Cardiovascular disease (CVD) and osteoporosis are major health problems in North America. CVD is the leading cause of death of North American women, and one in four Canadian women over the age of 50 has osteoporosis. Once a woman reaches menopause, the risk for both osteoporosis and CVD increases substantially. Both diseases were thought to be independent consequences of aging. However, mounting evidence shows links between these diseases. For example, a widely used class of cholesterol lowering drugs, known as statins, reduces atherosclerosis (hardening of the arteries) and also increases bone health. Exercise may also provide the same health benefits, but more than 60 percent of Canadian women between 50 and 70 are not active enough to reduce their risk of heart disease or osteoporosis. Dr. Darren Warburton is studying the combined effect of statins and exercise on cardiovascular and bone health, physical fitness and quality of life. The research could provide important new information to help develop prevention and treatment programs for these diseases in post-menopausal women.
Research Location: Providence Health Care
Cellular excitation contraction coupling of intact airway smooth muscle
Diseases of the airways, such as asthma, are often characterized by excessive constriction of tissues caused by the over-contracting of smooth muscle cells. This contraction can severely impair breathing and compromise oxygen exchange between the lungs and blood system. Calcium is a major activator of smooth muscle cell contraction, and the concentration of calcium within cells determines the extent of contraction. Using intact airway muscle tissues, Jiazhen Dai is undertaking an extensive survey of the pattern and the mechanisms of calcium-dependent contraction in both healthy and diseased airways. In particular, she will investigate a newly-uncovered pattern of asynchronous, wave-like calcium oscillation to assess its role in airway constriction. This research will provide a better understanding of the mechanisms of airway constriction and ultimately, new drugs to effectively treat respiratory conditions such as asthma.
Barriers to access and willingness to participate in an intervention program to reduce the incidence of HIV and Hepatitis C among drug dependent youth
In her Masters research Cari Miller showed there is a high prevalence and incidence of HIV and Hepatitis C among young injection users in Vancouver. Those at highest risk for HIV are young females and Aboriginal youth. Her research suggested that preventing infection requires a complex response, addressing risky drug and sexual behaviours. Cari is building on her earlier research to investigate the barriers to accessing current prevention tools such as clean needles and condoms. As well, she is examining the willingness of youth to participate in a behavioural intervention to reduce the risk of HIV and Hepatitis C. The research will inform policy on current methods of prevention and possibly help to develop new ones. Cari’s work could also help empower youth to better care for their health and for the health of their peers.
Factors impeding the success of HIV antiretroviral therapy today: Genetic variation, viral evolution and drug resistance, and cellular reservoirs of HIV
Revolutionary new therapies for HIV/AIDS introduced in the mid-1990s have helped to dramatically reduce deaths resulting from HIV infection. However, despite these advances, the prospect of a cure for HIV infection remains a distant goal. Drawing on the expertise at the BC Centre for Excellence in HIV/AIDS, Zabrina Brumme is researching the genetic factors that may influence HIV disease progression and individual response to therapies, with the goal of better optimizing and tailoring HIV therapy to each patient. Zabrina will also study “viral reservoirs,” cell types that are believed to “hide” HIV for long periods of time over the course of the infection. This project could lead to anti-HIV therapies directed specifically against viral reservoirs, increasing the chance of survival and improving the quality of life for HIV patients.
Role of alveolar macrophage proteinase genetic polymorphisms in the development of emphysema
Emphysema is a destructive lung disease that obstructs the airways and compromises oxygen transfer from the lungs to the bloodstream, causing a decrease in respiratory function. More than 1,100 people die of the disease in Canada each year. Currently, there are no treatments to cure emphysema. Cigarette smoking is the major risk factor for developing the disease. Yet only 15 to 20 per cent of smokers develop symptoms. An increase in protein-degrading enzymes called proteinases is believed to play a role in the origin of emphysema. Previous studies also suggest a genetic predisposition to airflow obstruction. Variations in the genes regulating these proteinase enzymes may be responsible for individual differences in response to cigarette smoke. Alison Wallace is researching whether genetic variants in proteinases increase smokers’ susceptibility to emphysema. If so, this information would help identify people at risk for the disease, contributing to early promotion of anti-smoking strategies and possibly leading to new methods for early detection and treatment. In addition, drugs that inhibit proteinases could be targeted to patients predisposed to emphysema, but unable to quit smoking.
