More than 50 million people worldwide suffer from epilepsy. Approximately 90 percent of those treated with current drugs experience significant side effects, and around 30 percent do not respond to current medical treatments at all. Therefore, significantly better treatments are required to improve the quality of life for epilepsy sufferers in Canada and worldwide. To achieve this, a far greater understanding of how the brain works both normally and during seizures is necessary.
Epilepsy is a difficult disorder to study in humans; however, in the 1980s, a strain of rats that naturally suffer from a type of seizure very similar to the human condition and involving the same brain regions was identified. These rats are extremely useful in helping us understand the causes of epilepsy in humans and test new drugs being developed to treat epilepsy. Two years ago, Dr. Stuart Cain’s research characterized a newly discovered genetic mutation in the epileptic rat strain responsible for a large portion of seizures. Epileptic seizures can be caused by changes in the way certain brain nerve cell proteins, known as "calcium channels," conduct electricity — the mutation characterized by Dr. Cain alters the way in which a specific type of calcium channel conducts electrical signaling. This was significant as these particular calcium channels are able to generate patterns of electrical pulses, known as “firing patterns,” predicted to contribute to epileptic seizures.
Dr. Cain’s research project aims to determine how the calcium channel mutation alters communication between nerve cells and affects different firing patterns. His laboratory is the only site in North America currently studying the epileptic rat strain. Understanding what causes the firing properties of epileptic nerves to change during seizures should allow the design of new drug treatments with the ability to block these changes directly, and to also reduce side effects compared to many of the broad-target drugs currently used clinically.
Performance in the health sector has conventionally been viewed in terms of volumes, such as the number of additional surgeries that were performed in a given year. Unfortunately, health status and outcomes are not routinely assessed in Canada. This is a substantive concern — imagine the case where your car manufacturer's performance metric did not include car safety and performance but merely focused on production volume. Health status is a more appropriate outcome than volume for assessing system performance, and understanding variation in performance of the health system provides the opportunity to improve patients’ health-related quality of life. This study aims to develop a system to assess the performance of the health care system by measuring what it produces in terms of "health," such as health-related quality of life rather than only measuring the "production of health care" — for example, surgical volumes.
Dr. Jennifer Davis' research will address the use and analysis of “performance metrics” within health care, with a particular focus on patient-centred and outcome-based measures using Patient Reported Outcome Measures (PROMs). PROMs are detailed surveys that allow patients to report important changes as a result of a medical intervention and allow the assessment of health-related quality of life. Thus, instead of just measuring that a surgery took place, PROMs measure the patient’s perception of how the surgery has improved their life.
Dr. Davis will be applying knowledge from fields outside the health care sector, such as engineering and education, to improve performance assessment within the health care sector. By determining how specific measures improve performance outcomes in other fields, and by identifying which of these are most effective, she will then specifically determine the potential to adapt these measures as PROMS within the health care context to enhance the health of Canadians. This critical platform will enable the first performance assessments using a patient-centred and outcome-based approach in Canada.
Ovarian cancer is the most lethal cancer of the female reproductive system and the fifth leading cause of cancer-related death in Canadian women. Ovarian cancer is not one disease, but rather comprises several tumour types that likely develop through unique mechanisms from different cell types. Previous research suggests two types of ovarian cancer — clear cell carcinoma (CCC) and endometrioid carcinoma (EC) — may develop from ovarian endometriosis, a condition associated with increased inflammation. Dr. Alicia Tone is investigating how endometriosis-associated inflammation can influence the development of CCC and EC by looking at the specific role that the ARID1A gene plays in inflammation. ARID1A has been shown to increase the activity of the glucocorticoid receptor, which plays a crucial role in reducing the duration and intensity of an inflammatory response. In addition, the ARID1A gene was recently found to be mutated in both CCC/EC, and the mutated gene is associated with endometriosis lesions. Dr. Tone intends to 1) identify which specific inflammatory genes are altered in CCC/EC cells and associated endometriosis; 2) compare the response of cells obtained from endometriosis and CCC specimens with and without mutations in the ARID1A gene; and 3) determine the mechanism by which ARID1A regulates the response to inflammatory mediators. This study will help our understanding of how endometriosis may develop into ovarian cancer (CCC and EC); more importantly, pointing to the development of new preventive strategies. Research aimed at understanding what is involved in the early stages of development of these different cancers may reduce the number of deaths associated with ovarian cancer.
