Excessive force on the brachial plexus – the network of nerves in the shoulder that carry information to and from the arm and hand – can tear sensory nerve roots from the spinal cord. Traffic accidents, complications during childbirth and other situations can cause this common condition. As a result, people lose sensation and, paradoxically, develop a severe and untreatable condition called deafferentation pain. Sensation loss is permanent because sensory nerve fibres cannot regenerate into the spinal cord. However, recent studies have shown that groups of naturally occurring proteins called neurotrophic factors have the potential to promote re-growth of damaged sensory neurons, the nerve cells that carry information about touch and pain from sense organs like the skin to the cord. Some of these proteins can also prevent or reverse the deafferentation pain that results from the interruption of sensory input to the spinal cord. My research will examine the therapeutic potential of neurotrophins on regeneration in spinal cord injury and deafferentation pain. We will also assess the consequences of brachial plexus injury in the spinal cord and develop methods for assessing the resulting pain. This work will help explain why regeneration fails, and identify new therapies for treating brachial plexus and other spinal cord injuries.
Program: Scholar
Expanding and exploiting the catalytic repertoire of combinatorial nucleic acid selections for medical applications
Synthetic DNA can potentially be used to develop new drugs that target infectious diseases and cancer. I am studying how to create new molecules based on DNA. My research team is examining billions of molecules at a time and selecting synthetic DNA that may have therapeutic properties or act as catalysts. Part of developing new catalysts involves developing building blocks of synthetic DNA with particular properties that regular DNA doesn’t have. For example, we have been able to modify synthetic DNA to enhance its catalytic activity. I am examining whether the catalytic activity can be used to target the RNA sequence involved in the development of cancer. I am also studying a DNA catalyst with the potential to cut viral RNA sequences in HIV. In addition, we are screening molecules to find DNA that can stimulate or inhibit activity on a cell surface or in proteins. In particular, I am examining the proteins involved in cancer. Our goal for this research is to support the development of potent anti-viral and anti-cancer therapies.
Determinants of excessive waiting for cardiac catheterization and revascularization in British Columbia
Cardiovascular disease is the most common cause of morbidity and mortality in British Columbia and Canada, accounting for one-third of all deaths and over one-half of deaths among persons aged 50 years and over. The economic burden of cardiovascular disease is enormous. In BC in 1998, the most recent year for which there are reliable figures, the annual direct costs were approximately $1.1 billion and the indirect costs were estimated at $3 billion, making this the most costly of any category of diseases in the province. I have developed a research program for the systematic investigation of the delivery and outcomes of cardiovascular diagnostic procedures, and medical and surgical care in BC and the rest of Canada. The projects in the research program largely involve using linked administrative and clinical databases. One project of particular interest in BC is the issue of wait times for cardiac bypass surgery. In Canada in the late 1980s, a dramatic increase in referrals for coronary artery bypass surgery outstripped capacity for this procedure. The Ontario government expanded capacity and developed criteria for placing patients on cardiac surgery waitlists. Capacity was increased in BC, but patients were put on the waitlist in an ad hoc manner, which continues today. I am conducting a large study to examine waitlists for cardiac operations in BC. The official wait time is the interval between being booked for an open heart operation and actually having the procedure. There is evidence this wait has decreased in the past two years. I am investigating whether there is a true decrease or if patients are waiting earlier in their process of care, before the operation is booked. This study will compare wait times in BC to benchmarks established in Ontario, identify the proportion of patients who wait longer than recommended by medical guidelines, examine the characteristics that predict longer wait times, and propose ways to shorten the waitlist for people waiting the longest. The results of this research will help determine whether we need a more formal system for managing cardiac resources in BC.
Cell adhesion and signaling in oncogenesis
The main objective of my research is to understand the molecular basis of how cancer progresses and to use the knowledge to identify new cancer therapies. To achieve this, my research team is studying receptors found on the surface of most cells that cause them to attach to other cells. We want to determine how the receptors communicate information they detect on the outside of the cell to the inside of the cell. We have identified proteins that interact with these receptors on the inside of the cell and are responsible for transmitting information to other parts of the cell to control cell division, cell death, cell differentiation and cell movement. We are focusing on one protein – Integrin Linked Kinase (ILK) – whose function is tightly regulated in normal cells, where its activity rapidly turns on and off. But in cancer cells, ILK is on all the time, leading to increased cell division, decreased cell death and increased cell movement. We have determined that ILK is at least partly responsible for the abnormal behaviour of cancer cells, and ILK activity is considerably elevated in many types of cancer. We have also identified specific chemical inhibitors of ILK activity, which are currently being evaluated in pre-clinical trials. The results to date show these inhibitors are effective in blocking growth and spread of tumours. ILK is present in many tissue types, and it is likely that it plays a critical role in the development and function of these tissues, and in other diseases of chronic inflammation such as arthritis, asthma, kidney disease and heart disease. To investigate this further we are using genetic techniques to alter ILK expression and function in a tissue-specific manner. Such studies will lead to a better understanding of the role of ILK and related proteins in nomal and diseased tissues.
Origin and evolution of intracellular parasites apicomplexa and microsporidia
Apicomplexa and microsporidia are two groups of parasites that infect a broad range of animals, including humans. Apicomplexa cause serious diseases such as malaria and encephalitis. Traditionally, microsporidia were not prevalent among humans. However, microsporidia are increasingly becoming a problem in people with impaired immune systems. The relationships of these parasites to other organisms and how they evolved are not clearly understood. Yet recent molecular studies have revealed surprising evolutionary histories for both groups of parasites. Apicomplexa evolved from an alga, an unusual origin for a parasite. Microsporidia were originally believed to be simple, single-celled organisms that were not highly evolved. But we now know that microsporidia have evolved from fungi. I am studying the evolution and biology of apicomplexa and microsporidia to learn how they developed into parasites and how they function. This research may uncover weaknesses in the parasites that can be exploited to develop new treatments for disease involving herbicides or fungicides that would not have been considered earlier.
