Inflammation is a protective response generated by immune cells against infection. However, when inflammation becomes unregulated within the body, it can cause diseases. A key anti-inflammatory regulator of immune cells is a cytokine (a type of hormone), called interleukin-10 (IL-10). The importance of IL-10 in regulating immune cell function is illustrated by the fact that many tumour cells and intracellular pathogens produce or elicit production of IL-10 for their survival. A main target of IL-10 is macrophages. Activation of macrophages by interferons, or bacterial cell products such as lipopolysaccharide (LPS), induces a number of immunologic responses including production of pro-inflammatory mediators such as the cytokine TNF. IL-10 is able to suppress these events by interfering with pathways utilized by LPS, but its mechanism is unclear. Previous research on the intracellular signal transduction pathways utilized by IL-10 has shown that an important component is a protein called SOCS3 which is thought to target specific proteins for degradation. In order to understand how IL-10 uses SOCS3 to inhibit macrophage activation, Tsz Ying Sylvia Cheung’s research is focusing on proteins that interact with SOCS3 in cells stimulated with IL-10. Identification of these proteins will allow for a further research focus on understanding the role they play in macrophage activation and why they are targeted by IL-10. Developing a clear understanding of the mechanism by which IL-10 regulates the network of intracellular signal transduction pathways will better enable the development of therapeutics mimicking the beneficial anti-inflammatory effects of IL-10, and allow for the development of strategies to counter the immunosuppressive effects of certain tumours and immune cell pathogens.
Program: Trainee
Probing the gastrointestinal microbiota for microbial determinants of asthma
Allergic asthma affects over 100 million people worldwide and more than 20 percent of Canadians. Furthermore, it is increasingly prevalent among people living in industrialized countries. While the underlying cause(s) of asthma remain unknown, there is increasing evidence to suggest that the intestinal microbiota (normal flora) plays an important role in the development of atopic diseases. Data from several large birth cohort studies have indicated that there may be a strong association between alterations in the intestinal microbiota as a result of antibiotic use and increases in the incidence of allergy and asthma in young children. However, the role of the intestinal microbiota in asthma has not yet been explored experimentally, and no attempts have been made to identify microbial species that may be associated with or hinder the development of asthma. Consequently, Shannon Russell is researching how changes in the composition of the intestinal microbiota may induce changes in asthma susceptibility. She is doing a series of experiments designed to determine whether antibiotic treatment during the early stages of life may alter or delay normal immune development and predispose a person to allergic-type diseases like asthma. This research could establish entirely new roles for the intestinal microbiota and may ultimately aid in the development of novel therapies (e.g. probiotics, prebiotics, narrow spectrum antibiotics), to treat or prevent allergic diseases including asthma.
Job accommodations: Perspectives from people with bipolar disorder
Bipolar Affective Disorder (BD), also known as ‘manic depression,’ is a chronic, often recurrent condition that affects more than half a million Canadians. It is characterized by changes in mood and behaviour, which range from elevated, euphoric and irritable (mania), to sad, withdrawn and hopeless (depression). While symptoms such as depression and euphoria can be controlled to some degree by medications, they can still result in significant challenges for individuals living with the disorder. Several studies have shown an association between BD and impairment in social roles such as work. Notably, people with BD rate work as the role most important to their quality of life, and the ability to maintain financial independence and contribute to the social fabric of our world is tied to how people work. Consequently, satisfactory employment is associated with improved health outcomes. However, the ability of people with BD to engage in work varies widely. Symptom recovery from an episode of BD occurs before functional and occupational recovery, which suggests factors beyond clinical symptoms can influence a person’s capacity for employment. In her research, Sandra Hale is exploring both formal and informal job accommodations with a view to improving employment outcomes for people with BD. Formal accommodations are defined as changes made to job structure and/or demands, documented by employers, disability management or vocational rehabilitation services. Informal accommodations are defined by the person with BD to address workplace issues or job demands. The results of Ms. Hale’s project will be shared with health care providers and mental health organizations and may help inform policy promoting access to information about job accommodation for people with BD.
