The enzymes hepatic lipase (HL) and lipoprotein lipase (LPL) play a key role in the metabolism of cholesterol and fat circulating in the blood stream. However, their specific role and capacity to offer protection from heart disease are unclear. My research will identify the parts of each enzyme responsible for performing different functions. This knowledge will more clearly define how these enzymes influence the metabolism of cholesterol and fat and the development of cardiovascular disease. I am combining parts of HL and LPL to create new enzymes that will highlight the differences between the original enzymes’ functions. For example, a fundamental property of enzymes is how they are activated. We know a particular protein that does not activate HL does activate LPL. I will put the portions of LPL we think are responsible for activation into HL to test whether HL is activated and confirm that this part of LPL causes activation. When we know how these enzymes work to regulate and control the level of cholesterol and fat, we will understand their relationship with cardiovascular disease, and should be able to develop enzyme inhibitors or activators to improve cardiovascular health.
Program: Scholar
Epidemiological and population-based investigations of persons infected with HIV
I am a demographer who is currently involved in observational research into the impact of antiretroviral therapy on quality of life and life expectancy of persons with HIV disease in British Columbia. I am also interested in issues regarding access to antiretroviral therapy in developing nations. My most significant contributions to HIV research include: Studies monitoring seroincidence and determinants of HIV infection and risk behaviour among gay and bisexual men In a natural history study of HIV-positive gay and bisexual men, we demonstrated that lower socioeconomic status decreases the length of survival. Low income was significantly associated with shorter survival from HIV infection to death, even after adjustment for CD4 count (which measures immune suppression in persons with HIV), age at infection, year of infection and use of HIV therapies and prophylaxis. Studies measuring the impact of HIV infection on population health My primary goal in the area of population health research has been examining the impact of HIV on patterns of mortality, migration and hospitalization in Canada. One study I conducted showed that although there are barriers to widespread HIV treatment, limited used of antiretroviral therapy could have an immediate impact on South Africa’s AIDS epidemic. A second study demonstrated that the cost of making combination antiretroviral therapy available worldwide would be exceedingly high, especially in countries with limited financial resources. Studies evaluating the impact of antiretroviral therapy on the health and well-being of persons with HIV disease One of my studies demonstrated a significant reduction in mortality and AIDS-free survival for HIV infected individuals who initiated therapy with regimens including stavudine or lamivudine compared to those who initiated therapy with regimes limited to zidovudine, didanosine and zalcitabine.
The Genome Sciences Centre: a platform for large-scale high-throughput genomics in British Columbia
Our genes play a major role in our health and in our susceptibility to disease. In fact, the course of every disease is thought to be influenced to some extent by genetic factors. Confounding researchers’ attempts to understand the genetic basis of health and disease are the very large number of human genes (estimated at between 30,000 and 40,000) and the limitations in technology that, up until recently, allowed researchers to study only one or a few genes at a time. At the BC Cancer Agency Genome Sciences Centre, a new laboratory unique in Canada, we are developing and using state-of-the-art technology to examine thousands of genes simultaneously, searching for those that play a role in cancer. These genes will ultimately provide new tools for early diagnosis, improved treatment strategies and discovering cures to a disease that has touched the lives of almost all of us.
Early labour support at home: an RCT of nurse visits and telephone triage
Cesarean section rates have been considered too high in North America for a number of years, and the rate appears to be rising. My research will assess whether a different approach to early labour care lowers the rate and is cost-effective. Currently, women who phone British Columbia’s Women’s Hospital and Health Centre in labour, wondering whether they should come in to the hospital, receive telephone advice only. My research study will focus on women having their first baby who call the hospital for advice. Women who agree to participate in the study will be randomly assigned either the current method of telephone care or a visit from a delivery suite nurse, who will conduct an assessment in the woman’s home. This is the same assessment that takes place when women arrive at the hospital. The nurse will call the woman’s physician from her home, and the three of them will plan what to do next. In this study, I will compare the outcomes of home visits to telephone advice to determine whether the cesarean rate is lowered. We anticipate that early labour support and assessment at home will enable women to delay admission to hospital until labour is well established, reducing the use of cesarean sections and other interventions. We know from a small pilot project that babies seemed less likely to have problems at birth with this approach to maternity care. In addition, we will compare the cost of the two methods. We expect early labour support at home to reduce the costs associated with cesarean section and longer hospital stays.
Aminophylline bolus in bradyasystolic cardiac arrest: a randomized placebo-controlled trial
Cardiac arrest occurs when the heart stops pumping blood effectively. Without blood flow, no oxygen circulates and brain damage can occur within minutes. Bradyasystole, a type of cardiac arrest where the heart beats very slowly or not at all, accounts for more than half of cardiac arrests. Less than three out of every 100 people who experience this type of cardiac arrest survive. Bradyasystolic cardiac arrest may be caused or worsened by adenosine, a chemical that exists in our bodies and is released by cells when the heart is under stress. The drug aminophylline has been used to treat asthma for years, and may also counteract the adverse effects of adenosine during cardiac arrest. My research will evaluate the effectiveness of aminophylline in improving survival from bradyasystolic cardiac arrest. All advanced life support ambulances in Greater Vancouver and Chilliwack are participating in this double-blind, randomized study. Patients will receive either aminophylline or a placebo in addition to standard resuscitative care. The patient, paramedics, physicians and nurses will not know what the patient received. If the therapy proves beneficial, numerous lives could be saved. About 1,000 people experience cardiac arrest in North America every day, and the majority would be eligible for this treatment.
Primary deafferetation of the spinal cord: consequences and repair strategies
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.
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.