Asthma is the most common chronic disease in childhood and continues to increase in prevalence in adults. Every day, lung airways are subjected to challenges that damage their lining, known as the epithelium. The accumulation of damaged epithelium is a common and consistent feature in those with asthma, suggesting that asthmatics are more susceptible to damage, or are less able to repair the epithelium, than people without asthma. While the epithelium normally protects the underlying tissue from noxious particles, epithelial damage may account for airway hyper-reactivity in asthma, and the chronic nature of the disease. Previously supported by an MSFHR Scholar award, Dr. Delbert Dorscheid is researching the role of glycosylated proteins – proteins that have a sugar or sugar chain added to them – in epithelial repair. These proteins appear on the surface of cells that mediate repair, and their formation heralds the start of cell repair. Dorscheid has identified a specific protein that’s linked to the beginning of this process. His goal is to observe any changes in the modification and regulation of this receptor in asthmatic airways and healthy airways, and determine how this may influence injury and repair of the airway. The overall objective is to better understand the differences in asthmatic airways to develop new treatment strategies to improve the quality of life of those who suffer from this disease.
Research Location: St Paul's Hospital
Genetic Susceptibility to Inflammatory Airway Diseases
Chronic inflammatory airway diseases include asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF). Together, these conditions contribute to an enormous burden of death and disability worldwide. It’s estimated that 10 to 15% of 13- to 14-year-olds in Canada are asthmatic. COPD affects close to half a million Canadians 35 and older, currently ranking 12th worldwide as a cause of lost quantity and quality of life and projected to rank 5th by the year 2020. CF is the most common, fatal genetic disease affecting Canadian children and adolescents.
There is compelling evidence supporting a hereditary pattern to virtually all of the major inflammatory diseases. For example, more than 1,000 CF-causing gene mutations have been identified. Although some mutations are associated with less severe disease, patients possessing the same mutations often show great variation in disease severity and progression. Significant advances in molecular genetics make it possible to discover the specific genetic variants that determine individual susceptibility to these illnesses.
Dr. Andrew Sandford is investigating the genetic variants that cause susceptibility to asthma and COPD. He is also focused on the role of genetics in CF. He works with a unique group of patient families who have previously been involved in studies to establish the associations between their genetic variations and their disease symptoms. A better understanding of the causes of inflammatory airway diseases will contribute to better prevention and/or intervention measures and more efficient treatment strategies.
Increased nitric oxide bioavailability through regulated eNOS-Caveolin-1 antagonism
Hypertension (high blood pressure) has a direct link to aging and is a major risk factor for atherosclerosis (narrowing and hardening of the arteries over time), stroke, heart attack and chronic renal failure. All known cardiovascular diseases, including hypertension, have in common a disease called endothelial dysfunction. The endothelium is a layer of cells that line the cavities of the heart, as well as the blood and lymph vessels. With endothelial disease, these cells do not function as well. Aging is known to induce and aggravate endothelial dysfunction, suggesting that endothelial dysfunction is unavoidable. One of the hallmarks of endothelial dysfunction is a decrease in the synthesis and availability of nitric oxide, which promotes dilation or relaxation of the blood vessels. Under normal conditions, nitric oxide significantly contributes to resting vasodilator tone and works to maintain a smooth and healthy vascular endothelium.
Dr. Pascal Bernatchez has uncovered a novel molecular approach that increases endothelial function and nitric oxide availability in aged vessels, while young vessels remain unaffected by the intervention. This suggests that there may be a molecular cause for how endothelial dysfunction develops. Bernatchez’s research will contribute to knowledge about how this approach restores endothelial function in an age-specific manner, how it regulates blood pressure and how endothelial dysfunction occurs. The findings may lead to novel therapeutic avenues for the range of cardiovascular diseases characterized by endothelial dysfunction.
Sex differences in patients presenting with acute myocardial infarction or chest pain without angiographic evidence of coronary disease
Although heart disease is a leading cause of death for men and women, sex/gender differences in the disease have only recently received attention. Evidence suggests there are sex/gender differences relating to prevalence, presentation, diagnosis, treatment and outcomes of heart disease, but little is known about the underlying causes. An emerging area of interest is the fact the magnitude of the sex/gender difference in outcomes following a heart attack (favoring men) is much greater among younger women and men than among older patients. Research in this area suggests that this difference persists even after adjusting conventional risk factors.