Role of ionotropic glutamate receptors in ischemic injury and dendritic spine dynamics
Inadequate blood supply (ischemia), resulting in neuronal cell death caused by stroke, cardiac arrest or profound hypotension is a leading cause of death and permanent disability. Brain damage resulting from ischemic injury typically manifests as the immediate loss of neurons within the ischemic core, surrounded by a region of brain tissue exposed to reduced blood flow and oxygen called the penumbra or peri-infarct region. This peri-infarct region has been the target of therapeutic protection following ischemic insult (e.g. stroke), and is thought to play a potentially critical role in functional recovery following stroke. Although the precise mechanisms of underlying delayed neuronal cell death are multi-faceted, the over-activation of N-methyl-D-spartate receptors (NMDARs), is known to have a key role in mediating neuronal injury in both in vitro and in vivo models of stroke and traumatic brain injury. Dr. Allen Chan is examining the role of selective NMDAR activation and blockade on dendritic spine dynamics immediately following a focal ischemic stroke, with the aid of established pharmacological treatments and in vivo brain imaging techniques. Dendritic spines are hypothesized to be key structural substrates within the penumbra that mediate plasticity changes necessary for functional recovery after stroke. Dr. Chan’s project will increase our understanding of the mechanisms and pathology of stroke injury with respect to the damage and death caused to pivotal brain cell connections called synapses, and ways to potentially alleviate this damage and death. In so doing, rescue and protection of damaged but repairable parts of the brain may lead to treatments that enhance functional recovery and therapies that directly impact patient health and quality of life.
Understanding the influence of early childhood sexual trauma and resiliency on health outcomes among young Aboriginal people who use drugs in British Columbia
Recent research has determined that young Aboriginal people who have been sexually abused and who use drugs are at greater risk of several negative health outcomes including Human Immunodeficiency Virus (HIV), infection. It is now well recognized that building resiliency is fundamental to the success of traditional Aboriginal health care practices and that cultural buffers may moderate vulnerability. There are a number of aspects to building resilience including attending to the mind, the body, the emotions and the spirit and, notably, there may be gender and age-related differences in resilience dynamics. Consequently, focused research is required to develop practical theories of resiliency and targeted interventions that will address trauma and facilitate stress coping among Aboriginal young people. To that end, Margo Pearce is investigating specific questions about the role that historical trauma and protective factors have with respect to vulnerability to HIV and hepatitis C (HCV) among young Aboriginal people in BC. She is utilizing existing data from the Cedar Project, an ongoing initiative funded by the Canadian Institutes of Health Research that monitors HIV and HCV risk among 600-1000 young indigenous people aged 14-30 who use injection and non-injection drugs. She is analyzing gender differences in health outcomes over time related to early childhood trauma amongst the Project participants. Ms. Pearce’s work will provide a better understanding of the protective factors that prevent specific adverse health outcomes among young Aboriginal men and women. Furthermore, it will address trauma and protective factors from a global public health policy perspective.
Exercise Intensity Prescription in Breast Cancer Patients Undergoing Chemotherapy Treatment
Most people today know someone affected by breast cancer. The statistics are startling, one in nine women is expected to develop breast cancer during her lifetime, but thanks to modern therapies, including chemotherapy, only one in 28 is expected to die from it, and many women go on to have a normal life expectancy. Chemotherapy , while effective, is associated with many negative short-term side effects. Importantly, exercise programs during chemotherapy provide a beneficial influence on many of the treatment-related side effects, but the specific parameters of exercise associated with optimal benefits remain unclear. Furthermore, studies of chemotherapy and exercise use a method of exercise intensity prescription that does not account for chemotherapy side effects: often, the prescription will be based on the body's response to exercise prior to chemotherapy treatment. Amy Kirkham is undertaking research to provide information on how the body changes with respect to exercise ability throughout chemotherapy treatment – information that is not currently available. Specifically, she will frequently test indicators of physical fitness in a group of breast cancer patients who are participating in an exercise and chemotherapy study, to analyze and compare the changes between tests and over time. Additionally, she will try to develop and validate a simple exercise test that can be used easily and often to adjust the exercise intensity prescription of breast cancer patients currently involved in a chemotherapy and exercise study. The results of Ms. Kirkham’s research could lead to the development of a more accurate method for prescribing exercise for cancer patients, and ultimately affect how other research on cancer and exercise is conducted in the future.
Population trend in fertility drug use and its impact on birth outcomes.
The trend towards delayed childbearing has accelerated in recent decades, and as a result more women find it difficult to become pregnant. Consequently, the use of fertility drugs and assisted reproductive techniques, such as in-vitro-fertilization, has increased. The most profound population effect of these fertility treatments is an increase in multiple births (twins, triplets and higher order multiples), and recent data from Statistics Canada show a continued increase in these types of births. Unfortunately, this unintended increase in multiple births carries a considerably higher risk of pregnancy complications and adverse outcomes in newborns, and therefore carries implications for public health. While evidence suggests that use of fertility drugs is the most significant contributor to multiple pregnancies, identifying the proportion of births that result from the use of fertility drugs alone remains challenging. Further, there is little current information in Canada regarding the temporal trend in fertility drug use and the number of women who currently use these treatments. And, little is known about the impact of fertility drugs alone (without any invasive procedure). Dr. Sarka Lisonkova’s research will provide much needed information on pregnancy and perinatal outcomes including multiple pregnancies, congenital anomalies, miscarriages and pregnancy terminations, stillbirths, preterm births and neonatal deaths among women who did and did not use fertility drugs. By utilizing systematically collected population-based pharmaceutical and health related data available in BC she can identify the trend in fertility drug use among BC women between 1996 and 2006, as well as the maternal age distribution and demographic characteristics of those women. This information is important and timely, and the results will not only inform the women who have difficulty becoming pregnant about potential risks associated with fertility drugs, but also provide useful information to health services planners and administrators.
