The accumulation of mutations in the DNA of human cells can lead to tumour formation. More than 80 percent of solid tumours exhibit chromosome instability (CIN) – the property that results in an unequal distribution of DNA to each daughter cell upon cell division. The genetic instability associated with these tumours may allow them to adapt quickly and remain in the body.
Dr. Peter Stirling's research is focused on generating a comprehensive database of genetic mutations that lead to CIN, using the Baker's yeast cell model. The results will then be translated to related human genes. Using yeast to identify candidate human CIN genes has already been successful for a handful of genes and Dr. Stirling's project will extend this effort. The candidate CIN genes identified will provide important insight into the biology underlying tumour formation. Further, the results will validate interesting CIN genes relevant to cancer in human cells and provide greater understanding regarding the mechanisms of CIN for those genes.
Additionally, Dr. Stirling is also working to identify secondary genes whose mutations cause cell death in combination with a CIN mutation. By validating these "synthetic lethal mutant gene combinations" in human cells, Dr. Stirling will have defined drug targets for tumours carrying mutations in a particular CIN gene. And, working in collaboration with researchers at the University of British Columbia, Dr. Stirling will identify small molecules (i.e. drugs,) that selectively kill tumour cells based on the identified second-site mutations. Overall, the results will reveal new aspects of tumour biology, identify new anti-cancer drug targets and contribute to the development of new anti-cancer drugs.
Biochemical events in humans are influenced and triggered by cell signalling pathways and their associated feedback loops. Changes and mutations to members of these signalling pathways can cause cancer to develop. Trouble can also occur when alternative pathways are triggered or when built-in negative feedback (“”shut off””), loops are not triggered. In the case of cancer, the observed uncontrolled cell growth results in tumours that can eventually metastasize and send diseased cells throughout the body resulting in an aggressive, invasive cancer. Before the aggressive stage of cancer is reached, the disease often goes through stages of progressively worsening cancers. In breast cancer, Ductal Carcinoma In Situ (DCIS), is one such stage prior to invasive disease. With DCIS, the cancer is contained to a duct and has not yet spread to other areas of the breast or body. Research at the BC Cancer Agency’s Deeley Research Centre has revealed two proteins, S100A7 and Jab1, involved in a pathway associated with the transition from DCIS to invasive breast cancer. There is compelling evidence to suggest that if the interaction between S100A7 and Jab1 were prevented or disrupted, the critical signalling pathways would not be triggered and the progress of invasive breast cancer would be stopped. Amanda Whiting is researching the effects of blocking the interactions between S100A7 and Jab1 by using small, drug-like molecules. In particular, Ms. Whiting’s research uses the molecule 2,6-ANS, as the basis for modifications to improve binding to S100A7 and decrease binding to other important body proteins. Her research will provide an expanded understanding of small molecule binding requirements and, in turn, allow for appropriate modifications to the compounds. Moreover, her work explores a potential new target for breast cancer therapy using small molecule inhibitors to disrupt a cancer-associated protein-protein interaction.
Chronic Kidney disease (CKD), is relatively common among middle-aged and older adults and the incidence is increasing. For example, 119 million Canadians had CKD in 1996, while by 2004 that number had reached roughly 154 million. Furthermore, just under 1,000 people received kidney transplants in Canada in 2005, while three times that many remained on wait lists that year alone. Needless to say, the successful clinical management of CKD is dependent on a number of factors. Recently, Ms. Theone Paterson and colleagues have determined that cognitive abilities are impaired in patients with CKD following successful kidney transplant, in a similar way to that seen in patients with CKD prior to kidney failure. Importantly, they also recently found that difficulties completing both traditional and everyday cognitive problems are predictive of decreased medication adherence among renal transplant patients, and that depressive symptoms partially mediate the relationship between traditional cognitive performance and medication adherence. Therefore, the extent to which real world functional issues such as adherence is predicted by traditional and everyday problem solving, depression and self-efficacy is an important issue in renal transplant, for patients, their healthcare providers, and their caregivers. In her current research program, Ms. Paterson is focusing on the relationships among traditional and everyday measures of cognitive performance, general and medication adherence-specific self-efficacy, self-reported depressive symptoms and medication adherence in people who have undergone successful renal transplantation. The results of this work will aid not only in understanding difficulties faced by transplant patients, but also in the development of interventions designed to improve adherence and consequently, real-world functioning for these patients. Additionally, the results of this research will be used to develop sensitive and valid measures to assess real-world function in patients with CKD and ultimately improve their quality of life.
