Infectious diseases are responsible for roughly a third of annual deaths worldwide and contribute greatly to productivity loss. Antimicrobial resistance and newly emerging diseases are both cause for significant concern. With the advent of microbial whole-genome sequencing, there has been renewed optimism that computational analyses of microbial genomes will allow for faster identification of promising new therapeutic targets, which can then be further investigated with laboratory studies. At the moment, however, current computational practices are not accurate enough to be truly effective. Dr. Fiona Brinkman is interested in improving computational methods used to identify new potential bacterial vaccine components or drug/diagnostic targets. She is focusing in particular on improving identification methods for two regions: bacterial cell surface and secreted proteins, since they are the most accessible targets; and clusters of genes called genomic islands, which appear to disproportionately contain virulence genes and so could aid investigations of bacterial pathogenicity. Her research group is also studying the evolution of microbial virulence, both from the pathogen and host perspective, using bioinformatic approaches supported by laboratory studies. This work aims to develop methods and insights that may accelerate the identification of promising new targets from pathogen genomes. With the ability to analyze multiple infectious disease-causing microbes in parallel, this research has the potential to have a wide reaching impact on efforts to control multiple infectious diseases.
Program: Scholar
Population-Based Genetic Studies of Cancer and Healthy Aging
The number of elderly Canadians is increasing as the baby boomers age. Insight into how to promote healthy aging, coupled with advice that can be provided to our population as it ages, will influence Canada’s healthcare costs, as well as the quality of life of a large segment of our population. Cancer and aging are intimately connected. Cancer incidence rises with age, and this increase accelerates dramatically over 60 years of age. Cancer and other aging-associated diseases like cardiovascular disease are thought to result from the interaction of numerous genetic and environmental or lifestyle factors. Population-based studies that use large groups of affected and unaffected individuals are now the preferred method to study the genetics of complex diseases. This program has clinical relevance and involves close collaboration with clinical experts to study healthy aging and two specific cancers, non-Hodgkin lymphoma and cervical cancer. The overall objective is to discover genetic factors that contribute to susceptibility to cancer or confer long-term good health. The program will use state-of-the-art genetic analysis methods, and over the next 5 years will expand these projects and add additional types of cancer. This coordinated study of cancer and healthy aging is a unique and innovative approach by which we will increase our understanding of the connection between cancer and aging and benefit from new knowledge regarding the basis of common aging-associated diseases like cancer. This research will lead to development of clinically useful markers that will help individuals avoid developing diseases as they age.
Neighborhood Social Capital and Population Health: Exploring Community Resources and Access
Recently, the concept of community social capital – the extent and quality of community social ties – is receiving a great deal of interest from population health researchers and policymakers. This interest stems from efforts to understand relationships between the social and economic conditions of communities and the health and well-being of the people who live in these communities. Research on social capital to date has been focused primarily on the extent of social ties and interpersonal trust in communities. This limited focus has overlooked crucial elements that make community social ties useful for maintaining or improving population health: the various socioeconomic, political, and psychosocial resources that are possessed by members of social networks and how residents access (or are restricted from accessing) these network-based resources.
Dr. Richard Carpiano is determining how specific resources based in neighbourhood social ties, and access to these resources, matter for adult health and well-being. He will analyze one of the best available community health datasets for investigating social capital and neighborhood socioeconomic conditions: the Los Angeles Family and Neighborhood Survey (L.A.FANS). This project has two major benefits. It will extend population health planners’ understanding of community social capital by showing what aspects of neighbourhood social ties matter for health and well-being and how social conditions of local areas have health promoting and health damaging consequences. More broadly, it will help extend population health research on neighbourhoods and local communities by exploring the different ways that social context matters for adult health and well-being.
Toxicology of Natural Products and Synthetic Drugs
Adverse drug reactions are a major health risk that contributes to increasing health care costs and strain on the system. They are the sixth leading cause of death in the United States, and statistics indicate that the situation would be similar in Canada. There are many types of adverse drug reactions. Liver toxicity (poisoning) leading to fatal liver failure is one of the most common. In most cases, the mechanisms that cause drug induced liver toxicity are not well-known and even less is known about the effects of natural products (herbal products or dietary supplements) on liver function. With the ever increasing demand of herbal products by consumers, there is an urgent need to conduct detailed and systematic scientific investigations on their hepatic metabolic effects. Dr. Chang’s work is aimed at characterizing the effect of natural products and synthetic drugs on liver function and determining how they are able to give rise to damage in liver cells. A better understanding of the mechanisms will contribute to a safer and more rational use of natural/herbal products and synthetic drugs.