The effect of hyperoxia on baroreflex function in patients with sleep apnea
Obstructive sleep apnea (OSA), is a condition characterized by several stops and starts in breathing during sleep. This is caused by the collapse and re-opening of throat muscles. Unfortunately, the estimated one in four men and one in ten women who suffer from this condition are four times more likely to suffer from a stroke. The reasons for this phenomenon are not clear; however one likely explanation is an impaired ability among people with OSA to maintain normal blood pressure. In healthy individuals, when blood pressure increases the body reacts with a series of processes in order to bring blood pressure back down to normal levels. These processes are collectively called the baroreflex. However, the baroreflex is impaired in people with OSA, which results in dangerously high blood pressure and consequently, an increased risk for stroke. To-date, research has shown that baroreflex function is not only a powerful predictor of stroke, but also has strong prognostic value following a stroke. Indirect suggestions have been made of a potential improvement of the baroreflex in healthy humans when breathing supplemental oxygen (i.e. breathing high levels of oxygen). However, this remains to be investigated in people with OSA. In what is the first study to evaluate the effectiveness of supplemental oxygen in improving the baroreflex function in OSA, Jordan Querido is evaluating cardoirespiratory variables, including ventilated oxygen and carbon dioxide levels, sympathetic outflow, blood pressure, stroke volume, and heart rate, in both OSA patients and a group of healthy controls. Additionally, he will investigate the mechanisms which place OSA patients at greater risk for stroke, thereby potentially reducing their risk of stroke, and improving the prognosis following stroke.
The Role of Gap Junction Proteins in cytoskeletal rearrangements in B-lymphocytes
B-cell lymphomas are the most common type of blood cancer, accounting for 80-90 percent of non-Hodgkin’s lymphomas. Because lymphoma cancer cells can so readily spread from the blood stream to other tissues in the body, it is also a highly fatal form of disease. The key to preventing the spread of B-lymphomas is to prevent the proliferation and migration of these cancerous cells. To that end, an understanding of the underlying cellular processes is essential to the development of effective therapies. Recently, the Gap junction protein connexin43 (Cx43), was shown to cause neuronal migration in the brain. This novel role for gap junctions has led to speculation that Cx43 may be important for the migration of other cell types. Further, Cx43 expression on B-cells is important for hematopoiesis in the bone marrow, however the function of Cx43 on mature, circulating B-cells has remained elusive. Letitia Falk’s research involves a systematic dissection of the role of different protein domains of Cx43. Additionally, she is investigating the migration of B-lymphoid tumour cells expressing wild type and mutated forms of Cx43 in mouse models of tumour metastasis. These experiments will provide insight into processes that underlie normal lymphocyte development as well as the regulatory processes involved in the metastasis of B-cell leukemias, lymphomas and myelomas. Understanding in this area has the potential to aid in the development of novel anti-cancer therapeutics for the treatment of lymphoma cancers.
An ethno-epidemiological investigation of social and environmental contexts of HIV vulnerability among injection drug users
Outside of Africa, an estimated two-thirds of new Human Immunodeficiency virus (HIV), infections are believed to occur among people who inject illicit drugs. While an urgent need exists for tailored interventions to address HIV risk behaviour within vulnerable groups such as adult injection drug users (IDU), there are major knowledge gaps that must first be addressed if interventions are to be successful. Innovative approaches to examine how participation in particular social contexts and environments foster vulnerability to HIV are crucial to the development of effective intervention strategies among highly vulnerable populations of IDUs. William Small is conducting research to address this need using ethnographic methods to develop empirical information regarding transitions into particular high-risk social contexts, including drug markets and sex trade activities. Specifically, his research focuses on the risk environments in two different geographical settings, Vancouver, Canada and Sydney, Australia. The results will provide critical insight regarding how participation in these high-risk settings influences HIV risks as well as an individual’s ability to engage in risk reduction in the context of injection drug use. The information will be integrated with findings from ongoing epidemiological studies in the same locales to test socially-oriented hypotheses regarding the relationship between HIV vulnerabilities and particular social contexts. Ultimately, the findings from Mr. Smalls’ research will help advance the study of HIV risks among IDUs, and inform the development of social and community interventions designed to reduce HIV transmission.