A leading investigator in the area of cardiac health outcomes, Dr. Karin Humphries has found in previous research that among women and men with chest pain but no evidence of heart disease, women’s outcomes are worse. Now she is focusing on two primary questions: why these women have worse outcomes than men, and what is the relevance of non-traditional risk factors, such as quality of life and psychosocial factors, in young women and men who present to hospital with a heart attack. The results of these studies will provide new knowledge about sex/gender differences and heart disease. Humphries aims to increase understanding of quality of life differences between young men and women who suffer a heart attack, which may help explain the different outcomes and help with the development of new strategies for diagnosis, treatment and support of women with heart disease.
Economic studies of seniors at high risk of falls
Falls are a major public health problem in BC and around the world. Every year, approximately one third of adults in the community aged 65 years and older will fall. In BC, falls are responsible for 85 per cent of the $211 million annual direct cost of unintentional injuries. In New Zealand, a physiotherapist-initiated, progressive, home-based strength and balance training program reduced falls by 35 per cent; it proved cost-effective in persons aged 80 years and older. This program is currently undergoing a randomized clinical trial in BC for high-risk seniors. However, no economic outcomes have been published for any intervention to prevent falls in Canada. Jennifer Davis was previously funded by MSFHR for her early PhD work with the Falls Prevention Clinic at Vancouver General Hospital. Her current studies use economic data from the BC fall prevention trial to determine the cost implications of this program. Comparing this new program with the current standard of care, she will calculate the dollar cost per fall avoided, and the dollar cost per Quality Adjusted Life Year (a measure of disease burden, including both the quality and the quantity of life lived). She aims to perform cost-effectiveness and cost-utility analyses of the possible benefit of various types of exercise interventions compared with usual care. Davis’ long term research goal is to pioneer the improved economic evaluation of the burden of falls among seniors in Canada. This work will provide essential data for policy makers allocate health care resources in the most effective way.
Prediction of cardiovascular mortality in patients with coronary artery disease using plasma and genetic markers of oxidative stress
Coronary artery disease (CAD) is the leading cause of death worldwide. The consequences of CAD severely burden the Canadian health care system, and expensive therapeutic solutions have only limited capacity for preventing or reversing the disease. Oxidized low density lipoprotein particles (oxLDL) contribute to the progression of CAD. OxLDL are a harmful byproduct produced by oxidative stress, which occurs when the production of free radicals in the body exceeds the body’s ability to neutralize and eliminate them. The environmental factors that increase the risk of CAD, such as poor nutrition, smoking, obesity, and low physical activity, are the same factors that increase oxidative stress levels in the body. Claire Heslop is studying the influence of oxidative stress on long-term survival among people with CAD, and investigating genetic differences that contribute to this relationship. She is evaluating whether markers of oxidative stress in the blood, as well as markers of inflammation, can predict risk of death from cardiovascular disease in individuals with CAD. She will also investigate oxidative stress genes to determine how inherited differences affect oxidative stress in the blood, the risk of CAD, and the risk of cardiovascular death. As part of this project, the relationships between CAD, oxidative stress markers and various physiological, lifestyle and socioeconomic risk factors will also be examined. Heslop’s work will contribute to our understanding of the role oxidative stress plays in coronary artery disease. This study may inspire the creation of new tools for diagnosing CAD and predicting long-term risk.
The role of AMP-activated protein kinase on glycolysis and myocardial remodeling in the hypertrophied heart
A heart that has become enlarged in response to a pressure overload, such as with high blood pressure, has reduced function compared to a normal heart. This impaired function is particularly apparent during and after interruption of the blood supply, which can occur when a blood clot blocks a diseased coronary artery, or during open heart surgery. This reduced heart function can be very dangerous for the patient. Enlarged hearts use glucose to a greater extent than normal, a situation that appears to contribute to their exaggerated dysfunction. The mechanisms responsible for the accelerated utilization of glucose in enlarged hearts are not yet known. Dr. Minnie Dai was previously funded by MSFHR for her doctoral training. Currently, she is working to determine the mechanisms behind accelerated rates of glucose utilization in enlarged hearts. Using molecular biology techniques, she will selectively and specifically alter the activity of potentially relevant proteins in order to determine their role in causing accelerated glucose utilization. Her studies are unique in that the activity of proteins will be altered at specific times and will be altered only in the heart – ensuring that changes observed are truly related to alterations in these proteins. Many people suffer ill health because of an enlarged heart. By understanding the mechanisms responsible for their accelerated use of glucose, researchers may be able to identify targets for the development of drugs designed to altered glucose use by enlarged hearts, thereby improving their function.
