All successful viruses have evolved strategies to infect host cells and disrupt normal cell functions. However, the host can counteract these strategies by using its natural antiviral responses to detect and defend against viruses. Revealing the molecular mechanisms between the battle of the virus and host is vital in the fight against many of today’s viruses. Some viruses use an internal ribosome entry site (IRES) to infect cells. Molecular machines in cells called ribosomes translate genes into proteins, but viruses with an IRES can hijack the ribosome to replicate their viral proteins instead. IRESs are found in a number of human viruses, including polio, hepatitis C, herpes and HIV, but there is limited understanding of how these mechanisms work. Understanding the ways in which a virus hijacks the ribosome function is the focus of Dr. Eric Jan’s laboratory. He uses a unique IRES found in an insect virus called the cricket paralysis virus (CrPV). Jan’s previous work was critical in delineating important CrPV IRES functions. Building on this work, he plans to map the specific IRES elements that interact with the ribosome. He will also determine how CrPV disrupts cellular function that leads to IRES activity in Drosophila (fruit fly) cells, and elucidate the host antiviral response in these cells. The study of Drosophila antiviral responses will contribute to knowledge about fundamental virus-host interactions in humans. The research could lead to new drug targets for inhibiting viral IRESs and therapies that can augment antiviral responses. An exciting future goal will be to exploit viral IRESs to prompt the destruction of virus-infected cells – taking advantage of a viral mechanism against itself.
Year: 2008
Presynaptic voltage-gated calcium channels: binding and regulation by SNARE proteins
Electrical signals are the fastest signals in our bodies. These signals are mediated by ion channels, specialized proteins that allow particular charged ions to pass through cell membranes. One class of ion channels, known as voltage-gated calcium channels, is of particular importance. They allow calcium ions to pass through the cell membrane when an appropriate electrical signal is present. In doing so, these channels play crucial roles in regulating heartbeats, in muscle contraction and in the release of hormones and neurotransmitters. The role of calcium channels in human health is significant. Mutations in the channels cause severe genetic diseases, and many drugs that are currently used to treat cardiovascular diseases, epilepsy and chronic pain target calcium channels to limit their dysfunction. Efforts to develop new drugs are hampered by the limits of what is known about the channels, particularly about their atomic structure. Dr. Filip Van Petegram is working to shed new light on the intricate workings of calcium channels that are expressed in the heart, in the brain, and in skeletal muscle. Van Petegram uses cutting edge technologies to gain a precise understanding of calcium channels. X-ray crystallography determines a protein’s atomic structure, producing high resolution structural images that serve as excellent templates for the design of new drugs, and provide valuable information about how the channels work. Electrophysiology measures the tiny electric currents that are generated when calcium ions pass through the channels. This work will contribute to novel treatment strategies for targeting calcium channels.
Stimulation of Brain Activity and Recovery of Function after Stroke
Stroke is the third leading cause of death and the most common cause of adult disability in Canada and worldwide. Nearly half of all people with stroke do not have full use of their arms for daily tasks and seek rehabilitation to help restore their function. Recent discoveries have targeted effective treatments for individuals who are still able to move their wrist and fingers after stroke, but there are currently few therapies for individuals with poorer hand movement ability.
Dr. Lara Boyd is exploring whether learning and recovery of function can be enhanced by pairing direct stimulation of the brain with practice of a new motor task. Her research focuses on two areas: testing whether exciting the brain using transcranial magnetic stimulation (TMS) before practicing a new motor skill will promote faster learning and recovery of former motor function; and determining the effect of stroke severity on motor learning. Boyd expects that pairing brain stimulation and practice will help people with stroke learn new motor skills faster and more effectively than when brain stimulation is not delivered. This research may lead to new therapies to help people with stroke return to their regular activities of daily life. Brain stimulation using TMS may specifically offer an effective treatment for people with poor hand and arm function after stroke.
Building the Evidence-base to Support Rural Maternity Health Services Policy and Planning
Dr. Stefan Grzybowski is a family physician clinical investigator and co director of the Centre for Rural Health Research within the Vancouver Coastal health Research institute. He is co-Principal Investigator of the Rural Maternity New Emerging Team, funded by the Canadian Institutes of Health Research and also co directs the British Columbia Rural and Remote Health Research Network, a Health of Population Network funded by the Michael Smith foundation. Prior to moving to Vancouver in 1994, Dr. Grzybowski practiced for 12 years as a family physician on the Queen Charlotte Islands/Haida Gwaii.
