The ability for proteins to travel across cell membranes is critical to the life of all cells, yet research shows that bacterial cells differ from human cells in some of the components necessary for this movement to occur. In previous work supported by an MSFHR Scholar award, Dr. Mark Paetzel uncovered the three-dimensional structure of proteins that make up the molecular machinery involved in this movement in bacterial cells. Now a Senior Scholar, Dr. Paetzel will continue this work with the goal of learning more about these structures in order to determine how to inhibit the movement of proteins across cell membranes in bacteria. He will use X-ray crystallography to investigate the proteins involved in protein targeting, translocation, and membrane protein assembly in bacteria. Dr. Paetzel is also investigating a particular enzyme that functions at the membrane surface — one that causes the cleaving of interior peptide bonds in a protein. Understanding how to inhibit this enzyme and its role in bacterial cell movement could lead to the development of a novel class of antibiotics — a strategy that is required to meet the ever-increasing challenge of antibiotic resistance.
Archives: awards
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Detecting, Treating and Preventing Drug-Related Morbidity
In Canada, 7.5 per cent of hospital admissions are complicated by an adverse event related to medical care that leads to death, disability, or a prolonged hospital stay. Adverse drug related events (ADREs) represent the most common cause of preventable non-surgical adverse events, with up to 130,000 patients in British Columbia (BC) presenting to Emergency Departments with a symptomatic ADRE. However, there are currently no efficient screening strategies for ADREs. This team is working to develop and evaluate a clinically effective, resource-efficient screening strategy. Once the strategy has been proven effective in an Emergency Department setting, the team aims to adapt it for use in community-based practice, and determine its cost effectiveness in comparison to the current standard of care.
Team in Child and Adolescent Healthy Body Weights
At least one in four BC children and youth is overweight or obese, and many of these young people are already developing serious diseases, such as hypertension and type 2 diabetes. Preventative and therapeutic measures have not succeeded in curbing the prevalence of overweight and obese children and youth in BC and Canada. This award supports the development of a multidisciplinary team bringing together clinical, social and basic researchers. The team aims to study determinants of childhood and adolescent overweight at individual, family, community and population levels, and to develop targeted interventions that will result in sustainable outcomes and healthy body weights.
Genetic Factors in Premature Ovarian Failure
Although the average age of menopause is 51 years, approximately one per cent of women will experience menopause before the age of 40, a condition known as premature ovarian failure. Working on the hypothesis that multiple genetic factors may combine and interact in a single individual to determine the rate of reproductive aging, Karla Bretherick is examining the molecular genetic differences between women with normal reproductive function and women with premature ovarian failure. She hopes her work identifying specific genetic factors that contribute to early menopause may lead to the development of both treatment options for affected individuals and predictive testing for those at risk.
Molecular Basis of Cancer Cell Invasion
Tumour invasion is the cellular process that initiates the spread of cancer cells from the primary tumour to new sites in a patient’s body (metastasis). Inhibiting this process is important, as solid tumours are much more readily surgically removed if metastasis hasn’t yet occurred. Researchers have identified Dihydromotuporamine C (dhMotC) as a novel tumour invasion inhibitor that may have therapeutic potential. Lianne McHardy is investigating the molecular mechanisms of this compound, focusing specifically on how the protein SNF7 is involved in these mechanisms. SNF7 is normally required for the sorting of intracellular vesicles, which are a basic tool of the cell for organizing metabolism, transport, enzyme storage, as well as being chemical reaction chambers. Lianne will investigate a potential link between the mechanisms controlling vesicle sorting and the invasion abilities of a tumour cell. By pinpointing the mechanisms that allow for metastasis, her studies may aid in the development of dhMotC as a potential drug candidate for metastatic cancers.
Genetic determinants of the host response to infection in critically ill adults with systemic inflammatory response syndrome
Each year in Canada about 100,000 people develop sepsis—a severe illness caused by the presence of bacteria in the bloodstream. The condition causes blood pressure to drop, resulting in shock and may lead to multiple organ dysfunction and eventually death. With a mortality rate of 30 and 65 per cent respectively, sepsis and septic shock cause more deaths annually than heart attacks. Inflammation and immune response to infection varies greatly between patients. Some inflammation is a normal defense against infection. However, if inflammation is excessive, white blood cells and other cells can spill into the circulatory system and damage healthy organs. Continuing her previous MSFHR-funded research, Ainsley Sutherland is studying whether the genes that recognize bacteria and viruses play a role in determining which patients will develop the excessive inflammation that can lead to sepsis. This understanding could lead to the development of drug therapies for patients at higher risk of sepsis, and the avoidance of unnecessary drug side effects in patients who are not at risk.
