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.
Program: Trainee
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.
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.
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 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.
Bayesian Adjustment for Unmeasured Environmental Confounding
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.
Automated Malaria Diagnostic Test via Microfluidic Separation of Infected Red Blood Cells
Every year, 350 to 500 million cases of malaria occur worldwide, resulting in over a million deaths. The majority of these cases occur in sub-Saharan Africa and are responsible for 25 percent of pediatric fatalities under the age of five. In terms of the financial burden, estimates suggest that malaria costs Africa more than $12 billion annually. The global campaign to control and eradicate malaria requires accurate, rapid and cost-effective diagnostic tools. Inaccurate diagnosis results in patients failing to receive needed treatment as well as an overuse of malaria drugs which could contribute to the emergence of drug resistant strains. Currently, the most accurate diagnostic approach requires a trained technician to count the infected cells in a blood sample under a microscope, which is impractical for low-resource regions. Microfluidic devices have shown great potential for cell sorting applications. Such devices can have high selectivity and sensitivity while still being relatively inexpensive to produce. Ms. Sarah Mcfaul is utilizing microfluidics to construct an automated malaria diagnostic test that will be available as a small portable device, requiring no special training to use. Ideally, this automated diagnostic tool will provide sensitivity and quantitative results equal to microscopy, and will also be inexpensively manufactured in order to be accessible to low-resource regions where malaria is a serious threat. Not only will such a device aid in diagnosing malaria, but it will also track the effectiveness of malaria treatments over time in individual patients, enabling clinics can make the best use of their anti-malarial drugs. This in turn will help to lower the number of deaths from malaria and slow the emergence of drug-resistant strains of this deadly parasite.
Imaging Early Micro-Structural Bone Changes in the Rheumatoid Hand: A High Resolution-Peripheral Computed Tomography (HR-pQCT) Study in People with Newly Diagnosed RA
Rheumatoid Arthritis (RA), affects one percent of the general population. Radiographic (x-ray), evidence of bone thinning (osteoporosis), and bony destruction (erosions), in the bone surrounding inflamed joints is an important diagnostic criterion for RA. These changes are present in the hands and feet of 80 percent of people with RA and can have profound implications with regard to the development of hand deformity, functional limitations and the need for restorative joint surgery. Early presentation of destructive bone changes is associated with a more aggressive disease progression and evidence suggests that starting disease-modifying anti-rheumatic drugs (DMARDs), soon after the diagnosis of RA may help prevent some people from developing bone damage. However, not all people with early RA respond to DMARDs, with ‘non-responders’ requiring more aggressive interventions including trials of combinations of different drug treatments or biologic response modifier drugs. Unfortunately, the time delay associated with implementing effective treatment in people with more aggressive or resistant RA means they are at greater risk for permanent bone damage. Current clinical imaging with Dual X-ray Absorptiometry (DXA), Computed Tomography (CT), and Magnetic Resonance Imaging (MRI), can detect bone damage earlier than x-ray but these tools are not able to identify the initial ‘micro-structural’ changes in the early RA hand. Dr. Lynne Feehan is characterizing early ‘micro’ structural hand bone changes over a two-year period in people with newly diagnosed RA using High Resolution – Peripheral Quantitative Computed Tomography (HR-pQCT), a promising new imaging system capable of imaging the very fine bone internal ‘micro’ detail at a resolution equivalent to the diameter of a human hair. The results of Dr. Feehan’s research could improve patient’s early access to appropriate therapy, and thereby improve their quality of life.
Cataloguing Chromosome Instability Mutants: Implications for Cell Biology, Cancer and Therapeutics
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.
Small molecules with affinity for S100A7, a tumorigenic protein in breast cancer
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.