Dr. Grzybowski’s research has focused on building an evidence base supporting sustainable maternity health services for rural parturient women, translating this evidence into policy and practice and building research capacity for primary care clinician researchers. His interest in rural health services research was fostered by his experiences in facing the challenges of providing limited maternity services in an isolated hospital on the Queen Charlotte Islands without local access to Cesarean Section. His current projects include developing a Logic Model for sustainable rural maternity care in three isolated BC communities, investigating mechanisms in which GP surgery can be supported in BC, measuring population based maternal and newborn outcomes for rural service catchment areas across BC, and measuring stress associated with pregnancy for parturient women living in rural communities.
Individual differences in stress coping and predisposition to disease.
Glucocorticoids are hormones that the body releases into the bloodstream in response to stress, protecting our bodies in the short term against the damaging effects of stress. Chronic oversecretion of these stress hormones can lead to various mental health disorders such as anxiety and depression. Humans show extreme differences in how they adapt or succumb to the pathological effects of stress. Sex steroids play a critical role in individual and gender-based differences in stress-induced pathology, but the basis for this in the central nervous system is not understood. Independent studies in rodents and humans show that testosterone can regulate the magnitude of the glucocorticoid and behavioural responses to stress. With this data, Dr. Victor Viau is working to determine how testosterone operates on stress-related pathways in the brain, from a physiological and chemical perspective. He is investigating how early-life exposure to testosterone determines the brain’s response to stress during adulthood, and providing insights about the underlying factors that allow the individual to manage stress in different ways. Viau’s research program is unique as it aims to determine how, where, and when stress and testosterone interact in the nervous system and at the hormonal and behavioural levels. The research will ultimately provide a fundamental framework for understanding why some individuals succumb to the psychopathological effects of stress and others persevere in the face of it.
Identification of a novel obesity gene
The prevalence of obesity is increasing dramatically, and is occuring at an increasing rate among children. Obesity is a major risk factor for numerous diseases including diabetes, heart disease, high blood pressure, stroke, arthritis, and some forms of cancer. Inherited factors strongly affect an individual’s risk for becoming obese, especially in an environment with little exercise and diets high in fat and sugar. However, many of these genetic factors are not yet known.
Dr. Susanne Clee’s research seeks to identify one of these genetic factors. She is conducting genetic studies on mouse strains that differ in their risk of developing obesity when fed a high fat diet. Clee will progressively zero in on new candidate genes by comparing the suspected region’s DNA sequence between obese and non-obese mice, and identifying specific changes in genes that could lead to the development of obesity. At the same time, Clee will use these mouse strains to study the biology of how obesity develops. By comparing mice that become obese when fed a high fat diet compared to mice that resist obesity, she will be able to describe how the body's processes are altered as individuals become obese.
By identifying new genetic factors that cause mouse strains to become more obese, Clee hopes to gain a more specific understanding of how obesity develops. This knowledge will lead to new ways to treat or prevent this disease and to identify those individuals more at-risk of developing obesity.
Role of the startle reflex and cervical multifidus in whiplash injury
Low-speed rear-end collisions can generate whiplash injuries, especially when the victim is unprepared for the collision. Neck pain is the most frequent symptom experienced by victims of a car collision, and up to 30% of people injured in a car collision will develop chronic symptoms. In fact 6% of people who develop chronic whiplash from a collision have not returned to work 12 months after the injury. The precise cause of whiplash is not known, but an overreaction in unprepared individuals — known as a startle response — along with the sudden recoil movement of the head, is thought to damage the joints and muscles of the neck.
As an MSFHR-funded post doctoral fellow, Dr. Jean-Sébastien Blouin conducted research that suggested the presence of a startle response when people are exposed to low-speed rear-end collision. Now he is investigating whether the startle response is linked to stimulation of the deep neck muscles, and if activation of these muscles during a collision may increase the risk of injury. With volunteers acting as “crash test dummies,” Blouin is simulating very low speed (1.8 km/hour) collisions to observe their startle response and measure the corresponding muscle activity. He’s investigating the link between a strong startle response during a low speed collision and the development of whiplash symptoms. He’s also exploring if stimuli delivered immediately prior to the collision can inhibit the startle response, possibly providing protection against injury. Findings could contribute to development of a warning device in cars that will help prevent whiplash injuries.
