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.
Program: Trainee
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.
Functional characterization of the chorea-acanthocytosis gene VPS13A in the yeast Saccharomyces cerevisiae
Many diseases such as cancer, atherosclerosis (narrowing and hardening of the arteries) and neurodegenerative disorders stem from problems with the uptake, transportation, storage and recycling of molecules. Proper sorting is necessary for normal cell function since many molecules are only required in specific areas or compartments of the cell. In the case of neurodegenerative disorders, defective protein sorting in nerve cells can lead to brain tissue deterioration. Disease caused by abnormal protein sorting can be studied in very simple organisms such as yeast, and the findings directly applied to human cells. Dr. Leslie Grad is researching a yeast protein, Vps13, which is very similar to a protein encoded by the human gene VPS13A. Defects in this gene can lead to chorea acanthocytosis, a neurodegenerative disorder associated with abnormal red blood cells, epilepsy, and muscle and nerve cell degradation leading to premature death. The findings could provide insight into the complicated mechanisms that regulate sorting of molecules inside cells and explain the molecular function of Vps13. Ultimately, Dr. Grad hopes to apply his findings to human cells and contribute to the development of therapies for neurological disorders caused by abnormal protein sorting.
To define the role of caspases and caspase cleavage of htt in the pathogenesis of HD
Research has identified a genetic defect in the HD gene that causes Huntington’s disease, a devastating and ultimately fatal neuropsychiatric disease. Symptoms include progressive deterioration in the ability to control movements and emotions, recall recent events or make decisions, and leads to death 15 to 20 years after onset. One in 10,000 Canadians has HD. There is neither a cure nor treatments to prevent Huntington disease. Several years ago Dr. Hayden and his team discovered that huntingtin, the protein involved in Huntington disease (HD), is cleaved by âmolecular scissorsâ which are proteins called caspases. This discovery led to the hypothesis that cleavage of huntingtin may play a key role in causing HD. To explore the role of huntingtin cleavage in the disease process, we established an animal model of HD that replicated the key disease features seen in patients. A unique aspect of this particular animal model is that it embodied the human HD gene in exactly the same way seen in patients. This replication allowed researchers to examine the progression of HD symptoms including the inevitable cleavage of the mutant huntingtin protein. Dr. Rona Graham is continuing her earlier MSFHR-funded research into understanding the reason why the mutant form of the HD gene causes death of particular neurons in the brain. Her Masters and PhD work demonstrated that preventing cleavage of the mutant huntingtin protein responsible for HD in a mouse model, the degenerative symptoms underlying the illness do not appear and the mouse displays normal brain function. Dr. Grahamâs goal now is to investigate the role of caspase activation and the caspase-6 cleaved huntingtin fragment in the disease process. Since a similar splitting of disease proteins is involved in many other central nervous system diseases including Alzheimerâs and Spinocerebellar ataxia (which causes progressive deterioration in hand, speech and eye movement) Dr. Graham hopes the findings will lead to new treatments for other neurological disorders as well as HD.
A molecular basis for replacement tooth formation in reptiles
There are a great number of genetic diseases that affect tooth number in humans. Ectodermal dysplasia (ED), for instance, is characterized by a reduction in the overall number of teeth (i.e., hypodontia). In contrast, people with cleidocranial dysplasia (CCD) may form dozens more teeth than normal. In both disorders, only the secondary generation of teeth (‘adult teeth’) is affected, while baby teeth are largely unaffected. Since conventional mammalian lab models, such as the rat and mouse, form only a single generation of teeth during their lives, they can tell us little about the molecular cues controlling tooth replacement. For this reason, Dr. Gregory Handrigan has turned to an unusual animal model: reptiles. Like humans, reptiles form multiple generations of teeth throughout their lives. As part of the first research to directly address the molecular control of generational tooth formation, Dr. Handrigan is identifying genes from reptiles such as the python and bearded dragon that underlie their ability to continually form new teeth. Given the overwhelming similarity in tooth development between reptiles and mammals, these genes are likely to be performing comparable roles in humans. Handriganâs research could then generate important knowledge about the molecular control of tooth number in human development as well as for diseases like ED and CCD. Ultimately, his findings may provide a foundation for strategies to regenerate lost teeth in humans.
Measurement error issues in studying the effect of gene-environment interactions on disease risks
Complex diseases, such as different types of cancers, are influenced by genetic and environmental factors and their interactions. There is overwhelming evidence that the effects of environmental factors on most cancers are modified by individual genetic characteristics. The accuracy of assessing the effects of gene-environment interactions on disease risks depends on how accurately the exposure to environmental factors can be measured or how accurately genetic makeup can be classified or both. Measurement error or misclassification can seriously distort the true effects of gene-environment interaction and produce biased estimates of the effects. Dr. Shahadut Hossain is developing a flexible modeling approach to adjust for biases when some of the quantitative environmental exposures are measured inaccurately. Hossain is also working to extend this methodology so that it can incorporate both exposure measurement errors and gene misclassification. His research involves studies of non-Hodgkin lymphoma, ovarian cancer and prostate cancer conducted with the Cancer Control Research Program at the BC Cancer Agency. Hossain hopes his work will enable the assessment of gene-environment interactions to be done more precisely, contributing to a better understanding of the effects of these interactions and more effective intervention strategies to prevent these diseases.
A Preliminary Study to Assess and Develop a MĂ©tis Community Readiness Model and Indicators of Success
MĂ©tis in BC and Canada have significantly lower health status than the general population. Arthritis, high blood pressure, diabetes and stomach problems are common chronic conditions among the MĂ©tis population. Currently, the BC health care system addresses MĂ©tis health issues within the mainstream system of care â a system that lacks the resources and guidelines to address culturally and regionally specific health issues. Consequently, there have been calls for MĂ©tis-specific health services. The provincial organization, MĂ©tis Nation BC (MNBC), has recently begun working with MĂ©tis communities to plan and deliver MĂ©tis-specific health programs and services. The Community Readiness Model (CRM) is a method for assessing and planning culturally valid strategies in communities that takes community resources, attitudes, and experiences into consideration. Dr. Peter Hutchinson is collaborating with MNBC and Okanagan MĂ©tis Child and Family Services to assess the CRM and identify indicators of success for social services. Dr. Hutchinson will present the model to community members and MĂ©tis social service providers to gather suggestions for adapting it for MĂ©tis communities. In addition, Dr. Hutchinson will work with his MĂ©tis partners to identify indicators for gauging the success of MĂ©tis-specific health services, determining the Okanagan MĂ©tis communityâs priorities for specific health issues, and developing a proposal to pilot test the CRM. Ultimately, this research will improve health in MĂ©tis communities by enhancing health delivery and increasing access to services.