela Ginj is using a combination of non-invasive imaging methods to evaluate physiological functions in the tumour microenvironment, such as oxygen status, blood flow, and metabolism. This innovative study of tumour biology may enable physicians to monitor tumour response to therapy more rapidly and with greater specificity. This âpersonalizedâ approach for tumour treatment would maximize therapeutic effects and spare patients from side effects of treatments that may be ineffective. Findings from this study could have an impact on the clinical management of breast cancer in the near future.