Vascular Endothelial Growth Factor Signalling in Cardiac Allograft Vasculopathy
Atherosclerosis, also known as hardening of the arteries, is a common vascular disease caused by the buildup of a waxy plaque on the inside of blood vessels. This narrowing of blood vessels can cause blood clots, leading to heart attack or stroke. In almost half of all heart transplant patients, an accelerated form of hardening of the arteries, known as Transplant Vascular Disease (TVD), occurs in the transplanted heart. In fact, TVD is a leading cause of death one year after transplantation. The exact mechanisms behind this process remain unclear. Blood vessels are lined with endothelial cells, specific cells that create a barrier between blood and the artery. An important factor in TVD is damage to endothelial cells. This damage increases the size of gaps between cells, allowing fats to accumulate in artery walls. One protein that causes endothelial “”leakiness”” is called Vascular Endothelial Growth Factor (VEGF). VEGF is also important in many other serious diseases, such as cancer and degenerative eye diseases. David Lin is expanding on previous research that showed that VEGF is increased in the muscle cells in arteries of transplanted hearts. He is studying in detail the mechanisms by which VEGF alters the function and structure of endothelial cells. By learning how VEGF works in transplanted hearts, Lin hopes his research will lead to the development of new ways to maintain the health of heart blood vessels following transplantation.
The Genetics of Asthma, Atopy and Allergic Diseases
My research focuses on trying to identify why some children get asthma and others do not. By identifing specific environmental and genetic risk factors and determining how they work together to predispose children to developing asthma and other allergic diseases we can design better treatments. Studies have found a 1-in-5 risk of developing asthma if one parent has asthma. The odds rise to 2 out of 3 if both parents have asthma. However, in itself, a genetic predisposition does not ensure that asthma will develop. Asthma and allergic disease are the result of both genetics and the environment. The interaction between a genetic disposition and environmental factors is key in the development of – or in protecting against- asthma. I will use information from 250 French Canadian Asthma Families and two additional birth cohorts, and information from the town of Busselton Australia in my research. Home visits were conducted for all the families and children to collect information on environmental factors such as family history, number of children, parental occupations, daycare, pets, dust samples, infections, hospitalizations and medication usage. After reviewing the literature we have found 162 genes which may predispose children to developing asthma and we will be looking at these genes in conjuction with other environmental factors to try and better understand why some children develop asthma and others do not. Using statistical models we will look at what genetic and environment factors best explain why some children develop asthma and others do not. We will then do further laboratory experiments to try and identify these factors work together.
Mechanisms and consequences of aberrant repair in the lung
The World Health Organization estimates that between 100 million and 150 million people worldwide suffer from Asthma. The disease places a huge burden on the health-care system, with economic costs greater than of TB and HIV/AIDS combined. While less common than Asthma, Idiopathic Pulmonary Fibrosis (IPF) is a devastating disease since there is no cure or effective therapy. In North America and Canada there are over 200,000 patients with this disease. Of these more than 40,000 die annually. This is the same number of people that die from breast cancer annually. Currently we think that the pathology of both diseases follows a pathway similar to normal wound healing, although there is progression of the disease because the normal «braking» mechanisms do not function properly. As a consequence, too much connective tissue is produced. My research focuses on the cells that line the airways, called the epithelium and the cells that produce the connective tissue, called fibroblasts. Epithelial cells are important since they are the first cell in the lung that interacts with the air and are therefore most likely to be injured. We think that if the epithelium does not repair properly, it will signal the fibroblasts to continue making connective tissue inappropriately.