Absence of IL-6 results in increased autoimmune myocarditis severity following coxsackievirus infection

Myocarditis is a disease that results in inflammation of heart muscle. Myocarditis and dilated cardiomyopathy (DCM), a condition in which the heart becomes weakened and enlarged, are believed to be continuing stages of an autoimmune disease of the heart. This condition can progress to a stage that requires heart transplantation. Myocarditis is often brought on by a viral infection. In humans, coxsackie B viruses (CBV) are the most frequent cause of viral-induced myocarditis. It is estimated that 30 per cent of new DCM cases in North America are the result of CBV infection. Maya Poffenberger’s research aims to determine the specific immune components that control myocarditis disease severity following viral infection. She is studying cells and molecules that control immune cells. Using mouse models that lack certain immune genes, Poffenberger will be able to identify the genes that influence the induction and severity of myocarditis from CBV infection. With knowledge of how myocarditis is induced and controlled, researchers will be able to develop better disease specific therapies that target immune genes important to disease induction and severity.

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.

Can intrapulmonary arteriovenous shunting explain exercise-induced arterial hypoxemia in women?

The cardio-respiratory system (heart and lungs) is efficient in maintaining oxygen and carbon dioxide levels in the blood most of the time. However, during very strenuous exercise, the cardio-respiratory system may become less efficient in maintaining equilibrium of these gases. Known as exercise-induced arterial hypoxemia (EIAH), this condition is characterized by a reduction in oxygen levels in the arterial blood, starving muscles of oxygen and impairing exercise capacity. In men, EIAH has been found to be prevalent mainly in highly-trained endurance athletes at near maximal exercise intensities. However, research has demonstrated that women who are not highly trained may experience EIAH, and at lower exercise intensities. This may be due to anatomical differences: women have smaller lungs, airways, and surface areas for gas exchange relative to men. One potential explanation for the EIAH phenomenon is through intrapulmonary arteriovenous shunting, where instead of taking its normal route through the lungs to gain oxygen, deoxygenated blood from the veins is diverted directly back into the heart. This results in lower oxygen levels in the arterial blood and less oxygen available for the working muscles. Research suggests that intrapulmonary arteriovenous shunting exists in healthy, exercising humans. Jill Kennedy is conducting the first systematic study of whether intrapulmonary arteriovenous shunting accounts for EIAH observed in women during exercise. She will also explore whether this relationship is influenced by fitness. Kennedy’s research will shed new light on female physiological responses to dynamic exercise with respect to the pulmonary system. Ultimately, this knowledge could lead to the establishment of scientifically-based, gender-specific exercise prescription guidelines for women throughout their life span.

Cognitive contributions to checking compulsions

Obsessive-compulsive disorder (OCD) is an anxiety disorder that afflicts three percent of all Canadians. The disorder is characterized by intrusive and unwanted thoughts, images or impulses that cause anxiety, and that are temporarily relieved by the execution of specific compulsions. Obsessions and compulsions can occupy a large proportion of individuals’ time and energy and can interfere with daily routines, functioning at work, social activities and relationships with others. Checking compulsions are among the most common manifestations of OCD. Individuals with checking compulsions have intrusive concerns that they have failed to perform some task (such as locking the door or turning off the stove) and feel compelled to repeatedly check to ensure that the task was indeed completed. Preliminary evidence suggests that impaired prospective memory may play an important role in checking compulsions. Prospective memory is the ability to remember plans and intentions at a later moment. Everyday life and clinical observations show that checkers’ compulsions are related to this future-oriented aspect of memory and that the types of activities that tend to trigger checking compulsions are prospective memory tasks. Dr. Carrie Cuttler was previously supported by MSFHR with two research training awards. Her current work continues her exploration of whether individuals with checking compulsions have a cognitive deficit related to prospective memory. She hypothesizes that checking compulsions may develop to compensate for an impairment in prospective memory. In other words, individuals who frequently forget to perform tasks may develop a strategy of repeatedly checking to ensure that important tasks are not forgotten. Cuttler’s research focuses on improving our understanding of the mechanisms underlying OCD. The results will improve the quality of OCD patients’ lives by setting the stage for more effective treatments for reducing the frequency of checking compulsions.

