The role of O-Glycosylation in a mouse model of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the loss of motor neurons (specialized nerve cells) in the spinal cord, brain, and descending motor tracts. ALS leads to muscle weakness and paralysis, and is often fatal. Numerous biochemical processes have been linked to the progression of ALS, including increased levels of protein modification (phosphate units). Xiaoyang Shan is researching the role of modified sugar units, known as O-GlcNAc, in maintaining the proper functioning of neurofilaments (structural proteins) that give neurons support and shape but become damaged in ALS patients. He is also investigating the role of O-GlcNAc in maintaining healthy motor function. The findings could help increase understanding of the causes of ALS, and contribute to development of a potential treatment to slow or halt the progression of the disease.

Development and application of data standards for flow cytometry

Flow cytometry is a method of identifying and sorting cells and their components by staining with a fluorescent dye and detecting the resulting fluorescence (usually by laser beam illumination). Flow cytometry is widely used in health research (e.g. for stem cell identification and vaccine development), and in the diagnosis, monitoring and treatment of a variety of diseases, including cancers and HIV/AIDS.

Recent advances in high-throughput flow cytometry allows for the analysis of thousands of samples per day, creating detailed descriptions about millions of individual cells. Managing and analyzing this volume of data is a challenge that Dr. Ryan Brinkman is addressing through the development of data standards, algorithms, and bioinformatics tools. Dr. Brinkman is also applying these methodologies to the analysis of several large clinical flow cytometry datasets in an effort to identify biomarkers for lymphoma, neonatal auto-immunity, and graft versus host disease.

Germline and Somatic Cancer Genetics: Tools for population based individualized cancer care

Today’s cancer treatment is dictated by the anatomic location of the cancer, its histology, and how far it has spread. The Human Genome Project and the development of new drugs targeted against specific features of cancer cells have led to the possibility of individualized cancer care. This is a fundamental shift in cancer management and will involve integration of each patient’s inherited genetic characteristics and the molecular signature of their tumour. My laboratory uses genetic tools to predict inherited cancer susceptibility and genomic based tumour characteristics to determine therapeutic options. In British Columbia, the central referral system for cancer patients provides the opportunity to deliver equitable individualized cancer care across a whole population. I am fully committed to this challenge and dedicate my research, clinical practice, teaching, and administrative skills to this task. My clinical work occupies <25% of my time and involves the genetic based care of familial cancers. The remainder of my time is divided evenly between (1) research infrastructure development and furthering the translational research of my colleagues and collaborators and (2) the pursuit of my own research interests. My major research projects focus on the genetics and molecular pathology of hereditary cancers, with the goal of streamlining cancer susceptibility testing and identifying therapeutic opportunities for hereditary cancers and their sporadic counterparts. Current projects include the study of gastric, breast, and ovarian cancer susceptibility. My research in hereditary gastric cancer is already shaping the worldwide management of this cancer susceptibility syndrome. To develop useful laboratory tests based upon tumour characteristics, I developed and now co-direct the Genetic Pathology Evaluation Centre (GPEC) which is Canada's leading tissue based biomarker validation laboratory and a key element in the BC research landscape. My time spent directing GPEC and other such research entities is mutually beneficial as I am user of the research infrastructure I have helped to create. All of my projects are completely congruent with my stated vision of genetic based individualized cancer care for whole populations. Although this is an aggressive agenda, I believe my record in translational research during the first 4 years of my MSFHR scholarship indicates a great likelihood of future success.

Nervous System Regeneration and Repair: Lessons From the Olfactory System

The brain or central nervous system (CNS) is especially vulnerable to permanent injury and loss of function following stroke, trauma and seizure or the onset of genetic disorders such as Huntington or Parkinson disease costing billions of dollars in health care every year and long-term loss of productivity. Despite major advances in understanding of neural development in recent years, a major challenge facing neuroscientists today is how to use this knowledge to help direct repair and rebuild the CNS after it becomes damaged. Dr. Jane Roskams uses the mouse olfactory system (nose) to study CNS repair because cells in the system have a remarkable ability to remodel, repair and regenerate, compared to other regions of the CNS. Olfactory system repair is driven by two types of cells — one that replaces lost neurons (specialized olfactory stem cells) and another that guides these replacement cells to their target (olfactory glial cells). As part of the only team in the world focused on these complementary research areas, Dr. Roskams has developed a series of tools and approaches to determine which specific cells are activated to replace damaged neurons, and to test the signals that drive this activity. She is also working to determine the unique ways that these cells contribute to repair following spinal cord injury and stroke. While transplanting either of these types of cells into injured or damaged CNS tissue could help with repair. Dr. Roskams’ work is focused on understanding how repair mechanisms work at the molecular level, with the goal of discovering if there are ways that injured cells might be manipulated into repairing themselves — a potential new way of addressing or preventing long-term CNS damage.