Transcriptional regulation of genes in health and disease
The human genome contains all the genes, and their regulatory instructions, required to develop the human body and determine how it deals with the outside environment. Now that the genomes of many species have been sequenced, a major focus of genomics is to identify all gene regulatory elements within DNA sequences. How these building blocks of life work together to build a complex human body – with its different organs, tissues, and cell types – is not well understood. Although most human cells carry the entire genome, each cell is functionally different, suggesting that not all genes are equally expressed.
Gene expression – the full use of information in a gene – is regulated in several ways, including by transcription. Specific regulatory proteins called transcription factors bind to targeted DNA sequences in the genome. This kind of activity can control cells by switching gene expression on and off. To better understand transcription regulation in genes, and thereby better understand gene expression, binding sites for transcription factors have to be identified. It is a fundamental step in the analysis of gene expression, which is tightly regulated so that genes are only expressed in specific cells, at specific developmental stages, and at appropriate levels to ensure correct physiological function.
Dr. Jack Chen’s work investigates the properties of transcription factor binding sites (TFBSs) and determines how these properties can assist with effective genome-wide TFBS identification. Using the nematode C. elegans as the model organism, he will combine experimental and computational approaches to characterize the properties of TFBSs that distinguish functional DNA sequences from nonfunctional ones. This study may pave road for a deep understanding of transcription in C. elegans, which will in turn shed light on both healthy and dysfunctional transcription in humans.
Novel Antimicrobial Surface Coatings for Urologic Devices
Health Issue:Urinary catheters provide drainage of the bladder to an external collecting device and are the most commonly placed medical devices. Ureteral stents provide drainage of urine from the kidney to the bladder and are used in the treatment of kidney stones. Both of these devices are foreign bodies in the urinary tract and allow bacteria to adhere and result in urinary tract infections and encrustations leading to device blockage and malfunction. Catheter and ureteral stent-associated infections prolong hospital stay, result in greater health care costs and may result in blood-borne bacterial infections possibly resulting in death. Antibiotics may be given for the duration that the drainage devices remain in the body, but there is great concern that the overuse of antibiotics will lead to the development of antibiotic resistant bacteria, or superbugs. Novel ways to reduce catheter and stent related infections would certainly improve patient care and decrease costs to the health care system without inducing resistant superbugs. Project Objective: To develop and test a novel peptide (protein) coating on urinary devices to reduce device-related urinary tract infection. Work to Undertake: Urinary catheters and stents will be coated with this novel peptide and evaluated for their ability to resist infection and encrustation using test tubes, bacterial cultures, and animals. Ultimately, human trials will be required. Unique to this research program/proposal of research: This novel peptide coating was discovered at the University of British Columbia by two researchers and is already being applied to artificial joints and implants used in orthopaedics. This will be the first use of this novel, promising technique in protecting urologic devices from infection and encrustation.
Dopamine modulation of prefrontal cortex network dynamics
Schizophrenia is a debilitating condition characterized by cognitive deficits in the realm of working memory, attention and executive function. While these deficits are a core feature of the illness, they are not adequately treated by anti-psychotic medications. The working memory deficits in schizophrenia are thought to involve dysfunction of the dopamine system in the a region of brain called the prefrontal cortex. Dr. Jeremy Seamans is working to understand the neural mechanisms that support working memory in the prefrontal cortex and how these mechanisms are modulated (affected) by dopamine levels. Using computer models, he has been able to link certain phenomena to actions of dopamine at the level of individual neurons and in the synapses between neurons. New computer simulation results suggested an even richer dynamic for how dopamine modulates activity in the prefrontal cortex. By testing the predictions of the computer simulations in a rat model, he will move from describing the known effects of dopamine on single neurons to detailing its impact on large-scale networks of neurons involved in working memory. The work has relevance not only to the theoretical question of how working memory information is coded and modulated but also may provide insight into how variations in the levels and actions of dopamine in the prefrontal cortex produces cognitive dysfunction in schizophrenia.
