Studies in environmental epidemiology are often concerned with understanding the health effects of environmental exposure in various forms. Because these studies are, by nature, observational, it is often difficult to make valid statistical conclusions. Additional complications arise from the presence of confounding variables, which relate to both the exposure and health effect, and hence complicate the relationship. Traditionally these confounders are controlled for by including them as explanatory variables in a statistical model. Bias-free conclusions become much more difficult, however, when some confounders are unmeasured or inadequately measured. A wide variety of environmental epidemiology studies have suffered from this problem, including, for instance, estimating the association between air pollution and mortality, between magnesium levels in drinking water and mortality from acute myocardial infarction, and between ethnicity, income and limiting long-term illness. The focus of Luke Bornn’s research is the development of a coherent, unified framework for modeling environmental risk exposure in the presence of unmeasured confounding. His model will account for spatial dependencies between adjacent geographical groups as well as other factors that are important for these studies, such as ecological bias and pure specification bias. His hypothesis is that by accounting for spatial dependence and unmeasured confounding under a comprehensive and unified framework, the risk estimates will more accurately estimate the true exposure risk and provide more appropriate estimates of the corresponding uncertainty. By developing a model through simulations, analytic results and application to real data sets, Mr. Bornn’s research will create a model that is both practical and useable for environmental epidemiology practitioners.
Year: 2009
The role of leptin in the regulation of glucagon release from pancreatic alpha-cells.
The prevalence of diabetes is increasing worldwide due to population growth, aging and increasing frequency of obesity and physical inactivity. Diabetes mellitus is caused by a relative or absolute deficiency of the hormone insulin, which results in the characteristic feature of high blood sugar levels that play a key role in diabetes-associated complications. Inappropriately high levels of the sugar-raising hormone glucagon further aggravate the disease. Therefore, diabetes may be treated by increasing insulin levels and/or action, or inhibiting glucagon production and/or action. In an effort to identify the causes of diabetes, most studies have focused on better understanding the physiology of insulin-secreting beta-cells: despite the importance of glucagon, the counter-regulatory hormone to insulin, little is known about the physiology of pancreatic alpha-cells. Recently, Ms. Eva Tuduri and colleagues established that the hormone leptin controls both the secretion of insulin and glucagon, and thereby regulates blood sugar levels. Leptin is produced by fat cells and the levels of leptin in the blood typically correlate to the total content of fat in the body. Leptin is best known for its effects on feeding centers in the brain, where it regulates both food intake and energy expenditure. Ms. Tuduri’s current research project is focusing on understanding the role of leptin in regulating levels of glucagon, independent of leptin actions on body weight. An inhibitory effect of leptin on the function of alpha-cells could be considered as a potential therapeutic strategy to regulate glucagon levels and to normalize sugar levels in diabetic patients.
Do neurocognitive deficits in the evaluation of motor output contribute to falls risk in older adults?
A growing body of evidence suggests that cognitive impairment is a significant contributing factor in the increased incidence of falls among older adults. With that said, the exact neural systems within the brain that underlie an increased risk of falling remain unclear. Recently, it has been suggested that medial-frontal cortex, a region of the brain typically associated with cognitive control, plays an important role in evaluating the success or failure of movement. Therefore, one might assume that the ability of the medial-frontal system to evaluate motor output might be impaired with aging. Functional deficits within the medial-frontal system brought about by aging may result in a reduced ability to evaluate stride and/or balance, and subsequently contribute to the increased incidence of falls observed in older adults. Dr. Olave Krigolson’s current research utilizes neuroimaging techniques to assess the effectiveness of the medial-frontal system in evaluating motor output in two groups of older adults; a group of older adults prone to falling and a group not prone to falling. Dr. Krigolson is testing the hypothesis that evaluation capabilities of the medial-frontal cortex will be diminished in older adults prone to falling compared to the control group. The findings from Dr. Krigolson’s study will improve our understanding of the mechanisms that contribute to the increased propensity for falling evident with increasing age, and will also potentially provide a basis for the development of assessment techniques and interventions to decrease the occurrence of falls in older adults.
The effects of different forms of estrogen replacement on hippocampal neurogenesis and cognition in young and older female rats.
Neurodegenerative diseases associated with aging, such as Alzheimer's disease (AD,) effect millions of people annually. The development of AD may be related to gonadal hormones present in adulthood. Interestingly, women have an increased risk for developing AD compared to men. Additionally, the disease progresses more rapidly in women and the onset of AD is generally earlier in women than in men. The ovarian hormone estrogen has been implicated as a possible therapeutic agent for improving cognition in postmenopausal women and AD patients, and epidemiologic evidence indicates that hormone replacement therapy (HRT,) reduces the incidence of and/or delays the onset of AD in women. However, there is evidence to suggest that the beneficial effects of estrogen on cognitive impairment associated with aging in women may depend upon the type of estrogen (e.g. estrone versus estradiol), taken. Interestingly, estrogens are known to exert significant structural and functional effects on the hippocampus, a brain region which retains the ability to produce new neurons throughout adulthood in all mammalian species studied, including humans, and is known to mediate some forms of learning and memory. Importantly, previous research has shown that the increased survival of newly produced neurons in the hippocampus of adult rodents are related to better hippocampus-dependent learning and memory. Cindy Barha is researching the effects of different types of estrogen on cognition and the production of new neurons in the hippocampus of young and older female rodents. The results of these experiments will have important implications for determining which alternative forms of estrogen to incorporate into HRT in the future. Ultimately, the results from these and other studies may lead to the development of new therapeutics that halt or slow the progression of neuronal loss in age-related neurodegenerative disorders.