Centre for Drug Research and Development

Advances in the high through-put genome sequencing, informatics and proteomics technologies have increased the speed with which researchers are identifying new proteins and compounds that hold promise for the development of new drugs for the treatment of cancer, diabetes, infectious diseases and other acute and chronic health problems. This drug development and commercialization platform provides a structure and process for moving these early stage discoveries out of the laboratory and into commercial development, contributing to economic development and helping to bring much needed pharmaceuticals products into use faster.

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Exposure to Residential Air Pollution and Diagnosis of Acute Otitis Media During the First Two Years of Life in British Columbia, Canada

Middle ear infection, or otitis media, affects up to 80 per cent of children in North America and is the leading reason children under three visit the doctor, take antibiotics, or have surgery. The costs associated with doctors’ visits, prescriptions and parental work leave are considerable. Elaina MacIntyre is continuing her earlier MSFHR-funded research investigating whether exposure to air pollution increases the risk of middle ear infection in children. The condition is a common complication of upper respiratory tract infections. Since air pollutants irritate the upper respiratory tract, it’s plausible they could play a role in middle ear infections. Recent studies in Europe have found an association between living in areas with high air pollution and the incidence of middle ear infection, but this relationship has not been previously examined in North America. MacIntyre is conducting the first North American study to analyze whether this type of infection is linked to exposure to air pollution from industry, traffic and wood burning sources. Results of her study could be useful in assessing the public health impact and health care costs of middle ear infections, and in helping reduce the incidence through strategies to prevent or limit environmental exposure of young children to environmental conditions that contribute to the development of these infections.

Mechanisms of topical calcipotriol mediated tolerance induction

Autoimmune diseases such as type 1 diabetes, lupus, and multiple sclerosis are a serious health issue in North America, affecting more than 22 million people in the US alone. Unfortunately, current treatment options for individuals suffering from autoimmunity are limited, and patients are often faced with the prospect of life-long drug regimens designed to suppress their immune systems. While effectively managing autoimmune diseases, these drugs can also hamper the body’s ability to defend itself against infection and cancer, substantially reducing a patient’s quality of life. T regulatory cells (Tregs) are a class of immune cell that prevent the immune system from attacking the body. Because Tregs can prevent autoimmune disease, many attempts have been made at designing methods to generate them. As of yet, no practical and reliable means of producing Tregs has been achieved. Previous research demonstrates that Vitamin D may play a role in the Treg production process. Paxton Bach is investigating whether applying Vitamin D to the skin can be used to generate Tregs, and early results are promising. Ultimately, this research could lead to more effective, less invasive treatments for individuals living with autoimmune diseases around the world.

Heme binding and transport by the Staphylococcus aureus Isd system

Staphylococcus aureus is a bacterial pathogen that is of considerable medical concern. Though it normally lives externally on humans or animals, S. aureus causes problems when it is introduced into breaks in skin or mucosal surfaces, enabling it to invade the surrounding tissues and move into the blood stream. S. aureus poses an especially great threat in the hospital setting where it is one of the most commonly acquired bacterial infections and a serious cause of disease and death. The emergence of multidrug-resistant “superbugs” has highlighted the potential threat S. aureus poses in the health care system. There is an imperative need for new means of inhibiting the growth of S. aureus. As in many other organisms, iron is required for growth in S. aureus – an element that the bacteria must either extract or scavenge from within the human system. The majority of iron in the human body is found in heme, and many other organisms have evolved to utilize heme as an iron source. Recently, S. aureus was also shown to preferentially use heme-iron in early growth, but little is known about its heme uptake mechanism. Jason Grigg is exploring the function and structure of a set of four cell surface heme binding proteins found on S. aureus. By describing how the bacteria grows by extracting iron from its host, this research may lead to new ways to “starve” the bacteria and inhibit its pathogenesis.

Characterization of a kinase implicated in kinetochore function during S phase

Chromosomes, which are a compacted form of DNA, must be accurately duplicated and separated into two new daughter cells during each cell cycle. Genetic instability arises when chromosomes are separated improperly. This error is the source of many diseases, such as cancer and Down’s syndrome. Accurate chromosome separation relies on machinery assembled on each chromosome called the kinetochore. The regulation of the kinteochore is essential for cellular fitness and prevention of genetic instability. Understanding the mechanism by which the kinetochore is regulated will lead to a better view of cellular division and will provide insight into the treatment of diseases such as cancer. Because chromosome separation is a fundamental cellular process in all types of cells, Jennifer McQueen is using budding yeast as a model to study chromosome segregation. She is using many genetic and biochemical tools to examine the involvement of the Mck1 kinase in chromosome separation. Her project aims to discover a new role for the Mck1 kinase in kinetochore function and to produce a new model of kinteochore regulation that is applicable to human health.

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 – 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 – two each of H2A, H2B, H3, and H4 – 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 doesn’t 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. Wang’s ultimate aims for the research is to contribute to development of therapies for diseases that result from changes in chromatin structure.