Almost 200,000 thousand workers are hurt on the job every year in BC. The majority of incidents involve musculoskeletal injuries, with back injuries accounting for approximately 25 per cent of all work claims. To reduce the occurrence of back injuries, we need a better understanding of the aspects of a job that are associated with the risk of injury. Most research is done with a small sample of workers in a controlled test environment. However, in order to have representative and generalizable results about the risk of injury, researchers require exposure data on large numbers of individuals at work so that relationships can be observed. To do this, they need accurate, inexpensive and easy-to-use tools to take out into the field. Spinal compression is a major risk factor for back injury. Robin Van Drielâs research is investigating the potential of estimating spinal compression by using an inclinometer (usually used for posture analysis), instead of the traditional electromyography method, to measure spinal compression among workers in five heavy industries in BC. By developing a better understanding of the work factors associated with the risk of injury, this research will help reduce the large personal and economic burden associated with low back disorders, and could be applied to many other occupational groups with similar risk factors.
Program: Trainee
Mechanism of Histone Variant H2A.Z Deposition by SWR1-Com
DNA, which is packaged into highly condensed structures in the cell, carries genetic information that is passed from one generation to the next. Chromatin is the first level of DNA packaging that eventually results in the formation of chromosomes â threadlike parts of a cell that carry hereditary information in the form of genes. Many debilitating and life-threatening diseases, such as cancer, neurodegenerative diseases including Alzheimer’s and Huntington’s, and inherited childhood syndromes, result not only from changes in the basic DNA sequence, but also from changes in the structure of chromatin. DNA is condensed into chromatin with the help of DNA-packaging proteins called histones. DNA wraps around eight core histones â two each of H2A, H2B, H3, and H4 â to assemble into chromatin. H2A.Z is a variant of the core histone H2A that is conserved through evolution. Structurally, H2A.Z is different toward the end of the protein. A large protein complex called SWR1-Com, which binds to H2A.Z but doesnât bind H2A, deposits H2A.Z into chromatin. Alice Wang is researching the differences between the way H2A.Z and H2A are deposited into chromatin. She is specifically investigating whether the difference between H2A and H2A.Z lies in their different binding capabilities to SWR1-Com. The findings will help increase understanding of H2A.Z biology and how chromosomal neighbourhoods containing H2A.Z are made. Wangâs ultimate aims for the research is to contribute to development of therapies for diseases that result from changes in chromatin structure.
Identifying the Pro-Survival Actions of Glucose-Dependent Insulinotropic Polypeptide on the Pancreatic Beta Cell
Diabetes is a rapidly growing worldwide epidemic. Itâs estimated that by 2030, more than 366 million people will have the disease, many of whom will acquire additional conditions such as neurological dysfunction, kidney failure and cardiovascular disease. Between 90 and 95 per cent of diabetics have type II diabetes mellitus. This results in hyperglycemia and hyperlipidemia (high glucose and fat in the blood), which causes cell death in the beta cells that produce insulin. This further reduces insulin output, accelerating other conditions associated with diabetes. However, by increasing insulin secretion and promoting survival of beta cells, it should be possible to reduce or prevent the conditions associated with type II diabetes. Glucose-dependent insulinotropic polypeptide (GIP) is a gut-derived peptide hormone whose stimulatory actions enhance insulin secretion and inhibit beta cell death. However, the mechanisms by which GIP protects beta cells are unknown. Scott Widenmaier is studying the possibility that GIP prevents beta cell death by relieving the stress placed on the mitochondria, the cellâs energy producing machine. It is expected that this protective mechanism of GIP will provide key information regarding the effects of chronically-high glucose and lipids on beta cells in type II diabetics. This could lead to a novel class of therapeutics to prevent beta cell death, contributing to better health outcomes for type II diabetics.
