In 2007, an estimated 22,300 Canadian women were diagnosed with breast cancer, and 5,300 women died of the disease. To kill cancer cells, breast cancer patients undergo combinations of surgery, drug therapies, chemotherapy, and radiation. In spite of these aggressive treatments, certain cancer cells may not be completely eradicated and tumours may start growing again (relapse). In the event of breast cancer relapse, the prognosis is generally much worse than it was at the initial onset of the disease, and available drugs eventually become ineffective. It has been discovered that in breast cancer, only a small group of cells – called breast cancer tumour-initiating cells – can keep growing for a long period of time, while the other “”regular”” cancer cells cannot sustain themselves long term. With a better understanding of these aggressive tumour-initiating cells, researchers could design new drugs that target this special group of cells, and focus less on the cancer cells that will eventually stop growing on their own. Preliminary evidence suggests that tumour-initiating cells require a protein called YB-1 in order to grow and form tumours. Studies also show that patients whose breast cancers produce YB-1 have a higher chance of relapsing. Karen To is investigating whether she can stop the growth of tumour-initiating cells by blocking the production of YB-1. If this particular factor is proven essential for the growth of the tumour-initiating cells, drugs could then be designed to remove this protein. To’s research will contribute to the understanding of the small group of breast cancer cells responsible for maintaining tumour growth. Ultimately, this knowledge could lead to improved ways to treat this devastating disease.
Cystic fibrosis and chronic granulomatous disease are both life-threatening genetic disorders. Cystic fibrosis is the most common life-shortening genetic disorder affecting Caucasians, with the median survival age being only about 37 years in North America. A genetic mutation results in the buildup of sticky, dehydrated mucus in the airways of the lungs, leading to an inability to clear many microorganisms. The resulting persistent infections gradually destroy lung function. Individuals with chronic granulomatous disease are also susceptible to chronic bacterial and other infections, because a genetic mutation impairs the protective functions of certain immune cells, causing them to be unable to effectively kill infectious organisms. A group of bacteria that commonly cause severe and fatal infections in these patients is the Burkholderia cepacia complex (BCC). These bacteria represent a significant threat because they are highly resistant to many antimicrobial drugs. Recently, researchers in Agatha Jassem’s lab discovered B. vietnamiensis bacteria, a member of the BCC, which are sensitive to a particular group of antibiotics called aminoglycosides. This presents an opportunity to undertake comparative studies between drug resistant and susceptible strains of the BBC. Jassem believes the outer cell wall permeability of the newly discovered B. vietnamiensis bacteria may be responsible for its susceptibility to the aminoglycosides group of antibiotics. To establish this, she is first evaluating the level of resistance of the B. vietnamiensis bacteria to a variety of antibiotics. Then, she is carrying out molecular studies of the outer cell wall of these bacteria to clarify the mechanisms that affect their permeability and thus their susceptibility or resistance to antibiotics. Ultimately, Jassem hopes her research will lead to the development of new therapies for treatment in cystic fibrosis and chronic granulomatous disease.
More than 180 million people worldwide have either type 1 or type 2 diabetes. People with this condition are unable to maintain normal blood sugar levels due to a lack of, or insensitivity to, insulin, a hormone that regulates blood sugar levels. Whereas type 2 diabetes is usually caused by eating an unhealthy diet, type 1 diabetes is an autoimmune disease in which the affected person’s own immune system destroys the insulin-producing islet cells in the pancreas. Research shows that killer T cells (immune cells that normally attack virus-infected cells) cause type 1 diabetes by destroying islet cells. However, there has been little research completed to date regarding what causes T cells to attack the body’s cells. It has been hypothesized that sensors that recognize microbes like bacteria and viruses, called TLRs (toll-like receptors), may play a role. TLRs activate the immune system to fight off microbes; however, TLRs are also suspected of playing a role in the onset of type 1 diabetes. Andrew Lee is investigating whether a group of TLRs activate or accelerate the destruction of healthy cells in autoimmune diseases. Lee will also determine whether older, anti-malaria drugs and new designer DNA drugs can block these TLRs. Since symptoms of type 1 diabetes only appear when the pancreas is irreversibly damaged, this research could be used to identify people at risk of developing type 1 diabetes, and lead to new ways of preventing and treating the disease.
Autism spectrum disorders (ASDs) affect more than one in 250 people and are characterized by significant impairments in social interactions and communication as well as inappropriately focused behaviours and restricted interests. Research involving sibling, twin and family studies has revealed the predominant role of genetic factors in ASDs and also identified regions in chromosomes where genes conveying susceptibility to ASDs might be located. Furthermore, recent studies have shown that chromosome anomalies can be found in five to 28 per cent of persons with ASDs, depending on whether they have cognitive delay and/or physical anomalies. Noemie Riendeau is exploring the genomic changes and molecular genetics underlying ASDs, as well as their clinical presentation and associated genomic syndromes. She is using a genome screening method known as Comparative Genomic Hybridization (array-CGH) to detect small chromosomal imbalances called microdeletions and microduplications in people with autism. The hope is that identifying these imbalances will help pinpoint genomic regions where genes associated with Autism Spectrum Disorders (ASDs) are located. The research also investigates how these genomic changes correlate with the clinical phenotypes of the patients, especially those with dysmorphic features and/or intellectual disability, but also for those cases described as simple autism. By defining new microdeletion and microduplication syndromes, this research will contribute to a better understanding of the genetic basis of ASDs and potentially to improved methods for early detection and treatment.
DNA, which is packaged into highly condensed structures in the cell, carries genetic information that is passed from one generation to the next. Chromatin is the first level of DNA packaging that eventually results in the formation of chromosomes – threadlike parts of a cell that carry hereditary information in the form of genes. Many debilitating and life-threatening diseases, such as cancer, neurodegenerative diseases including Alzheimer’s and Huntington’s, and inherited childhood syndromes, result not only from changes in the basic DNA sequence, but also from changes in the structure of chromatin. DNA is condensed into chromatin with the help of DNA-packaging proteins called histones. DNA wraps around eight core histones – two each of H2A, H2B, H3, and H4 – to assemble into chromatin. H2A.Z is a variant of the core histone H2A that is conserved through evolution. Structurally, H2A.Z is different toward the end of the protein. A large protein complex called SWR1-Com, which binds to H2A.Z but doesn’t bind H2A, deposits H2A.Z into chromatin. Alice Wang is researching the differences between the way H2A.Z and H2A are deposited into chromatin. She is specifically investigating whether the difference between H2A and H2A.Z lies in their different binding capabilities to SWR1-Com. The findings will help increase understanding of H2A.Z biology and how chromosomal neighbourhoods containing H2A.Z are made. Wang’s ultimate aims for the research is to contribute to development of therapies for diseases that result from changes in chromatin structure.
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 protein’s 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.
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 – 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.
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.
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. Ochnio’s 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.
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 doesn’t 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.