Disentangling Relationships Between Mental Illness and Youth Violence
According to Statistics Canada, Canadian adolescents are more likely than any other age group to commit violent crimes. This violence has enormous costs, including the suffering of victims, the fears experienced within a community and financial costs to taxpayers. A significant effect is the reduced opportunity for these youth who commit violent crimes. Researchers have recently identified mental illness as a possible contributing factor for youth violence. While most teenagers with mental illness are not violent, rates of violence appear higher in this group. Currently, researchers do not have a clear understanding of which mental illnesses increase youths’ risk and why. Dr. Jodi Viljoen will advance this understanding by providing health professionals and society in general with information about key relationships between youth violence and specific mental illnesses. Viljoen will interview 200 adolescent offenders in the community. The youths’ mental health symptoms, social context (e.g., peers), protective factors (e.g., supportive relationships with adults), and violent behaviour will be assessed regularly for a one-year period based on the following: structured interviews with youth and their caretakers, clinician rating scales, self-reporting questionnaires, and justice and mental health records. Her analyses will carefully examine the role of youths’ strengths and social context in predicting violence, as well as possible gender and ethnic differences in links between mental illness and youth violence. By identifying core risk factors and treatment needs in adolescent offenders with mental health issues, her research will help inform the development of effective strategies to prevent and treat violent behaviour in this critical age group, and will also advance BC as a premier centre in youth violence research and training.
Effects of exercise on structural and functional plasticity in the aging hippocampus
In the past 10 years we have come to adopt a more dynamic view of the brain. While we used to believe that the adult brain did not produce new neurons, we now know that new neurons are produced continually through out our lives, a process known as neurogenesis. In conjunction with neurogenesis, both new and existing cells also possess the capacity to alter the number and types of connections they make with other cells, a process called synaptogenesis. These processes can dramatically affect our cognitive processing capacities, and current research indicates that abnormalities in either neurogenesis and/or synaptogenesis are linked to a variety of neurological disorders ranging from those normally associated with adulthood (i.e. Alzheimer’s disease. Major depression, and Schizophrenia), to those that are more developmental in nature (i.e. Fetal Alcohol Syndrome, Fragile-X Syndrome, Rett’s Syndrome. Dr. Brian Christie’s research has targeted how exercise can facilitate learning performance, synaptic plasticity, neurogenesis and synaptogenesis in the brain. He has shown that exercise can induce long-term structural and functional changes in the connections between brain cells. His current work will provide greater detail about the mechanisms underlying the marked effects of exercise, particularly in the aging brain. A deeper understanding of these mechanisms may ultimately result in new approaches for establishing, maintaining, and even enhancing brain cells and their connections as we age.
Use of the skin immune system and dendritic cells to alter systemic immunity
The skin is the largest organ of the human body and represents the body’s primary interface with the external environment. As such, the skin is challenged by a broad range of factors and conditions. These include both endogenous (genetic, immunologic, and systemic) and exogenous (solar radiation, allergens, irritants, pollutants, and microbes) factors. As a result, the skin is a major site for disease including inflammation and cancer. Dendritic cells are immune cells that begin and coordinate immune responses. The skin is one of the largest repositories of these dendritic cells. Thus, in addition to being a direct target for inflammation, the skin is one of the prime sites where systemic immune responses begin. The proposed program includes four primary themes. The first three themes revolve around the use of the skin immune system (and skin dendritic cells) to modify immune responses (The skin immune system in the induction of immune responses; The skin immune system in the reduction of immune responses and; The skin immune system in disease pathogenesis). The final theme involves the use of pharmaceutical agents to modulate the activity of nonskin derived dendritic cells. The skin offers a unique opportunity to observe and manipulate dendritic cells and thereby the immune system. The focus on the skin as an organ to manipulate immune responses is innovative. This program will lead to a better understanding of the role of the skin immune system in systemic as well as local autoimmune disease (examples include lupus, psoriasis and type 1 diabetes). Further, the program will lead to cost effective strategies to treat and prevent human disease with anticipated improvements in vaccine delivery and efficacy and novel methods to control autoimmune disease.