Injuries are a significant public health problem in BC. Every year about 1,600 British Columbians die due to injury, 42,000 are hospitalized, and an estimated 400,000 people throughout the province sustain some sort of injury. The cumulative effect of injury on a population is known as the burden of injury. Burden of injury data help policy makers and practitioners determine the effectiveness of current services in injury prevention and injury treatment, and provide direction about new interventions that would have the greatest impact. They also help provide estimates for recovery time across different injuries. However, very little is known about the burden of injury, making this an important priority for research.
Dr. Mariana Brussoni is leading a longitudinal study in BC to quantify the impacts of injury on individuals and on the health system. Drawing on her experience working in England with international experts in injury research and prevention, Brussoni is recruiting more than 1,400 injured people of all ages across urban and rural settings in BC. They will be followed for 12 months post-injury, with the research team tracking their quality of life and recovery, use of health and social services, and time away from school or work. The goal of this research is to more fully describe the various impacts of injury in British Columbia, and to identify areas where prevention and treatment interventions could make the biggest difference.
While completing medical training in clinical genetics, Dr. Cornelius Boerkoel was consulted on two patients with a rare disease called Schimke immuno-osseous dysplasia (SIOD). At the time, there was little known about the disease, other than that it involved kidney failure and abnormal bone growth causing short height. Dr. Boerkoel’s early research in this area highlighted several previously unknown features of this disease, including the cause of SIOD: mutations (alterations) in both copies of a gene named SMARCAL1. He has also shown that SIOD arises from abnormal activity across most genes. Working with fly and mouse models that he developed to study SIOD, Dr. Boerkoel has created a model for studying how many small alterations in gene expression can cause disease.
Since common diseases such as atherosclerosis, stroke, endocrine dysfunction, immunodeficiency, and poor growth are all features of SIOD, this research is relevant to a better understanding of various unstudied mechanisms underlying these common diseases in the general population. To continue this work, Dr. Boerkoel will complete characterization of the function of SMARCAL1 using biochemical, fruit fly and mouse studies. He will test whether hormone supplementation might be an effective treatment for SIOD. Dr. Boerkoel will also determine whether the gene expression changes observed in SIOD are a feature in other patient populations affected with diseases also found in SIOD. This research will develop a new and unique model for understanding how changes in gene expression can predispose individuals to disease.
Lysosomes are structures that digest materials within the cell. Lysosomal storage diseases are devastating diseases caused by deficiencies of specific enzymes within the lysosomes. Mucopolysaccharidosis I (MPS I) is a progressive lysosomal storage disease that affects most organ systems. In severely affected humans, this genetic disease leads to early death because of profound disturbances to the heart, brain and other organ systems. One way to correct lysosomal enzyme deficiency is through using purified enzymes for enzyme replacement therapies (ERT). However, the current methods used to commercially produce the enzymes for ERT are prohibitively costly. Because of this, sustained financial support for ERT among affected Canadians is uncertain. Dr. Allison Kermode is exploring whether using plants as hosts to produce these human enzymes will offer a more economical way to provide ERT treatments for MPS I, as well as for Gaucher disease, another lysosomal storage disease. She will test whether plant-made human enzymes are effective as ERTs. She will also establish a plant-based system for assessing potential small molecule treatments for these diseases. Finally, in collaborative work, Kermode will test plant-made lysosomal enzymes in assays for newborn screening of lysosomal storage diseases. Some of the research will be expanded to other therapeutic proteins relevant to Type I diabetes, providing a general platform for plant production of therapeutic proteins.
Ion channels are cardiac membrane proteins that control the flow of ions like sodium and potassium in and out of heart cells, regulating both cardiac electrical impulses and the contractions associated with the heart beating. Voltage-gated potassium channels, such as the human ether-a-go-go related gene (hERG). are a class of ion channels that open and close – an action known as gating – in response to changes in the electrical potential across the cell’s plasma membrane. In the heart, hERG channels play a crucial role in regulating heart rate and rhythm. Reduced hERG channel function has been associated with loss of the normal heart rhythm and sudden cardiac death. The unique role played by hERG channels in the heart is a result of their unusual gating properties. However, there is limited knowledge about the molecular mechanisms of these gating processes and how they are modulated.
Dr. Tom Claydon is using a new fluorescence technique that he established as a post doctoral fellow that provides a real-time analysis of the protein motions that cause hERG channels to open and close. With a small fluorescent probe attached directly to the channel protein, Claydon’s team can directly study movements that occur within the channel as it opens and closes and measure the electrical current passing through the channel during this activity. Only a handful of researchers worldwide are currently using fluorescence experiments to study ion channel gating. These experiments will provide a comprehensive and unparalleled view of hERG channel function and how it is modulated in health and disease. An understanding of these processes will lay the foundation for new therapies for cardiovascular disease.
Statistics show that two per cent of Canadians aged 60-74 years, and one-third over the age of 85, suffer from Alzheimer's disease and related dementias. By 2031, more than 750,000 Canadians are expected to have Alzheimer's disease and related dementias. The social and financial costs of managing people with these conditions is significant and puts a severe strain on families and on the health system. Sadly, by the time Alzheimer’s symptoms are recognized and confirmed, there is often substantial irreversible neurodegenerative damage. Current methods of diagnosing Alzheimer’s disease are frustratingly inexact. Lacking ways to identify the onset of disease within the brain itself, clinicians instead look for telltale symptoms, such as failing memory. Even when the disease has progressed and structural changes become apparent on magnetic resonance imaging (MRI) scans, neurologists do not have tools to precisely measure how advanced the disease is, relying instead on visual inspection. Dr. Faisal Beg is trained in engineering, biology and mathematics. Drawing from international MRI databases containing the brain scans of hundreds of older adults with and without Alzheimer’s, he is taking precise measurements to pinpoint where and how brain structures change with the onset of the disease. It’s a complex analysis, made even more challenging due to the normal variations seen in brain shape, size and structure. Beg anticipates that his research will help take the guesswork out of diagnosing Alzheimer’s disease, especially in its early stages. In the longer term, it also may contribute to more accurate assessments of whether new Alzheimer’s drugs are effective in slowing or halting progression of the disease
With an aging population comes an increase in a number of diseases and conditions of the eye. A recent advance in imaging – called optical coherence tomography (OCT) – provides a non-invasive way to create high resolution, cross-sectional images of inside the eye. OCT is particularly useful in providing these images of the retina, showing cross sectional images of the various layers with resolution equivalent to a low-power microscope and better than other imaging techniques such as magnetic resonance imaging (MRI).
A new technological development called Fourier Domain (FD) OCT provides these images much more quickly than existing systems. It has also been successful in creating three-dimensional images of the retina, which were previously not possible to obtain. However, clinical use of FD OCT is limited as it generates only an image of the eye’s structures, without providing any functional information about the biological processes at play.
Dr. Marinko Sarunic’s research builds on earlier work where he successfully combined FD OCT imaging with molecular contrast capabilities to provide functional information. He is now using this technology to determine its usefulness in retinal diagnostics, the study of disease processes, and the testing of new drugs and therapies. Development of FD OCT imaging techniques will help physicians better understand and manage ophthalmic conditions, through high resolution visualization and improved minimally-invasive, image-guided procedures.
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.
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.
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.
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.