Regulation and Function of Human T helper 17 Cells
Immune system homeostasis is determined by the balance between responses that control infection and tumour growth and reciprocal responses that prevent inflammation and autoimmune diseases. Dysregulated immune responses, such as those that occur with autoimmune disorders and organ rejection, result when and an individual’s immune system mistakenly attacks normal cells. Current treatment approaches involve following a strict regimen of immunosuppressive drugs for the duration of a patient’s life. These treatments, however, seriously compromise an individual’s ability to fight infection and are associated with an increased risk of developing cancer. Sarah Crome’s research has two main focuses. The first is on the regulation and function of a newly discovered class of inflammatory white blood cells (WBC), termed T helper 17 (Th17) cells, which serve an essential function in host defense against extracellular pathogens. While being key players that protect the body from harmful pathogens, Th17 cells are also linked to inflammatory diseases including rejection of transplanted organs and cells, rheumatoid arthritis, psoriasis and inflammatory bowel disease. Therefore, it is essential to understand the mechanisms that regulate this cell population in order to be able to treat patients with dysregulated immune responses. Secondly, Ms. Crome and colleagues are examining interactions between Th17 cells and another WBC population, termed T regulatory (Treg) cells, which serve a protective function by suppressing harmful immune responses. Currently, Treg cells are being clinically tested as a cell-based therapeutic alternative to immunosuppressive drugs. However, the diseases where Treg cell-based therapies are being investigated are the same diseases that are associated with Th17 cell activity. Therefore, understanding the interactions between these two cell populations will be essential for clinical based studies of Treg cells, and the development of improved therapies.
In vivo imaging of brain circuit plasticity during receptive field refinement
Just how neurons form appropriate connections to develop into functional neural networks remains an important unanswered question in neuroscience. During early brain development, sensory neurons form and refine synaptic connections to respond to and encode information about a specific set of inputs, which is termed their ‘receptive field’ (RF). While previous experiments have investigated the development of numerous RF properties, most studies have focused on individual neurons, or a small number of neurons distributed sparsely in a brain region. In contrast, the changes which are thought to underlie learning, such as synaptic plasticity, are intimately dependent on how the firing patterns of different neurons interact. In his research, Kaspar Podgorski is using two-photon imaging of calcium sensitive-dyes and a mathematical model of how neuron firing affects calcium levels to observe the RF responses of hundreds of interacting neurons in awake Xenopus tadpoles. These data will provide information about how networks of neurons work in synchrony to encode information about the world. Mr. Podgorski images network activity before, during and after visual training that improves the discrimination abilities of the neural network. The aim of his research is to form a mechanistic understanding of how the firing patterns of individual neurons and the interactions between them change in order to improve whole network function. By studying how local properties come together to make large neural circuits function more effectively in the intact, awake brain, we will gain a better understanding of normal brain circuit function and potentially determine the origins of developmental brain disorders such as schizophrenia, epilepsy and autism, which may be caused by abnormal circuit development.
The Role of Palmitoylation in the Pathogenesis of Huntington Disease
Huntington disease (HD), is an adult-onset progressive, degenerative disease affecting the neurons of a particular area of the brain called the striatum. The striatum is partially responsible for regulating movement, and HD affects the part of the striatum responsible for inhibiting unwanted movement. The primary symptom of HD is chorea, or involuntary “”dance-like”” movements. Currently, no effective treatment or cures exist, and death occurs on average 15 years after disease onset. HD is caused by a mutation in the Huntington gene where a short sequence at the beginning of the gene is multiplied, resulting in more than 36 repetitions. The mutation is inherited, so that people with HD have a 50 percent chance of passing it onto their children. The mutation has many effects on the function of the Huntington protein (htt), including interfering with how it interacts with other proteins, such as Huntington Interacting Protein 14 (HIP14). HIP14 is a “”PAT”” enzyme, which is a type of enzyme involved in a process called palmitoylation. There is a growing body of evidence to suggest that palmitoylation plays an important role in HD. Shaun Sanders’ research into HD involves the development of a new, genetically modified “conditional knockout” mouse model. Using this model, Sanders can “”turn off”” HIP14 when and where wanted, in a particular organ or area of an organ, like turning a light off in one room but not in another. He will then look for the symptoms of HD in the mouse model. His research will provide more evidence for the role of HIP14 in HD and further validate the model of palmitoylation in HD. The results will also improve our knowledge regarding “”PAT”” enzymes and palmitoylation which will expand the understanding of other neurological diseases, such as Schizophrenia and mental retardation.
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.
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.
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.