Repetitive-use tendinopathy, formerly known as tendonitis, is a major cause of repetitive strain injury (RSI). The occupational costs of RSI are enormous: work-related injuries cost Canada $8.6 billion annually and an estimated one-third of workers' compensation costs in industry are due to RSI of soft tissues, particularly tendons. In 2001, 2.3 million Canadians reported an RSI, and the average time lost from work per case of tendon-related injuries was 79 days (Source: StatsCanada 2001). Despite the enormous clinical, societal, and economic significance of RSIs, there is only limited understanding of the mechanisms that cause them.
In order to establish new treatments for RSI, Dr. Alexander Scott has established an innovative tendinopathy research program. He is incorporating a multi-disciplinary approach from basic to clinical science, which integrates a number of different methods, including molecular and cell biology, biomechanics, and rehabilitation science. His work will focus on the role of new blood vessel formation as a feature of chronic tendon injury. This work promises basic insight into the biology of RSI as well as directly applicable knowledge to develop new therapeutic strategies. This will be the first research program in Canada to have a primary focus on the biology of work-related tendon overuse injuries using a multidisciplinary approach. The ultimate vision of this program is to find better treatments for work-related tendon injuries.
Provoked vestibulodynia (PVD) is severe pain at the vaginal opening and the most common form of chronic genital pain in women. Although as many as 14 per cent of Canadian women and 20 per cent of adolescents are affected by this condition, it is frequently underdiagnosed and undertreated, and as a result, many women experience sexual difficulties, emotional distress, and multiple medical visits. Although different types of treatment exist, ranging from medication to psychological therapy, the best treatments to reduce PVD pain and distress, and which patients will benefit the most, are not known. Evidence indicates that psychological therapies such as cognitive behavioural therapy (CBT) and mindfulness-based therapy (MBT) are effective at reducing pain and sex-related distress for women with PVD. CBT is designed to challenge thoughts and uses active strategies (e.g. progressive muscle relaxation to decrease muscle tension) to change one’s experience, whereas MBT teaches individuals to be nonjudgmental and accepting of their experience and to learn to live without reacting to pain. Dr. Kelly Smith’s aim is to determine whether CBT or MBT is the most effective approach for reducing PVD pain and improving women’s quality of life, and she will determine which patient characteristics are associated with better responses to these treatments. She will be examining personal and medical characteristics for women with PVD who participated in the Multidisciplinary Vulvodynia Program, a treatment program based at Vancouver General Hospital for women with chronic genital pain. She will then study whether CBT or MBT is related to greater pain reduction and improvements in sexual function/emotional distress in a group of 70 women participating in an 8-session CBT or MBT group program. At the end of the study, women will be interviewed to assess their satisfaction with the program and provide feedback on how to improve the program. Dr. Smith’s studies will be the first to provide information on which of these psychological treatments works best for specific types of women with PVD. This information will provide clinicians with evidence-based guidance regarding potential treatment recommendations and will be essential in helping to reduce the health and economic burdens associated with PVD. Dr. Smith’s final results will be communicated to physicians and other health providers in British Columbia, and her findings will be submitted for publication in professional, wide-reaching health journals.
Motor vehicle crashes cause 15,000 serious injuries and over 2,000 deaths in Canada annually. The contribution of drug-impaired driving to these tragedies is unknown, but suspected to be significant. This lack of knowledge hinders the development of effective traffic safety policies to prevent drug-impaired driving.
The research of Dr. Jeffrey Brubacher aims to prevent injuries and fatalities resulting from motor vehicle crashes. His research program consists of three inter-related themes:
- Cannabis and motor vehicle crashes. This five- year study will examine 3,000 injured drivers from five BC trauma centres to determine whether there was recent marijuana use before their crashes and whether or not the driver caused the crash. The study will provide important information about the role played by marijuana in causing car crashes.
- Prescription medications and motor vehicle crashes. This project will involve combining BC prescription data with BC driver records, including traffic accident reports, to determine whether or not drivers are more likely to be involved in a crash when they are taking prescription medications such as sleeping pills or pain medications.
- The Injured Driver Platform. This study will provide information on the motor vehicle crash risk associated with recreational drug use. Over an initial three-year period, medical data will be collected and interviews will be conducted with injured drivers at five BC trauma centres, and drivers will then be followed for two years after their original crash to determine how often they are responsible in other accidents or drive while impaired.
This project will help to identify risk factors for impaired driving which may be used to develop targeted interventions to prevent this risky behaviour. Dr. Brubacher's research will contribute to an international effort to understand the role played by prescription medications, marijuana, and other illegal drugs in causing motor vehicle accidents. He will present his findings to government officials so they are better able to develop effective road safety policy and public education campaigns targeting impaired drivers and, by doing so, to improve safety on our roads.
