Stroke is the leading cause of neurological disability in Canada. Most stroke survivors have a number of other related conditions, including heart disease, diabetes, obesity and high blood pressure, which contribute to their risk of additional strokes. Exercise not only improves fitness, it also has the potential to reduce the risk of heart disease and stroke.
Dr. Ada Tang is working to understand how aerobic exercise can influence stroke risk factors and heart and arterial function in those who have already had a stroke. She will be evaluating the effects of an exercise program on 51 participants between the ages of 50 and 80, all of whom are one-year post stroke and can walk short distances without help. Participants will be randomly assigned to either an aerobic exercise program, or to a balance and flexibility program. Both programs are conducted at Vancouver General Hospital and feature three one-hour sessions per week. Program participants are carefully monitored during their exercise sessions. The participants’ fitness level and blood pressure will be tested at the start and the end of the six-month exercise program and two months after the end of the program to see if the benefits are maintained. Echocardiograms will be performed to look at heart size and function, blood tests will measure cholesterol levels and other signs of inflammation, and other tests will be done to determine how exercise can improve artery flexibility, heart rate and rhythm.
This study will help us better understand how exercise after stroke can improve heart function and heart health. Research results will help health professionals understand the best way to promote a healthy lifestyle after stroke to lower the risk of heart disease or another stroke.
Lung cancer is one of the largest health burdens worldwide: in Canada alone, lung cancer causes more cancer-related deaths than breast, colon, and prostate cancers combined. Smoking cessation programs have been highly successful, and the population of former smokers in Canada is well over seven million. Unfortunately, while quitting smoking is a proactive step, former smokers are still at risk for developing lung cancer. This cancer risk in former smokers will remain one of Canada’s most significant health concerns for the next 50 years. The molecular mechanisms responsible for the development of lung cancer in former smokers are not known. Recent studies have shown that although the majority of smoking-induced genetic damage returns to normal after smoking cessation, some genes are permanently damaged and never return to the pre-smoking state. Some of these irreversible genes are likely those that act as the gatekeepers for cancer development. Dr. Ewan Gibb’s research project will identify the genes in former smokers which do not return to normal after smoking cessation. He will be using integrative genomics to compare samples from former smokers with cancer and those without. This information will help Dr. Gibb understand why some former smokers go on to develop lung cancer while others remain cancer-free despite similar changes in lifestyle. This set of irreversibly damaged genes can serve as novel targets for anticancer therapies or may be developed as diagnostic markers for early detection of lung cancer while therapies are still effective.
Asthma patients are at risk of potentially severe and sometimes lethal exacerbations. These exacerbations can be caused by a variety of triggers, such as infections or exposure to allergens. Diesel exhaust and other traffic-related constituents can also be inhaled along with the allergen. This multi-inhalant mixture results in immune reactions that are more complex than exposure to the allergen alone. Although it is well established that multi-inhalant mixtures of allergens and pollution contribute to asthma exacerbations, research in this area typically focuses on exposures to single agents, either diesel exhaust or allergens alone.
Dr. Francesco Sava is investigating the relationship and the synergies that exist between diesel exhaust and allergen-triggered asthma exacerbations using a live-patient model. His aim is to demonstrate that inhalation of diesel exhaust increases allergen-induced inflammation in the lungs of asthmatic patients. Using state-of-the-art equipment, he will expose patients to controlled diesel exhaust concentrations. A very small amount of allergen will be introduced into a segment of the patients’ lungs, and the resulting inflammation will be measured. This multi-inhalant exposure model reflects the real-life conditions that patients are likely to encounter. The experimental model he uses has been widely studied, is very safe, and allows researchers to test allergens on humans without triggering an overt asthma attack.
The research will help define the synergies between the real-world concentrations of inhaled diesel exhaust and allergen exposure in the asthmatic population. This information will likely lead to recommendations for air quality and strategies to protect vulnerable populations.
The cilium is an extension on most cells and tissues that works similarly to a television antenna, in that it receives signals from the environment. When a mutation disrupts the function of cilia, cells no longer receive the proper environmental input. Mutations in cilia proteins have been identified in patients with clinical ailments such as blindness, obesity, diabetes and polycystic kidney disease; some are also found in syndromes encompassing all or most of these disorders. Although some of these syndromes affect entire families, the molecular and cellular causes of these disorders have not been identified or characterized; for this reason there are no therapies available. Dr. Victor Jensen aims to study and identify novel cilia genes that are associated with multiple disorders, including blindness and obesity. These results will provide essential information about the association between disease and different genes, as well as the function of cilia. This unique approach to gene discovery and characterization was developed in the laboratory of Dr. Leroux, and has already led to the discovery and understanding of numerous disease genes, including those associated with the multi-systemic Bardet-Biedl syndrome. Dr. Jensen’s research work is therefore aimed at providing novel insights into the nature and function of disease genes, a step that will eventually lead to improved treatments or prevention of common human medical ailments.