Translating mechanistic understanding of the systemic inflammatory response syndrome (SIRS) to clinical practice via genomics
Each year, about 75,000 patients in Canada will develop sepsis (severe infection). Although it is reversible, sepsis often causes death. Sepsis and a related condition, systemic inflammatory response syndrome (SIRS), lead to multiple organ dysfunction and are the most common reasons for admission to intensive care units. Using genetic information that became available after completion of the human genome project, Dr. Keith Walley is researching the genetic determinants of the acute inflammatory response and organ failure associated with sepsis. His aim is to clarify the genetic mechanisms which give rise to the inflammatory response and to apply this information to identify patients who are at risk for adverse outcomes based on their genotype (genetic make-up). His ultimate goal is individualized management of patients with sepsis, based on knowledge of the way their genotype will influence their susceptibility to and risk of developing life-threatening symptoms, as well as their ability to respond to treatment.
Drug-related mitochondrial toxicity in HIV and HCV antiretroviral therapy: impact of mitochondrial DNA/nuclear DNA ratio changes on therapy outcome
Triple combination antiretroviral therapy has greatly reduced the rate at which people with HIV infections progress to AIDS. However, the medications used in the therapy can be quite toxic, leading to serious liver, kidney, muscle and nerve problems and reducing the length of time patients are able to tolerate the treatment. Dr. Hélène Côté and colleagues at the BC Centre for Excellence in HIV/AIDS have developed a blood test to measure toxicity from antiretroviral therapy and are now assessing its effectiveness in detecting and monitoring toxicity levels. She is also investigating whether the test could predict complications from drug therapy before serious symptoms appear. If so, it could be used to tailor use of antiretroviral therapy and improve treatment outcomes. As part of the research, Dr. Côté also is studying the effectiveness of the blood test in measuring toxicity of medications used for hepatitis C.
Regulation and role of granzyme B in Atheromatous Diseases
Atherosclerosis – hardening of arteries – is caused by buildup of plaque inside artery walls. This constricts blood flow and elevates blood pressure, and is the leading cause of heart attacks, stroke and lower limb loss due to poor circulation. There is evidence that immune cells provoke a tightly-regulated form of cell death known as apoptosis (programmed cell death) in atherosclerotic blood vessel walls, which contributes to progression of the disease. While the mechanisms are not clearly understood, the result is a change in the architecture of blood vessel walls that leads to additional plaque build-up and also to plaque instability. The latter increases the danger of pieces of plaque breaking off and potentially lodging in and blocking blood flow in smaller vessels. In previous work, Dr. David Granville and his research team have found that an enzyme used by the immune system to kill abnormal and infected cells is released in atherosclerotic blood vessels. Dr. Granville is studying the role of this enzyme – granzyme B – in vessel wall restructuring and cell death associated with atherosclerosis and transplant vascular disease. Findings from this research may reveal new opportunities for intervening to prevent or treat these vascular disorders.
Genetic modifiers of pulmonary disease severity in cystic fibrosis
Cystic fibrosis is a severe genetic disorder caused by a single gene called the cystic fibrosis transmembrane regulator (CFTR). The disease is characterized by chronic and persistent respiratory infections, which progressively damage and eventually destroy lung function. Research has shown that cystic fibrosis patients with the same alteration in the CFTR gene may each follow a very different clinical course: with one patient having very mild lung disease and infrequent lung infections, while another will have frequent lung infections and significantly decreased lung function. Dr. Andrew Sandford is investigating genes other the CFTR gene that may play a role in causing lung disease to progress more quickly in some cystic fibrosis patients than in others. It is thought that cystic fibrosis patients may also have compromised immune function. For this reason, Dr. Sandford is looking for genes involved in fighting infections and in controlling the inflammatory response to the bacteria and viruses that attack the lungs.
The value of cardiac specific troponin in predicting cardiac outcomes in an asymptomatic chronic kidney disease population
Chronic kidney disease is associated with a high risk for heart attack, even after accounting for traditional cardiac risk factors such as smoking and high cholesterol. The risk increases as kidney function deteriorates. Elevated levels of a cardiac enzyme called cardiac specific troponin (cTn) have been shown to predict heart attack or death in people with acute coronary conditions. Some studies also suggest that elevated cTn can predict cardiac outcomes in patients with chronic kidney disease who do not present cardiac risk factors. Nadia Khan is researching whether elevated levels of cTn can be used to accurately predict heart attack and death in patients with different levels of chronic kidney disease. The results could help clinicians identify patients with chronic kidney disease who are at high risk of heart disease, and also provide the foundation for developing therapies that prevent cardiac disability and death in this patient population.