Diabetes mellitus is a chronic, debilitating disease in which the body is unable to adequately dispose of circulating glucose. As a result, diabetes mellitus causes damage to the eyes, kidneys, peripheral nerves and cardiovascular system. Type 2 diabetes accounts for about 90 percent of diabetes cases and is typically caused by the development of obesity with its associated resistance to the glucose-lowering actions of insulin, compounded by decreased circulating levels of insulin. Insufficient insulin levels in Type 2 diabetes are caused by the diminished function and increased death of the important insulin-secreting beta-cells located in the pancreas. Therefore, therapeutic interventions that improve the function and survival of beta-cells would clearly benefit patients with Type 2 diabetes. Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are insulin secreting (incretin) hormones that do just that. As a result, drugs have been developed that enhance the activity of these hormones and they have demonstrated powerful anti-diabetic actions in patients with Type 2 diabetes. Scott Widenmaier’s current research project is building on his earlier work involving the development of a long-acting GIP analogue that has demonstrated potent effects on cultured beta-cells, and triggered acute increases in insulin levels during single dose treatments of diabetic rodents. More recently it has shown potential to decrease fat levels in obese rodents. Mr. Widenmaier’s current project will evaluate the ability of long-term administration of this same GIP analogue to improve the function and survival of beta cells, and decrease circulating glucose levels and obesity in rodent models of Type 2 diabetes. Ultimately, the information resulting from these studies could contribute to a better understanding of the underlying basis for the beneficial effects of incretin therapy, and potentially lead to the development of next generation therapeutics.
In BC, child poverty has reached 22 percent (First Call, 2008), the highest provincial rate within Canada. BC is characterized by its ethno-cultural diversity, with 20 percent of all children having recently immigrated, and more than 50 percent of children in some urban school districts having English as their second language. Furthermore, BC has been affected by rapid economic, environmental and demographic changes. An understanding of how personal and contextual factors are associated with developmental patterns of resilience and vulnerability among the different communities and subpopulations of BC is important. More specifically, it is critical to identify to what degree developmental needs and strengths differ from one context and subpopulation to another, and in which ways these differences in needs and strengths are associated with the cultural and socio-economic characteristics of those different communities and subpopulations.
Dr. Guhn's research draws from a unique, population-level linked database that provides an unprecedented opportunity to examine the social determinants of developmental health and education of children in BC. By utilizing population-level data on health and education outcomes for 40,000 children, and data on socio-economic and demographic characteristics for all of the 478 neighbourhoods in BC, Dr. Guhn will provide a detailed analysis of how social, cultural, demographic, and socio-economic factors are jointly related to health and education trajectories of children in BC. His findings have important implications for further developmental health research as well as for practices and policies in health and education. Furthermore, his data will inform practitioners and policy makers in health and education with respect to the process of adapting health and education service delivery according to characteristics that are specific to particular subpopulations and communities.
A growing proportion of new HIV infections, both locally and globally, are among women of childbearing age, and heterosexual contact is an increasingly important risk of HIV transmission. While it is clear that HIV-positive women continue to desire children, become pregnant, and give birth after knowing their HIV-positive status, the reproductive health concerns and rights of people living with and/or affected by HIV have received little attention. Highly active antiretroviral therapy (HAART), the standard of HIV treatment in BC, is reducing the health risks and barriers to reproduction for people living with HIV. With appropriate adherence to treatment, HAART increases life expectancy, decreases morbidity, and dramatically reduces the risks of HIV transmission from mother-to-child and to sero-discordant sexual partners. Angela Kaida’s research seeks to describe the reproductive trends of HIV-positive women in BC’s “”HAART era”” (roughly 1996 and onwards) and to investigate the complex interplay between pregnancy, antiretroviral adherence, and HIV disease progression. Owing to the structure of HIV-related services and population-level data capture methods, BC provides an entirely unique and highly valuable environment in which to investigate critical questions related to HIV, HAART, and pregnancy. Notably, no other jurisdiction in the world has published population level findings on this topic. This research will provide evidence to guide the development of effective and responsive reproductive and sexual health services and policies for HIV-positive women in BC and beyond. These services are intended to support the rights of HIV positive women to be sexually active and achieve their fertility goals, while minimizing associated risks to maternal, fetal, and partner health. The findings will contribute vital information to the development of provincial, national, and international guidelines that support reproductive decision making among HIV-affected couples and inform the use of antiretroviral therapy during pregnancy.
Streptococcus pneumoniae is a common bacterium that can cause serious infections like acute respiratory disease (pneumonia), infections of the brain and central nervous system (meningitis), blood infections (septicaemia, sometimes leading to sepsis), and ear infections (otitis media). This organism is one of the leading causes of death from infectious disease across the globe. In addition to showing a lethal synergism with the influenza virus, many strains of S. pneumoniae are rapidly becoming resistant to antibiotics and some strains have even been dubbed “”superbugs. From the practical perspective of combating S. pneumonia, there is a clear need to better understand how it makes us sick. Numerous studies have revealed that the ability of this germ to cause disease strongly depends on it attacking the sugars present in its host’s tissues. Dr. Pluvinage’s work focuses on one protein that performs this type of function, a large enzyme called StrH, which is necessary for S. pneumoniae to infect its most commonly targeted human organs, the lungs and the ears. StrH is responsible for removing an abundant sugar (N-acetylglucosamine) from the surface of host cells and the protective sugar layers found in mucus. Though the activity of StrH is known, precisely how it performs its job is not. Consequently, Dr. Pluvinage is working to characterize the protein’s complex, three-dimensional structure in order to better understand the protein’s function. The results of this research will provide a foundation for generating new small molecular inhibitors that might allow for the effective treatment of infections caused by S. pneumoniae “superbugs”.