Step towards the prevention of gastric cancer and ulcers: understanding the role of water in Helicobacter pylori transmission
Peptic ulcers affect approximately 3 to 5 per cent of the Canadian population. Helicobacter pylori (H. pylori)—a bacterium that causes chronic inflammation of the inner lining of the stomach—plays a key role in the development of peptic ulcers, chronic gastritis and gastric cancer. As H. pylori has been detected in water, drinking water may play a direct role in transmission of the bacterium. To date, minimal research has been conducted regarding the potential association between H. pylori infection and detailed water system characteristics, such as water source, treatment, well depth and aquifer. Neil Bellack is now conducting the first population-based research project that will examine the association between H. pylori infection and exposures to different water system characteristics, as well as other factors that may affect transmission of H. pylori such as sewage disposal methods and land use. Results from this study will identify the role that water systems and water quality play in the transmission of H. pylori, and point to potential mechanisms for blocking transmission of the bacterium and preventing infection.
Biophysical Investigation of Mutations In The P/Q Type Calcium Channel Associated With Familial Hemiplegic Migraine
Migraines affect about 15 per cent of the population, with the incidence being two times greater in women than in men. Symptoms of common migraines include pain, nausea, vomiting, sensitivity to light, sound, and smells, sleep disruption, and depression. Progress in developing new treatments has been slow due to a lack in understanding regarding the complex genetic roots of the disorder. Familial Hemiplegic Migraine (FHM) is a sub-type of common migraines with similar symptoms, but with simple genetic roots, making FHM a good model for study purposes. Most patients with FHM experience a visual aura – such as shimmering lights, wavy images or temporary vision loss – before the headache starts and varying degrees of paralysis in one side of the body (called hemiparesis). The symptoms can last from a few minutes to several days, in some cases outlasting the headache. About 50 per cent of patients with FHM have mutations in the CACNA1A gene. Paul Adams is investigating these mutations to better understand the molecular mechanisms that underlie migraines – an important step towards developing effective new treatments to alleviate all migraines.
Entry of Dendritic Cells into the Brain: Regulation by Endothelial Cell Adhesion Molecules and Chemokines
Immune reactions in the central nervous system (CNS) – the brain and spinal cord – differ from other organs. Under normal conditions, the endothelial cells lining blood vessels in the brain act as a “blood-brain barrier” to block the entry of most immune cells into the CNS. In some CNS diseases like multiple sclerosis, and in trauma, stroke and infections, this barrier is compromised. As a result, immune cells migrate to the brain in large numbers causing inflammation, which can lead to serious consequences. Azadeh Arjmandi is studying how immune cells gain access to the brain and spinal cord in infectious, inflammatory and autoimmune diseases. Immune cells called dendritic cells have been found in the central nervous systems of patients with these diseases and their numbers increase with more chronic conditions. Azadeh is examining dendritic cell trafficking across the blood-brain barrier in order to further characterize the molecular mechanisms of inflammation in the brain. This will provide important information about how certain CNS diseases develop and may contribute to more effective treatments.
Lung disease epidemiology: evaluation of methods suitable for analyzing change in respiratory symptoms in longitudinal studies
In the past two decades, researchers have examined how lung health is affected by changes in smoking and environmental and occupational exposures, and in the process have learned a great deal about the way lung disease develops. However, most of these studies focused on lung function tests rather than information on chest symptoms, even though detailed information on these symptoms has been collected in a questionnaire used around the world since 1978. A change in symptoms, not in lung function, is the most common reason people seek medical attention and express concerns about potentially harmful workplace exposures. Victoria Arrandale is examining data on changes in coughing, phlegm, wheezing and breathlessness to determine if unused data on these symptoms can help explain the development of chronic pulmonary disease, and contribute to disease prevention through occupational surveillance programs. The results could flag early signs that have been overlooked until now. Ultimately, the goal is to lessen the impact of occupational lung disease by controlling exposures and developing early methods of diagnosing disease onset.