Myelodysplastic syndrome (MDS) is one of the most frequent bone marrow malignancies, affecting around 1,500 Canadians every year. It is characterized by anemia and a high risk of transformation to acute myeloid leukemia (AML). The only curative option is bone marrow transplantation, which carries high mortality and morbidity. Other standard treatment modalities such as lenalidomide and 5-azacytidine are characterized by a short response and a high degree of relapse. The molecular causes of treatment resistance and disease transformation in this situation are not fully understood. Dr. Martin Jadersten aims to investigate the genetic changes associated with initiation of MDS and understand how these changes contribute to subsequent therapy failure or disease progression. He will investigate serial samples from 10 MDS patients before and after leukemic transformation. RNA and DNA will be extracted from bone marrow cells and marrow fibroblasts (non-malignant control cells), and global genetic investigations such as exome (DNA), transcriptome (RNA) and micro RNA (regulatory RNA) sequencing will be conducted. Powerful bioinformatics methods will be used to analyze the data and identify genomic alterations, including gene fusions, DNA insertions/deletions, and alternative expressions of genes (isoforms). These identified genetic alterations will be validated for recurrence in a large group of MDS patients, and candidate genes will be tested functionally with cell line experiments and mouse models. Dr. Jadersten’s work is already well underway. He has processed three samples from one MDS patient with all of the methods above and has shown that there are significant changes in micro-RNA expression between these time points. As the disease has progressed in this patient, a number of alternatively expressed genes appear, which potentially indicates alterations in the RNA-splicing machinery. By the time the patient develops AML, there is almost a complete loss of two clusters of important regulatory genes involved in embryogenesis and cancer. As this patient sequentially received the only two registered drugs for MDS (lenalidomide and 5-azacytidine), Dr. Jadersten will attempt to determine potential resistance mechanisms using the data already obtained. Identification of key mediators of disease development, leukemic transformation and drug resistance may sharpen our prognostic tools, improve clinical management and provide a basis for development of targeted therapy.
Type 2 diabetes currently affects 2.5 million Canadians. Elevated blood cholesterol levels increase the risk of developing diabetes. Scientists are starting to understand the molecular basis of diabetes and have recently discovered that a deficiency of the ABCA1 molecule, a transporter that removes cholesterol from cells, leads to the accumulation of cholesterol in the insulin secreting-beta cells in the pancreas. This cholesterol accumulation leads to impaired insulin secretion and contributes to diabetes. Therefore, influencing the levels of ABCA1 molecules in beta cells may help control both cholesterol and diabetes. The objective of Dr. Nadeeja Wijesekra’s research is to discover new ways to regulate ABCA1 levels in beta cells in order to improve beta cell function and survival. Her project involves the use of small molecules called microRNAs to regulate ABCA1 levels in mouse beta cells. She will identify specific microRNAs that regulate ABCA1 levels in beta cells and determine how they influences beta cell function by measuring insulin secretion and changes in cholesterol levels. Furthermore, these microRNAs will be used in diabetic mouse models to assess whether their disease condition can be improved. Since increased ABCA1 has been shown to have a positive impact on beta cell function, finding ways to increase ABCA1 levels in these cells may be helpful in ameliorating beta cell defects present in diabetes. Thus these studies are the first to outline a therapeutic strategy to modulate cholesterol in beta cells in order to improve whole body glucose homeostasis.
An estimated 86,500 people are currently living with spinal cord injury (SCI) in Canada, and approximately 4,300 more will experience SCI each year. In persons with SCI, the bladder can't receive or send the signals required for normal organ function, and 80 percent of persons with SCI are affected by acute or chronic urinary tract complications that negatively influence their health, quality of life and impact their life expectancy. Currently, evaluation of bladder function is limited to periodic urodynamic testing (UDS), an invasive procedure that requires patients to have catheters inserted into the urethra and rectum. Besides being a painful and inconvenient procedure, the invasive nature of this diagnostic method exposes patients to the risk of serious complications such as urinary tract infection, trauma and bleeding that may further complicate urinary tract conditions. Dr. Babak Shadgan is investigating the use of near-infrared spectroscopy (NIRS) as a novel non-invasive diagnostic method to evaluate the physiologic mechanisms underlying bladder dysfunction in people with SCI. Detecting when the bladder has filled to a given volume or size is essential to avoid accidental incontinence and also to prevent damage to the kidneys from backpressure secondary to a full bladder. NIRS is a non-invasive optical technique that uses light to monitor changes in tissue oxygenation and changes in blood supply to the bladder as the organ fills and empties. Using NIRS for bladder monitoring in this population will demonstrate both scientific relevance and commercial potential and will lead to the development of an NIRS device capable of more effective, more comprehensive, and safer evaluation of bladder dysfunction than current methodologies. The health care burden associated with bladder dysfunction secondary to SCI is considerable; hence, the further development of NIRS for monitoring devices and diagnostic techniques for persons with SCI has potential to reduce complications associated with current invasive tests and improve the standards of care in this population.