Type 1 diabetes mellitus (T1DM) is an autoimmune disease in which insulin-secreting islet beta cells of the pancreas are destroyed by a type of white blood cell called a T cell. While most people with T1DM must receive insulin injections to maintain proper blood glucose levels, a recent option for some patients is to undergo islet transplantation, which replaces the insulin secreting cells they have lost with new donor cells. However, the immunosuppressive drugs required to prevent graft rejection are costly and have serious side effects. Researchers continue to search for new methods to achieve long term transplant survival. T regulatory (Treg) cells have great potential to protect islet grafts from rejection. Treg cells are a subset of white blood cells with the capacity to suppress immune responses. It has been shown that a key protein named FOXP3 is essential for the development and function of Treg cells. T cells expressing this protein can reduce autoimmune disease and reverse established diabetes in mice. Researchers recently developed a method for converting human T cells into Treg cells. Alicia McMurchy is generating human Treg cells and testing their ability to inhibit graft rejection in a mouse model. Her prediction is that the generated Treg cells will inhibit graft rejection and allow long-term survival of transplanted islets. If validated, this approach could indicate a promising future for clinical use of Treg cells in transplantation, potentially alleviating the need for expensive and harmful immunosuppressive drugs and improving the health and quality of life of T1DM patients and other transplant patients.
Cardiovascular disease, and in particular, the atherosclerotic disorders, are the chief cause of illness, disability and death in many regions of the developed world, where they inflict very high personal, community and health care costs on society. Atherosclerosis, commonly referred to as hardening of the arteries, is an inflammatory disease and is the primary cause of heart attacks, strokes, lower limb loss in diabetics, aneurysms and chronic transplant rejection. Atherosclerosis results in the narrowing of arteries which leads to reduced blood supply, oxygen and nutrients to the affected tissues. Occasionally these plaques can rupture causing a complete blockage of blood supply which can be fatal if it occurs in the heart (eg. heart attack) or brain (eg. stroke). Damage to the inner lining of the blood vessel wall is believed to be the initiating event of this disorder but the mechanism(s) responsible for this injury remain unclear. In the current project, we are interested in how long term use of certain pain relief medications, referred to as anti-inflammatories, contributes to the generation of deleterious oxidative stress which can trigger the onset and progression of atherosclerosis. In recent years there has been much attention given towards this topic as certain pain remedies such as VioxxTM have been pulled off the shelves due to their association with increased cardiovascular events that occur with their chronic use. Based on our previous research, we believe we have identified an oxidative stress pathway that may be induced indirectly as a consequence of the chronic administration of these drugs. We have previously shown that a group of enzymes (CYP2C) can produce reactive oxygen during heart attacks which leads to the abnormal functioning of blood vessels. This dysfunctioning of blood vessels, which is also an early event in atherosclerosis, can be blocked with inhibitors, but it is not known whether CYP2C inhibition prevents atherosclerosis. The current proposal will investigate whether we can prevent atherosclerosis if we inhibit the activation of the CYP2C enzyme. We will also examine whether the administration of certain anti-inflammatories, known to increase cardiovascular events, increase the activity of CYP and reactive oxygen production. Finally, as many people depend on chronic administration of pain relievers such as these, we will investigate the effects of combined administration of CYP2C inhibitors and anti-inflammatory agents towards atherosclerosis pathogenesis. Results from these studies will help us to establish the role CYP2C in atherosclerosis and whether CYP2C inhibitors could be used as pre-emptive treatment for patients identified to be at a high risk for atherosclerotic disease
Stroke is the primary cause of adult disability in Canada. Recovering brain function after stroke is dependent on the brain’s ability to rewire itself and replace tissue that has died during the stroke – something that is difficult to achieve in the adult brain. Rewiring the brain requires that existing neurons sprout new fibres (axons) and connect to other neurons in a way that allows proper functioning of neural circuitry. Recovery also involves the birth of new cells to replace dead cells and to form functioning connections with new and existing neurons. These processes all occur within the extracellular matrix (ECM) – a network of fibrous proteins, gel-like sugars and linking molecules – and are promoted by a large number of growth factors and intercellular signalling molecules. Anthony Berndt’s research focuses on the role of the SPARC protein in the generation of new neurons. SPARC binds to the ECM and regulates the potency of growth factors that normally promote cell division and migration. Berndt is examining the influence of SPARC on the development of the embryonic brain and on the generation of new neurons in the adult brain. His studies will determine if SPARC’s presence or absence affects the rate or manner in which brain tissue regenerates after stroke. He hopes to formulate an approach that will prompt neural stem cells normally found in the adult brain to follow the developmental steps required to form functional tissue after stroke. By understanding the function of SPARC after brain injury, he could also determine at what point of recovery such an intervention would be of greatest use. By understanding the role of SPARC, Berndt’s research could eventually lead to improved therapies for treating major brain injuries by augmenting the body’s natural repair processes.