Voltage-gated sodium channels as modulators of electrical excitability in the heart and therapeutic targets in the management of atrial arrhythmias
Electrical disturbances in the heart are a serious health threat for many people. For example, cardiac atrial arrhythmias (a type of irregular heart beat) affect 4% of people aged 60 and older, and have an associated fivefold increase in stroke. As our population ages, this incidence is expected to increase up to 2.5 times over the next half century. Cardiac membrane proteins called ion channels control the flow of sodium and potassium in and out of heart cells, regulating both the cardiac electrical impulses and the contractions associated with the heart beating. Dr. Christopher Ahern is interested in drugs that interact with the sodium ion channel to correct atrial arrhythmias. Although these drugs are widely prescribed, scientists still don’t fully understand exactly how they work. More critical is that these drugs can become lethally toxic in cases where the arrhythmia co-exists with other common heart problems, such as an enlarged heart. This dangerous shortcoming seriously limits their use for many people who could otherwise benefit from their therapeutic effects. There is a need for better anti-arrhythmic therapies – ideally, designer drugs for atrial arrythmias that exploit the positive attributes of current therapies while minimizing their negative side-effects. Dr. Ahern is using new chemical methods that are providing much more detailed information about how these drugs bind to and interact with the sodium channel. Using these new methods in combination with computational approaches that bypass previous limitations with the research, his team will take a fresh look at drug binding and ion channel function with the goal of designing safer anti-arrhythmic drugs
Transformational teaching and physical activity adherence among adolescents: From measurement and prediction to intervention
Physical inactivity in adolescence has been linked to a vast array of physical and mental health problems that extend across the lifespan. Canadian adolescents are required to undertake regular physical education as part of their school curriculum, guided by physical education teachers. However, more than half of adolescents are considered not sufficiently active to meet international guidelines for optimal growth and development. In workplace settings, “transformational leadership” is exemplified by business leaders whose behaviours and interactions inspire employees to reach new heights of work performance and self confidence. Transformational leaders inspire, energize and intellectually stimulate their followers. Training programs in business and military settings have also shown that people in leadership positions can successfully acquire and develop these behaviours.
Exercise and health psychologist Dr. Mark Beauchamp is taking this leadership model out of the workplace and applying it to school physical education and health promotion settings. He’s studying whether training physical education teachers in transformational leadership can positively affect the attitudes and behaviours of their students around adopting and maintaining physical activity. If this approach is proved effective, this research could be used to help develop evidence-based initiatives (across Canada and beyond) that inspire a greater proportion of adolescents to become and stay physically active.
Understanding how cationic antimicrobial peptides and lipopeptides function in order to design better antibiotics
With the ever-increasing prevalence of antibiotic resistance, it has become critical for scientists to develop alternatives to antibacterial agents and offer long term sustainable health care solutions. Bacterial resistance to common antibiotics has a dramatic impact on hospital and community health care, affecting entire hospital wards and communities. This creates significant – and largely avoidable – pressure on current health care budgets. Two types of microbe-fighting peptides are generating much interest as potential alternatives to current antibiotics: cationic antimicrobial peptides (CAPs) and anionic lipopeptides (ALs). Both types of peptides are commonly found in nature and have remained effective, displaying little to no antibiotic resistance effects. Both are believed to act by targeting and perturbing the bacterial membrane, which eventually leads to cell death – a process that is strikingly different from current antibiotics. Dr. Suzana Straus aims to find novel alternatives to current antibiotics by investigating how promising candidates from the CAP and AL peptide families function and by designing more potent versions derived from these candidates. Her work is focused on three peptides: two CAPs from amphibians and one AL called daptomycin, which is known to be effective against particular complicated skin infections. Straus is researching the structural and functional properties of these membrane-associated peptides and proteins, which is crucial in the design and development of new and effective medicines. Ultimately, her work will provide insight into which factors should be considered in the design and development of a new generation of antibiotics.