Mechanistic studies and engineering of an endo-beta-galactosidase (EABase) from C. perfringens: blood group antigen synthesis

The ABO blood groups – comprising the A, B, AB and O blood types – are vitally important in blood transfusion and organ transplantation. The four types are differentiated by the presence or absence of two sugar antigens on the surface of red blood cells: a terminal alpha-1,3-linked N-acetylgalactosamine (A-antigen) or an alpha-1,3-linked galactose (B-antigen), both of which are absent in the O-blood type. As all individuals have antibodies to the antigen(s) they lack, transfusion with an incorrect blood type results in destruction of the incompatible blood cells, which can result in death. The enzyme EABase is capable of releasing both the A and B trisaccharides from the surface of red blood cells, giving it the potential to be used to convert blood cell types by the addition or removal of their antigens. Fathima Shaikh’s studies seek to determine the mechanisms underlying EABase activity, and identify the residues that are created as a result. Knowledge of these enzyme properties is crucial for the next stage of the project: engineering EABase into a glycosynthase, which is a mutant form of the enzyme that can synthesize (form) antigens, rather than removing them. She will conduct further work to optimize the efficiency of this glycosynthase, as well as increasing its synthetic utility by broadening its ability to transfer different sugars. If Shaikh’s experiments are successful, this process would allow for the conversion between blood groups. These enzymes could be of great benefit to human health, helping to overcome shortages in donated blood, and helping in the modification of related antigens on other cell types.

Studies of KshAB, a cholesterol-degrading oxygenase from Mycobacterium tuberculosis

Tuberculosis kills more than two million people worldwide every year. More than one-third of the world’s population is currently infected with Mycobacterium tuberculosis (Mtb), the bacterium that causes tuberculosis. Because of its synergy with HIV infection, TB is the leading cause of death in HIV-infected individuals. Contributing to this global health crisis is the emergence of multi-drug resistant strains (MDR-TB), including extensive drug resistant strains (XDR-TB). The drug course to clear MDR-TB lasts up to two years, and XDR-TB is virtually untreatable with current therapies. These factors, combined with the high toxicities of current drugs, underline the urgent need for novel therapeutics to combat this disease. One of the major contributing factors to the prevalence and persistence of the disease is the bacterium’s ability to survive within the human macrophage, a type of scavenger cell that normally combats disease-causing bacteria. The mechanisms by which Mtb survives inside the macrophage in the immune system are largely unknown. However, a set of genes that encode (produce) a series of cholesterol-degrading enzymes in Mtb has recently been discovered as essential to the bacterium’s survival. Compounds that inhibit Mtb’s cholesterol-degrading enzymes might be useful starting points for the design of novel therapeutics. Jenna Capyk is focusing on one of these cholesterol-degrading enzymes, known as KshA. She is studying how this enzyme works and how it is inhibited by small molecules. Her work also involves determining KshA’s three-dimensional structure and synthesizing potential inhibitors for the enzyme. By investigating the mechanisms of this promising new enzyme target in tuberculosis, Capyk’s studies may help lay the foundation for the development of new classes of therapeutics to treat this deadly disease.

Community Learning Centres: A Model of Community Engagement in Health, Education & Training

There are disproportionately high rates of poor health among First Nations populations in comparison to the general Canadian population. A contributing factor is the limited access many geographically-isolated rural and remote First Nations communities have to health information. Dr. Sandra Jarvis-Selinger is focusing on a new and innovative approach supporting community access to health information. This approach involves the formation of Community Learning Centres (CLCs) in four communities located in the Ktunaxa Nation in southeastern BC. A CLC is both a physical and a virtual space for community members to access Internet-linked computers and web-based resources developed according to community-defined health priorities. Health information is created by and for community members and is both accessed at and disseminated via CLCs through information and communication technologies. Community engagement is the cornerstone of this project, with due emphasis placed on community input and governance, local health priorities and inclusion of traditional medicine, language and knowledge. Dr. Jarvis-Selinger is conducting a program evaluation to determine the effectiveness and sustainability of the CLC design and implementation. The evaluation is being co-developed with each community in order to match the communities’ needs, workflow, schedule and style of participation. This research will increase our understanding of how to successfully and sustainably: 1) support community-university partnerships; 2) improve community wellness; 3) expand access to and awareness of community health resources; and 4) increase employment opportunities through technical, research and interpersonal skills training. Overall, this research promises to make a meaningful contribution to the domain of First Nations community health through the use of technology.