Immune system homeostasis is determined by the balance between responses that control infection and tumour growth and reciprocal responses that prevent inflammation and autoimmune diseases. Dysregulated immune responses, such as those that occur with autoimmune disorders and organ rejection, result when and an individual’s immune system mistakenly attacks normal cells. Current treatment approaches involve following a strict regimen of immunosuppressive drugs for the duration of a patient’s life. These treatments, however, seriously compromise an individual’s ability to fight infection and are associated with an increased risk of developing cancer. Sarah Crome’s research has two main focuses. The first is on the regulation and function of a newly discovered class of inflammatory white blood cells (WBC), termed T helper 17 (Th17) cells, which serve an essential function in host defense against extracellular pathogens. While being key players that protect the body from harmful pathogens, Th17 cells are also linked to inflammatory diseases including rejection of transplanted organs and cells, rheumatoid arthritis, psoriasis and inflammatory bowel disease. Therefore, it is essential to understand the mechanisms that regulate this cell population in order to be able to treat patients with dysregulated immune responses. Secondly, Ms. Crome and colleagues are examining interactions between Th17 cells and another WBC population, termed T regulatory (Treg) cells, which serve a protective function by suppressing harmful immune responses. Currently, Treg cells are being clinically tested as a cell-based therapeutic alternative to immunosuppressive drugs. However, the diseases where Treg cell-based therapies are being investigated are the same diseases that are associated with Th17 cell activity. Therefore, understanding the interactions between these two cell populations will be essential for clinical based studies of Treg cells, and the development of improved therapies.
Rheumatoid Arthritis (RA), affects one percent of the general population. Radiographic (x-ray), evidence of bone thinning (osteoporosis), and bony destruction (erosions), in the bone surrounding inflamed joints is an important diagnostic criterion for RA. These changes are present in the hands and feet of 80 percent of people with RA and can have profound implications with regard to the development of hand deformity, functional limitations and the need for restorative joint surgery. Early presentation of destructive bone changes is associated with a more aggressive disease progression and evidence suggests that starting disease-modifying anti-rheumatic drugs (DMARDs), soon after the diagnosis of RA may help prevent some people from developing bone damage. However, not all people with early RA respond to DMARDs, with ‘non-responders’ requiring more aggressive interventions including trials of combinations of different drug treatments or biologic response modifier drugs. Unfortunately, the time delay associated with implementing effective treatment in people with more aggressive or resistant RA means they are at greater risk for permanent bone damage. Current clinical imaging with Dual X-ray Absorptiometry (DXA), Computed Tomography (CT), and Magnetic Resonance Imaging (MRI), can detect bone damage earlier than x-ray but these tools are not able to identify the initial ‘micro-structural’ changes in the early RA hand. Dr. Lynne Feehan is characterizing early ‘micro’ structural hand bone changes over a two-year period in people with newly diagnosed RA using High Resolution – Peripheral Quantitative Computed Tomography (HR-pQCT), a promising new imaging system capable of imaging the very fine bone internal ‘micro’ detail at a resolution equivalent to the diameter of a human hair. The results of Dr. Feehan’s research could improve patient’s early access to appropriate therapy, and thereby improve their quality of life.
Inflammation is a protective response generated by immune cells against infection. However, when inflammation becomes unregulated within the body, it can cause diseases. A key anti-inflammatory regulator of immune cells is a cytokine (a type of hormone), called interleukin-10 (IL-10). The importance of IL-10 in regulating immune cell function is illustrated by the fact that many tumour cells and intracellular pathogens produce or elicit production of IL-10 for their survival. A main target of IL-10 is macrophages. Activation of macrophages by interferons, or bacterial cell products such as lipopolysaccharide (LPS), induces a number of immunologic responses including production of pro-inflammatory mediators such as the cytokine TNF. IL-10 is able to suppress these events by interfering with pathways utilized by LPS, but its mechanism is unclear. Previous research on the intracellular signal transduction pathways utilized by IL-10 has shown that an important component is a protein called SOCS3 which is thought to target specific proteins for degradation. In order to understand how IL-10 uses SOCS3 to inhibit macrophage activation, Tsz Ying Sylvia Cheung’s research is focusing on proteins that interact with SOCS3 in cells stimulated with IL-10. Identification of these proteins will allow for a further research focus on understanding the role they play in macrophage activation and why they are targeted by IL-10. Developing a clear understanding of the mechanism by which IL-10 regulates the network of intracellular signal transduction pathways will better enable the development of therapeutics mimicking the beneficial anti-inflammatory effects of IL-10, and allow for the development of strategies to counter the immunosuppressive effects of certain tumours and immune cell pathogens.