The Role of Ubiquitin/Proteasome System in Heart Failure
Heart failure is a disorder in which the heart loses its ability to pump blood efficiently. Despite recent advances in treatment, heart failure remains the leading cause of death in Canada. One in four Canadians suffers from heart disease, and more than 70,000 Canadians die from heart diseases each year. Treatment of heart failure is a major economic and social burden. The proteasome is a large multiprotein complex found in all cells, which breaks down unwanted or damaged proteins that have been âtaggedâ for elimination with a small protein called ubiquitin. The ubiquitin/proteasome system contributes to many cellular functions, including cell division, quality control of newly-produced proteins, and immune defense. Impairment of this system has been linked to several diseases, including cancer, Alzheimerâs and Parkinsonâs diseases. It may also play a role in the development of heart failure. Tse Yuan Wongâs research is exploring the contribution of the ubiquitin/proteasome system to heart failure. This involves examining the functional changes of this system in heart failure and determining how it is regulated. He will also explore how disturbed proteasome function affects the progression of heart failure. This study will provide valuable insights into the mechanisms of heart failure, which could lead to novel therapeutic strategies that could have a huge impact on health care in Canada.
Characterization of a dioxygenase and a hydrolase critical to persistence of Mycobacterium tuberculosis in the macrophage
Tuberculosis (TB) is a contagious illness of the respiratory system that is spread through coughing and sneezing. This chronic infectious disease is caused by a bacterial microorganism, Mycobacterium tuberculosis. This bacterium infects one in three people worldwide and claims the lives of two to three million people each year. The incidence of TB is on the rise due to the emergence of multi-drug resistant strains and escalating numbers of HIV-linked deaths. These alarming trends have led the World Health Organization to declare tuberculosis a global health emergency. Pathogenicity of this bacterium is due in part to its unusual ability to survive for long periods of time and to replicate in human immune cells. The mechanisms behind this persistence are poorly understood which is why Katherine Yam is investigating a number of genes essential to pathogenesis of M. tuberculosis. Studies recently revealed that some of these genes are involved in degradation of cholesterol â a source of energy for the bacterium during infection. Yam is studying two of these cholesterol-degrading enzymes, HsaC and HsaD, which help the bacterium survive in the human body. By designing inhibitors for these enzymes, the cholesterol-degrading pathway of M. tuberculosis can be blocked, which will reduce the bacteriumâs ability to cause disease. These enzymes are excellent new targets for TB drug treatments as they are not targets of current drugs and thus will circumvent the problem of drug resistance in TB.
PTEN Regulates Alternative Splicing
Prostate cancer is the most common non-skin cancer among Canadian men and the second leading cause of cancer death. Prostate cancer starts in the prostate gland, part of the male reproductive system. Frequently, men with early prostate cancer have no warning symptoms. PTEN is a tumour suppressor gene that has been linked to prostate cancer. PTEN helps promote apoptosis (cell death), which helps regulate the uncontrolled cell growth that occurs in cancer; unfortunately, PTEN is often mutated in advanced stages of prostate cancer. Alternative splicing is an integral part of normal cell function, and is important for generating protein diversity and controlling protein function. Tien Yin Yauâs study investigates whether PTEN plays a role in regulating alternative splicing. Yau is studying whether changes in normal mRNA splicing increase susceptibility to prostate cancer by affecting genes implicated in tumor progression. The findings of Yauâs study will increase our knowledge of the molecular mechanisms that regulate alternative splicing. Understanding what changes occur and their effects may result in the development of more effective cancer treatments.