Between 2005 and 2009, more than 16,000 infants in British Columbia were born prematurely. Prematurely born infants are at increased risk for developing motor problems that, in many cases, significantly interfere with daily life and school performance. This degree of motor difficulty is often referred to as developmental coordination disorder, or DCD. Children with DCD struggle with many typical tasks, such as tying shoes, riding a bike, handwriting or participating in sports. While it was once believed that children with DCD would outgrow their motor difficulties, studies have shown that these difficulties can persist into adolescence and adulthood. In addition to physical concerns, children with DCD experience other issues, including difficulty with social and peer relationships, lower self-worth and self-esteem, anxiety and depression, and other emotional health concerns. Thus, there is an urgent need to develop rehabilitative therapies to prevent these lifelong complications.
Dr. Jill Zwicker's research program focuses on understanding how the process of early brain development influences motor-skill development. Previous work suggests that DCD may be caused by abnormal brain development, but this has yet to be confirmed. Dr. Zwicker, an occupational therapist with a clinical and research interest in DCD, is using different brain-imaging techniques and is collecting information about health and treatments from a group of 175 premature infants. The babies will have a brain scan in the first few weeks after birth and will have a second scan around the time they would have been born, had they made it to full term. Measurement will be used to compare brain development between these two points in time.
Dr. Zwicker suspects there may be a relationship between brain development and exposure to pain, and that these factors may affect motor development, so she will also gather information about the number of skin-breaking procedures (for example, needle pokes) that the infants receive. In addition, her research team will collect information about other factors that may influence brain and motor development, including medications received, days on oxygen, illness severity, infection, and lung disease.
By having a stronger understanding of the factors that contribute to the development of DCD in children born prematurely, Dr. Zwicker hopes her research will help prevent poor motor outcomes and help develop new therapies to improve motor and functional outcomes for children born prematurely.
Although cure rates for childhood cancer now exceed 80 percent, many childhood cancer survivors will experience long-term effects of both their cancer and its therapies. These long-term effects may be medical, emotional or psychosocial and can include second cancers, neurocognitive deficits, reproductive challenges and mental illness. For these reasons, follow-up health care for young cancer survivors is recommended and should include screening for second cancers, surveillance and management of physical and psychosocial late effects of cancer and treatment, and promotion of psychosocial adjustment.
Despite these recommendations, the majority of adolescent and young adult cancer survivors are lost in transition from pediatric to adult follow-up care; at the age of 19 years, cancer survivors in BC are no longer cared for in the children's system and are advised to obtain follow-up care from a family physician who manages adults. Yet, some adolescents and young adults do not have a family physician, and still others are unaware of their heightened risk for second cancers and late effects stemming from cancer treatments. Moreover, the delivery of health services varies widely across urban, rural and remote areas of British Columbia, undoubtedly resulting in differences in medical and psychosocial needs.
Dr. Fuchsia Howard's work will determine the medical and psychosocial needs of cancer survivors in their adolescent and young adult years. First, she will determine the specific medical and psychosocial issues faced by these survivors and what their experiences are in managing and obtaining assistance with these issues. The second objective of this study is to determine health care professionals' experiences and challenges in providing medical and psychosocial services to these cancer survivors. The third objective will be to engage cancer survivors and health care professionals in the exchange and translation of knowledge to lead to health service recommendations and interventions tailored to benefit this high-risk population. Young adulthood, in particular, is a stage of development involving many life-related changes, including decisions about education, employment, relationships and family that can be severely affected by the late effects of cancer.
Ultimately, this work will contribute to a comprehensive program of research focused on understanding and addressing the unique needs of high-risk patients throughout the cancer trajectory, from prevention to survivorship. Addressing medical and psychosocial challenges in the transition from adolescence to young and middle adulthood is key to bolstering the formative years that promote, or limit, lifetime potential.
Each human cell contains instructions — in the form of genetic material or the genome — to direct its growth, function and death. The genome is made up of three billion molecules called nucleotide pairs, which are joined in a specific sequence. Sometimes the nucleotide sequence in a cell’s genome can become altered, or mutated, and these mutations can lead to changes in the cell that cause cancer. The spread of cancer cells from the primary tumor is known as metastasis. Relatively little is known about the mutations in the genome that create, control and direct metastasis. Next-generation sequencing allows researchers to rapidly “read” the sequence of the three billion nucleotide pairs in the genome of cancer cells. Using this technology, Dr. Jill Mwenifumbo aims to identify the sequence mutations that are unique to, and perhaps essential for, colorectal cancer metastasis. Ultimately, discovering the genetic mutations that drive metastasis will help identify potential drug targets, which will lead to more effective treatments for this disease. Given that colorectal cancer is the second leading cause of cancer death in Canada, effective treatment has enormous potential to improve personal and population health.