Functional imaging of neuronal Ca2+ in vivo and in vitro brain slice
My research lab uses fluorescence imaging technology combined with electrophysiological measurements to study problems with the transmission of information in the brain. Such problems are the foundation of numerous brain disorders including schizophrenia, depression and Parkinson’s disease. We need a thorough understanding of the brain’s communication process to understand and develop treatments for these disorders. Brain function depends on the activity of neuronal circuits, which are formed by thousands or millions of neurons (nerve cells) that communicate with each other at points of contact called synapses. Neurons communicate when the pre-synaptic neuron releases a chemical transmitter that diffuses across the synaptic space and binds to receptors on the post-synaptic (receiving) neuron. The receptors are often located on branches of the neuron called dendrites. My research examines the factors that control the amount of chemical transmitter released, and in particular, the regulation of release by calcium ions in pre-synaptic neurons. Transmitter release is stimulated by an influx of calcium into the pre-synaptic neuron. Calcium influx is controlled by changes in the electrical potential of the pre-synaptic neuron that regulate the opening and closing of the voltage sensitive “”gates”” of calcium permeable pores in the neuron’s surface. By changing calcium influx and accumulation in neurons, the strength of the synaptic connection can be varied to adapt to new conditions or tasks. Using fluorescent dyes that are sensitive to calcium, we monitor calcium in pre-synaptic neurons at the same time that we measure synaptic transmission electrically. Our laboratory has the unique capability to make these measurements in an intact living mammalian brain. We are investigating how activity in the pre-synaptic neuron and substances such as dopamine or serotonin control transmitter release by their effects on calcium, and the biochemical machinery that release transmitter in response to calcium. We also are studying how the signal reception at the post-synaptic neuron is regulated by electrical properties of the dendrites.
Dietary lipids in growth, development and health
My research focuses on the role of dietary fat in providing essential fatty acids to support growth and development, including long-term effects on children’s physical, cognitive and behavioural health. I am investigating how specific fatty acids influence brain development and nerve function, the dietary intakes needed to ensure optimal development, and the role of altered fatty acids in disorders such as liver disease and cystic fibrosis. Clinical applications of this research have ranged from developing special feeds to support optimal brain development in premature infants, to research into diets for prevention of seizures and liver damage in children with cystic fibrosis. I also head a nationally funded Nutritional Research Program exploring how our genetic makeup blends with our nutritional intake, particularly in the maternal and early childhood period, to affect our life-long susceptibility to disease. Findings will provide important new information about tailoring nutritional intake to meet individual needs in health and disease.
Genetic studies in common, complex diseases with special emphasis on Multiple Sclerosis
Multiple sclerosis (MS) is one of the most common neurological diseases, usually striking people between the ages of 20 and 40. My research focuses on understanding genetic epidemiological, molecular genetic and environmental factors that increase susceptibility for MS and other common complex diseases that begin in adulthood. As part of my work in the Canadian Project on Genetic Susceptibility to MS, a BC and Canada-wide database on MS has been established. This is the largest database of information on family histories of MS in the world. Using this information, we have shown that both hereditary and environmental factors do have a role in causing susceptibility to MS. Now we are focusing on identifying the genes and non-genetic factors responsible for MS. This research will help identify people at high risk of developing MS, and possibly contribute to treatments that slow down or prevent the onset of the disease. In addition, the results of this research are relevant for addressing other common adult onset diseases such as Alzheimer’s disease, breast cancer and diabetes.
Quality improvement of stroke surveillance, prevention and care in a sentinel health region
Stroke is the third leading cause of death in BC and the leading cause of brain disability. Stroke is also estimated to be the most expensive disease in Canada that, until recently, was considered untreatable. My research team is evaluating a three-step stroke program in the Vancouver Island Health Region to improve prevention and treatment options. The first step will be developing a surveillance system to collect information on all strokes in the region and to find people who are at high risk. Next, the project team will work on providing new tools to help patients and their doctors plan ahead and implement life style changes that will reduce stroke risk. The third component will use Stroke Victoria’s computer system as a tool for quality improvement initiatives in stroke care. The team will evaluate every stage of the project to assess the effectiveness of this approach for saving lives, improving care and reducing the costs of health care delivery. Stroke is so debilitating, complex and costly that it is worth investing in innovative approaches to prevention. We believe relevant, rapid and rigorous epidemiology is key.
Patient-focused care over time: issues related to measurement, prevalence, and strategies for improvement among patient populations in B.C.
Patients often see multiple health professionals in a variety of places for the care of their health problems. Linking care from different providers over time is challenging, with the risk that some care may be missed, duplicated or ill-timed. Concern about this fragmentation of care is growing in Canada and worldwide. Continuity of care, which is accomplished when the connections between care are seamless, is thought to improve patient outcomes, patient satisfaction with their care and physician and health providers’ satisfaction as well. I am studying the impact of continuity of care on costs and quality of care. A common way to connect care over time is to have one central person, usually a primary care physician, responsible for providing the majority of services and linking a patient to specialists. I am examining a variety of data to measure the concentration of care in this type of sustained relationship. A growing trend is team care provided at a clinic, where patients see any one of the physicians working there. My study will compare outcomes for patients who use health care teams to those who primarily see one physician, and I will look at the way walk-in clinic care affects continuity and patient outcomes. I will also examine how continuity of care affects patient health over time for people with severe and persistent mental illness, individuals with workplace injuries, and patients with HIV/AIDS.