I am examining angiogenesis – the process of how blood vessels grow – to learn how to make more blood vessels grow and discover ways to stop their growth. New blood vessels sprout from existing blood vessels. In addition, stem cells from bone marrow go to areas that require new blood vessels and differentiate into blood vessel-lining cells called endothelial cells. Endothelial cells line the inside of every blood vessel. My research lab has confirmed that when we turn on a protein receptor on the surface of the endothelial cells, we can block blood vessels from growing. We are also studying whether blocking this receptor will have the opposite effect of increasing blood vessel growth. All tissue needs blood to deliver nutrients to survive and grow. In heart disease, blood vessels are blocked by hardening of the arteries. When not enough blood gets to the heart, tissue dies, causing a heart attack. If we can make new blood vessels grow and bypass the blockage, heart tissue could potentially survive without surgery. Cancer tumours also require blood vessels to grow, and will only grow to 1-2 millimetres without a blood supply. If we can stop the growth of blood vessels to this tissue, tumour growth could be blocked. Stopping blood vessel growth could also stop tumours from spreading. Blood vessel growth also promotes chronic inflammatory conditions such as rheumatoid arthritis and psoriasis, so blocking growth may ultimately help treat these conditions as well.
Year: 2001
Molecular and genetic mechanisms of obstructive lung disease
Asthma and chronic obstructive pulmonary disease (COPD), also known as emphysema, are major causes of disease and death worldwide. The prevalence of asthma is increasing, and in some Canadian communities, up to 20 per cent of children are affected. Globally, emphysema ranks twelfth as a cause of lost quantity and quality of life, and is projected to rank fifth by the year 2020 as smoking and air pollution increase around the world. Significant gaps exist in our understanding of these disorders, and while limited therapies are available, none is universally effective or without side effects. I am examining genetic susceptibility for asthma and COPD. Many people smoke and are exposed to allergens, but only a small percentage develop asthma or COPD. For example, cigarette smoking is the major risk factor for COPD, but only 10-20 per cent of smokers develop the disease. Similarly allergy is common, but only some individuals develop asthma. The evidence suggests that susceptibility runs in families, but few genetic risk factors have been identified. My research team is using a registry of lung tissue from patients who have had lung surgery, as well as DNA from large groups of individuals who have these conditions, to identify the genes that account for this susceptibility. We want to discover the molecular mechanisms that cause asthma and COPD, and to predict if an individual’s genetic makeup puts them at increased risk for these disorders. Ultimately, this research should increase understanding of these disorders and contribute to the development of new diagnostic tests, preventative strategies and therapies.
Key signaling pathways controlling survival and death of hemopoietic cells
All cells are programmed to die eventually. If cells don’t die normally, they can become harmful. For example, cancer can result when cells that should die keep growing instead. Each cell produces 10 to 15,000 proteins, with approximately 25 to 50 per cent of these involved in transmitting signals from the outside to the inside of the cell. My research is investigating how signals are sent within individual cells during the process of cell death. Signalling proteins bind to receptors on the cell surface to regulate growth and determine whether a cell lives or dies. The function of many signal proteins is to keep cells from undergoing apoptosis (cell suicide). My research team has deciphered the function of some key proteins and is continuing to study how proteins determine whether cells live or die. Our goal is to find ways to stimulate or block cell growth or death, which could lead, for example, to the ability to force cancer cells to die. We are also examining macrophages, scavenger cells that clean up debris and are important in the development of atherosclerosis (narrowing of the arteries), and the function of inflammatory cells in the immune system that respond to infection. This research will increase understanding of cell death and may lead to the development of new drug therapies for cancer, cardiovascular disease or inflammatory conditions such as asthma.
Investigation of the apolipoprotein C-II activation site of human lipoprotein lipase
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.
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.