Lung cancer is one of the largest health burdens worldwide: in Canada alone, lung cancer causes more cancer-related deaths than breast, colon, and prostate cancers combined. Smoking cessation programs have been highly successful, and the population of former smokers in Canada is well over seven million. Unfortunately, while quitting smoking is a proactive step, former smokers are still at risk for developing lung cancer. This cancer risk in former smokers will remain one of Canada’s most significant health concerns for the next 50 years. The molecular mechanisms responsible for the development of lung cancer in former smokers are not known. Recent studies have shown that although the majority of smoking-induced genetic damage returns to normal after smoking cessation, some genes are permanently damaged and never return to the pre-smoking state. Some of these irreversible genes are likely those that act as the gatekeepers for cancer development. Dr. Ewan Gibb’s research project will identify the genes in former smokers which do not return to normal after smoking cessation. He will be using integrative genomics to compare samples from former smokers with cancer and those without. This information will help Dr. Gibb understand why some former smokers go on to develop lung cancer while others remain cancer-free despite similar changes in lifestyle. This set of irreversibly damaged genes can serve as novel targets for anticancer therapies or may be developed as diagnostic markers for early detection of lung cancer while therapies are still effective.
Program: Trainee
Beyond VO2peak: Understanding exercise-induced in cardiovascular function after stroke
Stroke is the leading cause of neurological disability in Canada. Most stroke survivors have a number of other related conditions, including heart disease, diabetes, obesity and high blood pressure, which contribute to their risk of additional strokes. Exercise not only improves fitness, it also has the potential to reduce the risk of heart disease and stroke.
Dr. Ada Tang is working to understand how aerobic exercise can influence stroke risk factors and heart and arterial function in those who have already had a stroke. She will be evaluating the effects of an exercise program on 51 participants between the ages of 50 and 80, all of whom are one-year post stroke and can walk short distances without help. Participants will be randomly assigned to either an aerobic exercise program, or to a balance and flexibility program. Both programs are conducted at Vancouver General Hospital and feature three one-hour sessions per week. Program participants are carefully monitored during their exercise sessions. The participants’ fitness level and blood pressure will be tested at the start and the end of the six-month exercise program and two months after the end of the program to see if the benefits are maintained. Echocardiograms will be performed to look at heart size and function, blood tests will measure cholesterol levels and other signs of inflammation, and other tests will be done to determine how exercise can improve artery flexibility, heart rate and rhythm.
This study will help us better understand how exercise after stroke can improve heart function and heart health. Research results will help health professionals understand the best way to promote a healthy lifestyle after stroke to lower the risk of heart disease or another stroke.
Mutational drivers of metastatic colorectal cancer
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.
Health Service Needs of Adolescent and Young Adult Survivors of Childhood Cancer
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.
Relationship of Neonatal Pain and Early Brain Development of Preterm Infants on Motor Outcomes at 18 months
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.
Near infrared spectroscopy of the bladder: Novel application for evaluation and monitoring of bladder function in patients with spinal cord injury
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.
The role of ABCA1 and microRNAs in the regulation of beta cell function
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.
IL7R signalling in lymphocyte development and function
Serotonergic mechanisms underlying sex differences in stress neuroendocrine function
Depressive disorders are a leading global cause of disability. Although the incidence of depressive disorders is two-fold higher in women compared to men, the neurobiological basis for this disparity is unknown. Depressive disorders are often characterized by elevated blood levels of the glucocorticoid steroid hormone, cortisol. In both humans and rodents, females secrete greater levels of glucocorticoids than males in response to stress, which may at least partially explain the increased rates of affective disorders in women.
Dr. Nirupa Goel's research aims to elucidate the mechanisms behind the gender differences in stress responses. Previous studies suggest that deficits in serotonin neurotransmission may be a central cause for the increase in glucocorticoid secretion in depression. Most of these findings, however, come from research using male subjects. A critical first step for Dr. Goel is to identify how serotonin contributes to the gender difference in stress responses. The results of her preliminary studies indicate that blocking the serotonin 1A receptor reduces the glucocorticoid response to stress and that this effect is larger in male than in female rats. In brain tissue from the same animals, there were marked gender differences in stress-induced neuronal activation of the serotonin-producing dorsal raphe nucleus and of forebrain regions that regulate glucocorticoid release.
Based on the strength of her initial findings, Dr. Goel will further examine how stress, gender and serotonin intersect in the brain. To do this, she will measure biochemical markers of serotonin function in male and female rats under basal conditions and in response to repeated stress exposure. She will use serotonin receptor blockers to determine which receptors are involved in the gender differences in stress adaptation. Overall, these studies will elucidate the mechanisms by which serotonin mediates sex differences in stress responses. The findings have realistic clinical implications for discovering individual and sex-based differences in the development and potential treatments of affective disorders.
Investigating the role of endometriosis-associated inflammatory signalling in ovarian clear cell carcinoma development
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.