Diabetics are two to four times more likely than non-diabetics to suffer a stroke during their lifetime, and their prognosis for recovery from stroke is poor. Diabetes is known to negatively affect blood vessels throughout the body, including the eye, heart, kidney, and limbs, leading to a heightened risk of stroke in diabetics. Poor circulation and peripheral nerve damage can lead to blindness, hearing loss, foot injury and amputation. High blood pressure is common in diabetics and increases the risk of heart disease and stroke. However, little is known about how the vascular changes associated with diabetes affect the brain and contribute to poorer recovery of function following stroke.
Dr. Kelly Tennant's research will determine why diabetics suffer from greater impairments following strokes. She will monitor changes in neurons and blood vessels over time following a stroke in diabetic mice and assess the relationship between these changes and recovered use of the forelimb. Dr. Tennant will employ cutting edge in vivo imaging technologies such as intrinsic optical signal, two-photon, and voltage sensitive dye imaging, combined with behavioural testing of forelimb function.
These experiments will shed light on how neurons and blood vessels of diabetics respond differently to ischemic stroke and how these differences contribute to poor behavioural recovery in diabetic stroke survivors. This research will aid understanding of the greater impairment caused by stroke in diabetic patients and lead towards development of treatments that ameliorate the negative effects of diabetes on the brain.
Inflammatory diseases are common, debilitating and affect the well-being of millions of people worldwide. Almost any part of the body can become inflamed, resulting in pain and suffering. For example, Crohn's disease, or colitis, is caused by intestinal inflammation and is manifested by pain, diarrhea and weight loss. Asthma is caused by the inflammation of lung airways and impacts breathing. Atherosclerosis, which involves blood vessel inflammation, leads to heart attacks, strokes, blindness and poor circulation. Because of the wide impact of these diseases, there is an urgent need to control and treat inflammation. The Conway lab was the first to determine that a protein called CD248, plays an important role in controlling inflammatory disorders. When inflammation is present, CD248 is made in high amounts by both stromal and perivascular cells, which reside in all tissues of the body. By generating mice that lack CD248 or a part of the molecule, Dr. Conway's group tested the hypothesis that CD248 might make inflammation worse. Indeed, CD248 ""knockout"" mice develop less severe joint inflammation (arthritis). This finding — that CD248 is involved in inflammation — was very significant, as it points to CD248 as a potential drug target for anti-inflammatory drugs. Dr. Yanet Valdez is now taking this research one step further to determine exactly how CD248 increases inflammation. She is using various biochemical methods to determine which inflammatory diseases are affected by CD248 and what parts of the CD248 protein influence inflammation. The studies will help her figure out how to better turn off the pro-inflammatory effects of CD248 and devise therapies to reduce inflammation severity.
Multiple sclerosis (MS) is a relatively common neurological disease. Because of its chronic nature and because it typically first appears in people in their mid 20s to 30s, people with MS are usually expected to live for many years following disease onset. Little is known about survival expectations, predictors of long-term survival, how survival is influenced by MS drug therapies, and causes of death in this population. Ever since immunomodulatory therapies first became available to Canadian MS patients in the mid 1990s, there has been a rapid uptake of these drugs. These medications appear to be at least partially effective in modifying some aspects of the disease, such as relapses, but they are associated with significant side effects, require frequent injections, and are expensive. The long-term impact of treatment is unknown and opportunities to study treatment-naïve patients have diminished over the years, as there are fewer patients with MS who have not taken these therapies. In British Columbia, we have a valuable data resource that includes both unexposed (untreated) and treated MS patients.
Dr. Elaine Kingwell is combining several large, powerful, clinical and administrative longitudinal datasets, including the population-based BC MS clinical database (containing data from approximately 7,000 MS patients over a 30-year period), BC Ministry of Health medical services plan registration data, BC Vital Statistics death data and BC Cancer Agency data. She will use this data set to determine the long-term health impacts of MS and how they are influenced by immunomodulatory drugs. She will specifically compare the causes of death (including cancer, suicide, heart disease and infection) between people with MS and the general population.
Dr. Kingwell will also investigate cancer survival of MS patients in comparison to the general population, which is an area of some controversy. She will determine how frequently MS is listed as an underlying or contributing cause of death, which will help to facilitate planning and interpretation of population-based studies of MS mortality trends. Findings from this study will further our understanding of the role that MS plays in long-term health outcomes, such as cancer survival, and will broaden our existing knowledge of factors associated with longevity in MS. These results will also provide a vital estimate of the impact of immunomodulatory therapy on survival and specific causes of death for MS. The findings from this research will have a profound impact on the care, monitoring and treatment of the disease.