Crohn's disease and ulcerative colitis, two forms of Inflammatory Bowel Disease (IBD), are disorders believed to be caused by the cells of the immune system mistakenly attacking the tissues of the digestive tract. This phenomenon, known as autoimmunity, leads to massive inflammation of the affected area and consequently causes severe pain, diarrhea, bleeding and other debilitating symptoms. With few treatments and no cure to date, this disease continues to impact both the general population and our health care system. Current research suggests that the inflammation associated with IBD is caused by self-reactive immune cells called T cells that attack the gut tissue, along with a loss of T regulatory cells (Tregs), which act to 'turn off' the immune system. Furthermore, flagellin, a protein present on all motile bacteria including the microflora found within the intestine, may also contribute to the establishment of IBD associated inflammation through its influence on T cells and Tregs. Indeed, studies have shown an immune response is generated against flagellin in 50 percent of patients with Crohn’s disease. However, the nature of these responses remain largely uncharacterized. Megan Himmel's research aims to optimize a novel method of identifying T cells and Tregs which are specifically reactive to flagellin, in order to study their function and their possible contribution to the pathogenesis of IBD. This work may lead to a novel diagnostic marker for IBD, as well as further insight into the immune mechanisms contributing to this disease. Furthermore, Ms. Himmel’s research will provide important insight into the overall role of T cells and Tregs in the establishment and progression of IBD in humans, with the ultimate goal of establishing methods to therapeutically manipulate the balance of pathogenic versus regulatory immune responses.
Inflammation is the body's normal physiological response to injury, infection or foreign substances. While the ability to mount an inflammatory response is essential for survival, the ability to control inflammation is also necessary for health. Inflammatory diseases such as rheumatoid arthritis, osteoarthritis, Chrohn's disease, ulcerative colitis, inflammatory bowel disease, asthma, allergies, septic shock, atherosclerosis and many others are a group of disorders characterized by uncontrolled or excessive inflammatory responses. Often, clinical intervention is required to prevent tissue damage and organ dysfunction in these disorders. While there have been advances in anti-inflammatory therapies over the years, long term use of steroidal and non-steroidal anti-inflammatory drugs (NSAIDS,) is limited due to drug-induced toxicities such as stomach ulcer, gastric erosion, exacerbation of asthma and nephrotoxicity. Therefore, the identification of novel agents that can effectively suppress inflammatory responses without associated long term toxicities represent a major unmet medical need. One of the key ways that the body controls inflammation is through the expression of immunoregulatory enzymes. An example of this natural immunoregulation occurs in pregnant mammals: cells of the placenta that surround the fetus express an immunoregulatory enzyme called indoleamine 2,3-dioxygenase (IDO). IDO expression protects the fetus from being attacked by the mother's immune system. Earlier research has revealed that the small molecule drug, borrelidin, could be used to specifically mimic the signalling effects induced by IDO expression and suppress the action of inflammatory cells. Nadya Ogloff's research builds on this evidence by providing pre-clinical proof-of-principle data to support further development of borrelidin as a potent immunosuppresive agent for treatment of inflammatory diseases.
Alzheimer’s disease (AD) is the most common neurodegenerative disorder leading to dementia, affecting approximately 10 per cent of the Canadian population over the age of 65. One of the pathological hallmarks of AD is increased deposition of the beta-amyloid protein, which forms amyloid plaques in the brains of AD patients. This is caused by dysfunction of the BACE enzyme, which regulates processing of the amyloid precursor protein to generate beta-amyloid proteins. Levels of the BACE enzyme have been shown to be elevated in Alzheimer’s. Philip Ly is interested in studying the underlying molecular mechanisms regulating the BACE enzyme expression and activity. He is studying a region of the BACE gene called the BACE promoter. This region has been demonstrated to be important for BACE expression. However, the regulations at the level of BACE gene transcription – the first step in the expression of the genetic information – remain elusive. Using a series of molecular and biochemical approaches, Ly is examining the transcriptional controls that regulate BACE gene expression in neurons. He is also examining if specific mutations in these transcription factors affect BACE expression and contribute to AD pathogenesis. Ly’s research will be the first to thoroughly characterize the transcriptional regulation of the BACE1 and the role of abnormal gene expression in AD pathogenesis. In addition to providing much needed information regarding signal transduction in amyloid precursor protein processing, these studies have important pharmaceutical implications, such as potential development of BACE enzyme inhibitors to improve treatment of Alzheimer’s disease.
The prospect of reward or punishment is known to affect how people make decisions. However, it is not clear which neural systems are involved in this process. This is an important topic in healthcare, because impaired processing of reward information is known to affect the decision-making abilities of many people, including those with damage to the frontal lobe of their brains, Parkinson’s disease, depression/anxiety, obsessive compulsive disorder, and even normal aging. A striking example of this situation occurs among some people with Parkinson’s disease, who can develop pathological gambling behaviours as a result of taking dopaminergic drugs. An effective way to study these neural systems is to track eye movement decisions – in other words where people focus their visual attention. Typically, people are faster to make an eye movement and are more accurate in their eye positions when the movement is rewarded by monetary gain. However, these effects are degraded in certain psychiatric conditions, such as anxiety and depression. Dr. Linda Lanyon is investigating the brain circuits that mediate these reward-related decisions in healthy humans. Her findings will enable her to develop a computer model of the brain circuitry and function that is able to simulate the behaviours observed in humans. In addition to demonstrating how these systems operate in healthy humans, the computer model can also be selectively damaged in order to simulate pathological behaviours observed in patients. By using healthy subjects to create a computer model for decision-making, Linda hopes to improve the understanding of the pathology of neurologically-impaired circuits.