The role of secreted protein acidic rich in cysteines (SPARC) in neurogenesis and gliogenesis in the embryonic and adult mouse brain: applications to models of Cerebral Ischemia Reperfusion Injury

Stroke is the primary cause of adult disability in Canada. Recovering brain function after stroke is dependent on the brain’s ability to rewire itself and replace tissue that has died during the stroke – something that is difficult to achieve in the adult brain. Rewiring the brain requires that existing neurons sprout new fibres (axons) and connect to other neurons in a way that allows proper functioning of neural circuitry. Recovery also involves the birth of new cells to replace dead cells and to form functioning connections with new and existing neurons. These processes all occur within the extracellular matrix (ECM) – a network of fibrous proteins, gel-like sugars and linking molecules – and are promoted by a large number of growth factors and intercellular signalling molecules. Anthony Berndt’s research focuses on the role of the SPARC protein in the generation of new neurons. SPARC binds to the ECM and regulates the potency of growth factors that normally promote cell division and migration. Berndt is examining the influence of SPARC on the development of the embryonic brain and on the generation of new neurons in the adult brain. His studies will determine if SPARC’s presence or absence affects the rate or manner in which brain tissue regenerates after stroke. He hopes to formulate an approach that will prompt neural stem cells normally found in the adult brain to follow the developmental steps required to form functional tissue after stroke. By understanding the function of SPARC after brain injury, he could also determine at what point of recovery such an intervention would be of greatest use. By understanding the role of SPARC, Berndt’s research could eventually lead to improved therapies for treating major brain injuries by augmenting the body’s natural repair processes.

Exposure to asbestos in the slums of a sub-population of migrant ship dismantlers in Bangladesh

“Shipbreaking” is the dismantling and recycling of obsolete vessels, their hulls and superstructures. In Bangladesh, this work is carried out on beaches. Salvaged items are resold in local markets and workers and their families live in adjacent slums. Ships often contain hazardous substances such as polychlorinated biphenyls, heavy metals and asbestos, which are all recognized carcinogens. Most work is done without adequate training or protection, and there is high potential for exposures to toxic materials in the shipyards, shops and the community itself. According to the International Labour Organization, shipbreaking is one of the world’s most dangerous occupations. On average, one worker dies every week; the long-term consequences of mortality due to cancer and other chronic illnesses are unknown. Few studies have been performed in Bangladesh on the environmental impact of dismantling ships, the health of shipbreakers, or the impact on the surrounding community and maritime environment. Working in collaboration with local university and non-governmental organization researchers, Midori Courtice is measuring the concentration of asbestos in workers’ living quarters, in shops selling salvaged items, and in areas downwind of ship-dismantling operations. She will interview people about their knowledge, attitudes and practices with respect to their handling of, and hazards associated with, asbestos. Courtice’s findings will be made available to the participants and the local community, and her recommendations could inform local workshops on hazards and reducing risk. Her work will also provide the basis to approach policy makers and strengthen the link between research and policy, to raise awareness of personal health and safety among workers, and to build local capacity for future research on sustainable solutions related to the shipbreaking industry.

Peripheral neurophysiological basis of sensorimotor deficits in individuals with essential tremor

Essential tremor (ET) is a neurological disorder characterized by shaking of the hands (and sometimes other parts of the body) that occurs with voluntary movement. Often mistaken for Parkinson’s disease, it is the most common tremor disorder. Approximately 75 per cent of people living with ET experience some limitation in their activities, and these limitations typically get worse with increasing age. Therapies for essential tremor focus on tremor reducing medications, but effective treatments remain limited. Consequently, new insights into disease mechanisms are needed to guide the development of more effective therapies. The origins of essential tremor are believed to involve abnormal rhythmic activity in the brain, which then travels down to the peripheral nervous system. However, the specific neural pathways that the tremor travels, as well as how ET influences the recruitment of muscles for movement, remains unclear. Also unknown is the impact of tremor on sensory receptors found within skeletal muscles, which provide the sense of position and movement of the limbs. Dr. Martin Héroux is conducting studies on British Columbians with ET to determine how their muscles and sensory receptors are affected by abnormal rhythmic activities of essential tremor. He hopes these studies will increase our knowledge of the neural mechanisms involved in the generation of essential tremor and provide a better understanding of the motor-sensory deficits associated with tremor disorders. Ultimately, this knowledge could contribute to the development of more effective anti-tremor therapies.