Myelodysplastic syndromes (MDS) are diseases of the blood and bone marrow. MDS originate when a stem cell, from which all other blood cells originate, becomes mutated and then overgrows and crowds out other cells. This results in reduced numbers of red cells (anemia), white cells (leukopenia) and platelets (thrombocytopenia) circulating in the blood. As the disease progresses, bone marrow may completely fail to produce normal cells, and the myelodysplastic stem cell may develop into cancer, Acute myeloid leukemia (AML). The exact molecular causes for MDS are unknown; however, a common feature of MDS is chromosomal abnormality, the loss of the long arm (q) of the chromosome 5 being one of the most common in a subtype of MDS called 5q- syndrome. This lost region of 5q likely harbors several important genes, which may prevent MDS.
Dr. Joanna Wegrzyn Woltosz's research project will decipher the molecular mechanism of the disease and identify targets of a new drug (lenalidomide) currently used in MDS treatment. She is studying two important factors that are located on the 5q arm and are involved in the development of MDS (1) the RPS14 gene, which is thought to be responsible for the anemia seen in MDS patients, and (2) microRNAs, whose loss allows the abnormal MDS stem cells to survive and grow more than the other bone marrow cells. Since lenalidomide reverses symptoms resulting from loss of the microRNAs, she will also study whether lenalidomide increases the expression of these microRNAs. Currently, the only treatment for MDS is high-dose chemotherapy with stem cell transplantation, which is risky and challenging for patients to endure.
The information Dr. Wegrzyn Woltosz expects to obtain from this study will not only help to better understand the molecular mechanism underlying MDS, but will suggest novel steps towards the development of better therapies that will improve treatment and quality of life and increase survival for MDS patients.
Sleep apnea occurs when a person repeatedly stops breathing for a short period of time while they sleep. This common disorder affects about 20 per cent of Canadians. During sleep apnea episodes, blood oxygen levels fall, resulting in persistent low levels of oxygen, called hypoxia. Consequently, people with sleep apnea commonly experience adverse health outcomes, including high blood pressure, heart attacks and strokes. Preliminary findings from Dr. Philip Ainslie’s research lab have shown that reductions in brain blood flow can worsen sleep apnea, while increases in brain blood flow may reduce it. Dr. Shawnda Morrison’s research will expand on these exciting initial findings by exploring the possibility of treating sleep apnea by manipulating brain blood flow. Dr. Morrison will use sophisticated imaging techniques to examine the effect of an oral medication, which alters brain blood flow, in patients at rest and while they sleep. Her first study will examine patients with and without sleep apnea in a controlled laboratory setting. In her second study, Dr. Morrison will induce sleep apnea in otherwise healthy humans at high altitude (5,000 metres, near the base camp of Mt. Everest, Nepal). In this study, she will also conduct the same experiments on a group of high-altitude residents who do not develop sleep apnea, and compare any differences observed between the two groups. The results of these studies will have major implications for understanding what influences brain blood flow and how these different factors can then affect sleep apnea. Those people who do not develop sleep apnea will provide insight into future sleep apnea treatments. Indeed, these studies will provide a “proof of concept” that an oral medication, which alters brain blood flow, can be an effective treatment for sleep apnea. This will, in turn, dramatically reduce the incidence of heart disease and stroke in patients who have sleep apnea.
Cardiac arrhythmias are on the rise in our aging population. They are electrical disturbances in the heart that can cause a wide variety of potentially life-threatening conditions, including an increased chance of stroke or, in the case of heart failure, sudden death. Anti-arrhythmic drugs that target a particular type of protein called an “ion channel” are useful in converting these irregular heart rhythms back to a normal beating. Unfortunately, many available anti-arrhythmic drugs have serious side effects. The basic action mechanisms of anti-arrhythmic drugs are not understood, and the chemical characteristics of good/safe anti-arrhythmic drugs are not known. This makes it difficult to engineer the next generation of life-saving cardiac drugs. Dr. Stephan Pless is aiming to fill crucial gaps in our understanding of how anti-arrhythmic drugs regulate heart function. By combining cutting-edge chemical methods with computer modeling, he has already made significant progress in defining the essential characteristics of what makes a “good” anti-arrhythmic drug. His next goal is even more important, as it aims to define the precise nature of the heart receptor through which anti-arrhythmic drugs modulate electric excitability. For this purpose, he will employ novel artificial amino acids to delineate the precise location of the receptor and will use novel fluorescent probes to give us insights into the atomic-level movements of the receptor during drug binding. All of the technologies used here have been tested in other relevant systems, but never for this application; therefore, it places Dr. Pless in a position to make a substantial contribution to the cardiovascular health of Canadians.
