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.
Program: Scholar
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.
Optimizing functional ability in stroke rehabilitation
Each year, approximately 50,000 Canadians suffer a stroke—the number one cause of neurological disability leading to impaired balance and mobility. Almost 90 per cent of stroke survivors have difficulties with everyday tasks, a reduced tolerance for physical activity, a sedentary lifestyle and multiple secondary complications. Many of these complications can be reduced with rehabilitation.
As a MSFHR-funded scholar, Dr. Janice Eng researched the effectiveness of a specific exercise program in improving balance and mobility in people with stroke. Now, Dr. Eng is working to optimize the functional abilities of people with stroke through innovative and effective rehabilitation interventions. One of these treatments includes a novel, cost-effective therapy where the patient manages their own amount of therapy for the arm and hand using a self-guided program. Dr. Eng will conduct a series of clinical studies aimed at improving arm and leg function in people living with stroke. People with stroke will be invited to participate in these studies and measurements of their abilities will be evaluated before and after the treatment. Changes in their abilities will then be analyzed and compared to individuals with stroke who receive what is considered standard therapy.
The development of effective rehabilitation interventions will improve the functional abilities of people with stroke, enable participation in social roles and physical activities, reduce secondary complications, and enhance quality of life. Novel interventions can also serve as a model for rehabilitation interventions in populations with other chronic health conditions.
Microfluidic Instrumentation for Single-Cell Chemical Genetics
Healthy cell behavior, cell differentiation and disease progression are all governed by complex protein interactions and regulatory networks across different cells. Unraveling the specific, time-dependent chain of events within cells has proven challenging for several reasons. First, diversity in cell types and the cumulative effects of past cell history mean that cells may vary in their response to chemical environments. Additionally, conventional methods of cell analysis are generally restricted to averaging measurements of large populations of cells, or analyzing cell response at a single point in time. Because these ensemble measurements and snapshots obscure persistent and time-dependent behaviour, deciphering the underlying molecular mechanisms of cellular response is difficult. A deeper understanding of such pathways is essential to the advancement of fundamental biological research, to the diagnoses of disease, and to the development of medical interventions. New technologies are needed to enable continuous monitoring of large numbers of single cells, subject to precisely-controlled sequences of chemical stimuli. Recent developments in micro-fabrication technology has led to micro-scale cell culture “chips”, with features similar to electronic micro circuits. Thousands of microscopic channels and valves can be tightly integrated into powerful biomedical sample processing devices the size of an iPod. Dr. Carl Hansen will focus on maximizing these state-of-the-art systems to develop new instrumentation capable of rapidly analyzing thousands of isolated single cells exposed to precisely defined and time-varying chemical conditions and drugs. Experimentation at the single cell level will accelerate fundamental biomedical research and will ultimately improve both our understanding of, and our ability to treat, disease. The ability to precisely manipulate and interrogate single cells will find broad application in health research fields including cancer biology, regenerative medicine, and drug development.
Exploring and exploiting the protein psoriasin as a new target for breast cancer therapies
Ductal carcinoma in situ (DCIS) is a precursor to invasive breast cancer, and the protein psoriasin is one of the most highly expressed genes in DCIS. Psoriasin is present at abnormally high levels in many pre-invasive breast cancer cells and in a smaller subgroup of invasive breast cancer cells. Recent research has shown that the interaction of psoriasin with the signaling protein Jab1 may be a keystone of the signal network of the breast cancer cell, and that psoriasin binding can cause Jab1 to stimulate the development of invasive and metastatic breast cancer cells. Inhibiting protein-protein interactions is an exciting new approach in the search for targeted cancer therapeutics, and the psoriasin-Jab1 interaction is a promising new target for the treatment of breast cancer. Dr. Fraser Hof’s work deals with fundamental questions about the interactions of proteins and small molecules and with the applied design of small molecule therapeutics. His proposal is to design and develop novel drug molecules to block this psoriasin-Jab1 interaction, first to validate the target and then to guide subsequent drug development. A drug that inhibits this interaction may offer a novel therapy to directly target pre-invasive breast cancer and prevent the development of invasive breast cancer. This therapy may also hold promise as a new approach to target the small subgroup of invasive breast cancers where psoriasin is also present, as this subgroup is typically not eligible for current targeted therapies such as tamoxifen and herceptin.