Palmitoylation in the Pathogenesis of Huntington Disease
Huntington disease (HD) is a devastating inherited neurological disease characterized by loss of motor control, cognitive decline and psychiatric disturbances, resulting in eventual death 15 to 20 years after symptoms first appear. In Canada, one in 10,000 people have Huntington disease, and have a 50 per cent risk of passing on the disease to their children. The underlying genetic cause of HD is an expansion of a specific portion of the HD gene, known as the CAG trinucleotide repeat, which results in an expanded stretch of an amino acids in the huntingtin protein. This expansion leads to cell death in specific parts of the brain through mechanisms that are the subject of intense investigation. When the HD gene is translated into huntingtin, the protein undergoes alterations at many sites. Palmitoylation is an example of such an alteration, which involves the addition of a small fatty-acid chain to a protein. Palmitoylation enhances the ability of a protein to associate with membranes (e.g. cell walls), and influences that proteinâs trafficking and function. Most notably, palmitoylation is a reversible protein modification. Decreased palmitoylation may play a role in the cellular events underlying the development of HD. Fiona Young is investigating the role of palmitoylation in the development of Huntington Disease as well as in the context of the normal function of the huntingtin protein. The research could lead to new therapeutic approaches for Huntington disease that involve increasing palmitoylation of the huntingtin protein.
Characterization of Salmonella Type III effector: Host protein interactions and their contribution to immune evasion
Salmonella bacteria cause severe intestinal infection and diarrhea in humans. Millions of cases of Salmonella infection occur every year, predominantly in developing countries. However, salmonellosis is still a persistent problem in developed nations; young children, the elderly, and people with compromised immune systems are the most likely to have severe infections. Salmonella bacteria infect human cells and somehow manage to avoid activating the immune system from attacking them, allowing the bacteria to replicate. How these bacteria evade the host immune system response is poorly understood. Salmonella bacteria secrete proteins, called effectors, directly into the host cell through a needle-like channel. Dr. Amit Bhavsar is researching how these effectors bind to other host proteins in human cells; how the host proteinsâ ability to function is affected; and how this enables Salmonella to evade the immune system. This research will result in a better understanding of how Salmonella bacteria evade the host immune system. It could also lead to new ways of restoring the immune system to fight infection, providing an alternative to conventional antibiotics, which have become less effective in the face of antibiotic resistance.
The heart as an immunologic organ: Cardiac myocytes in innate immunity
Itâs well established that severe infection in critically ill patients can result in heart damage, but what causes this damage is unclear. One possibility is that heart muscle recognizes and responds to infectious pathogens and their products, triggering events within heart cells that ultimately lead to heart failure. Dr. John Boyd is researching the link between serious infection and cardiac dysfunction. The immune system uses Toll-like receptors to recognizes infectious products. Boyd aims to establish the role and function of Toll-like receptors in the heart, and what response occurs in heart muscle cells when incubated with infectious pathogens that are known to activate these receptors. Because Toll-like receptors also recognize and respond to tissue damage arising from ischemic heart disease (when there is a decrease in the blood supply to the heart caused by constriction or obstruction of the blood vessels) and heart transplant rejection, the research could have relevance beyond cardiac response to acute infection. Ultimately, Boyd aims to provide novel insights into the connection between the heart and immunity, which could lead to the development of new strategies to improve outcomes in diseases that involve inflammatory responses of the heart.
Imaging the Remodeling of Individual Synapses and Vessels in the Living Brain after Stroke
Stroke is the leading cause of adult disability, often rendering its victims with profound impairments in sensory, motor or cognitive function. Fortunately, many individuals experience some partial form of recovery over the ensuing weeks, months and years after stroke. This recovery of function is thought to be dependent on how well surviving brain cells (called neurons) and their connections adapt and form new circuits. However, the nature by which these neurons change in a living organism and the factors that regulate these changes, has not been determined. Craig Brownâs research is aimed at determining how the parts of the neuron that receive information (dendrites) and those that transmit information to other cells (axons) reorganize after stroke. Given that neurons are critically dependent on sufficient levels of blood flow to survive and flourish after stroke, he is also examining structural changes in brain blood vessels and their delivery of blood to vulnerable regions of the brain. He will then examine how therapeutic interventions, such as movement-induced therapies or sensory/electrical stimulation, influence brain reorganization. A better understanding of how the brain adapts to injury and the factors that regulate these process will pave the way for future therapies to optimize recovery of function after stroke.