The recruitment and retention of health care professionals is one of the most pressing challenges currently facing the Canadian health care system. In rural communities, the number of obstetricians and general surgeons is diminishing for a number of reasons, including difficulties in recruitment, an aging workforce, resistance to a demanding call schedule, and an increase in sub-specialization resulting in fewer ‘general’ surgeons. In some rural communities, maternity care is provided by general surgeons with enhanced obstetrical skills.
There are approximately 4,000 pregnant women in BC living in rural communities whose maternity care comes from these general practice (GP) surgeons. Despite the important role these practitioners play in sustaining rural maternity care in BC, to date, there has been no systematic research into their current experiences, and no official policy regarding guidelines for the practice, training, and maintenance of skills. Dr. Jude Kornelsen is investigating the role of these practitioners in rural health care in BC and their contribution to sustainable maternity care in these communities from a multi-disciplinary perspective.
Primarily through in-depth interviews, she will detail the experiences of GP surgeons in providing obstetrical care to rural communities including understanding their motivation, the nature of support received, and identifying any barriers to practice. She will describe the relationship between GP surgeons and specialists in their local community and in referral facilities, and determine how they receive ongoing training, mentoring and education. Ultimately, this research will provide a greater understanding of the culture of GP surgeons’ role in rural maternity service delivery in rural BC, and will help to inform policy guidelines regarding the practice, training, and maintenance of skills.
HIV has tremendous capacity to mutate and evolve due to the body’s immune response. However, the extent to which the virus has adapted to its human hosts over the course of the pandemic remains poorly understood. Repeated cycles of immune selection and transmission may allow the accumulation of key “escape mutations” — changes in the viral genome that help HIV evade the body’s defences. If immune targets in the HIV genome were disappearing over time due to the accumulation of these mutations, our ability to generate natural and vaccine-induced protective immune responses would diminish as the epidemic progresses.
Furthermore, the extent to which immune escape has influenced HIV pathogenesis remains unknown. Studies investigating the evolution of HIV virulence have largely focused on population-level trends in clinical markers over time, but few have addressed this issue using biological assessments of replication capacity or viral protein function.
Dr. Zabrina Brumme’s research team will undertake the first large-scale investigation of immune-driven HIV evolution and its implications over the 30-year history of the epidemic in North America. Host and viral genetic sequences from 1979 to the present will be analyzed to characterize the extent of population-level HIV adaptation over the epidemic’s course. Functional assessments of viral replication capacity and protein function will be performed to determine whether HIV is evolving towards increased virulence, gradual attenuation, or simply adapting to changing host-pathogen pressures over time.
With this study, Brumme is poised to answer two key questions of HIV biomedical research, namely, to what extent the virus has adapted to its hosts since AIDS was first recognized, and what implications this has for the future of the epidemic. Results have the potential to significantly advance HIV vaccine research.
Protein aggregation is a pathological feature of a large number of diseases with a strong preponderance in age-related neurodegenerative disorders like Parkinson’s disease. Failure to eliminate aberrant proteins in the cell plays a major role in these pathologies and is often linked to the impairment of the ubiquitin proteasome system, which degrades proteins labeled (or modified) with ubiquitin. The overall goal of Dr. Thibault Mayor’s research is to further define the involvement of the ubiquitin proteasome system in aggregation diseases using proteomic and cell biology approaches.
Mayor’s team has developed a new cellular assay to monitor the formation of aggregates induced by proteasome inhibition. They have identified by mass spectrometry more than 500 proteins that localize in these structures. Using a computational approach, Mayor will determine which features are shared among these proteins to give better insight into the mechanisms leading to aggregation. The UCHL1 enzyme may also be a major player in the aggregation process, and Mayor’s team will use the cell assay and mass spectrometry to further characterize UCHL1 and determine whether other enzymes related to the ubiquitin proteasome system may promote aggregation.
Current treatments for most aggregation diseases are primarily based on symptom management instead of directly treating the cause. Mayor’s work may potentially lead to a better understanding of the aggregation mechanism and identify novel targetable pathways to prevent formation or favor clearance of protein aggregates that could be used for new therapeutics.
Mobility of the upper extremities has a significant impact on independence and quality of life. For individuals with neuromuscular disorders due to aging, stroke, injury, or other diseases, the activities of daily living (such as eating and dressing) can be very challenging. However, biomedical robotic technologies offer a promising tool with which to improve the mobility of individuals with impaired upper extremities.
Collaborating with experts in the field of neuromuscular rehabilitation, Dr. Carlo Menon is leading the design and development of a smart assistive medical device that is portable and wearable. The objective is to develop a device that will assist with functional movements and strengthen muscular tone of the weakened or impaired extremities. The device will have potential use for both upper extremity assistance and rehabilitation.
This research will improve the quality of life for individuals with neuromuscular disorders by restoring mobility of the upper extremities. The proposed project will include the following phases: a) interaction with the neuromuscular collaborators to iteratively reformulate the design; b) the engineering design and development of the biomedical robotic device; c) the engineering testing of the device; d) a study of the interactions between the device and both healthy volunteers and individuals with neuromuscular disorders to verify that the device can assist functional movements; e) technology transfer to neuromuscular scientists and clinicians.
To date, the only successful approach for curing type 1 diabetes is to replace the insulin-producing beta cells that have been destroyed by the disease. Pancreas- and islet-cell transplantation are promising therapeutic strategies; however, scarcity of transplantable tissue has limited their widespread use. One way to produce enough beta cells to cure type 1 diabetes is to determine how the cells develop normally within the embryo and apply this knowledge to the regeneration of beta cells in the culture dish or directly in people with diabetes.
Using human and mouse model systems, Dr. Francis Lynn’s research aims to enhance our understanding of normal regulatory pathways that govern pancreas- and insulin-producing pancreatic beta cell genesis and function. The hope is that a greater understanding will enable cell-based approaches for treating and curing diabetes. Lynn’s long-term objective is to understand how regulatory DNA-binding proteins called transcription factors drive beta cell formation and function. This research specifically focuses on one member of the Sox gene family of transcription factors named Sox4. Preliminary data suggest that Sox4 is instrumental in governing both the birth of beta cells and their replication later in life. These observations place Sox4 as a novel and previously unappreciated key regulator of beta cell biology.
Lynn hopes that a thorough characterization of the pathways through which Sox4 regulates beta cell formation and function will inform novel approaches for generation of large numbers of functional beta cells from human embryonic stem cells or induced pluripotent stem cells.
Existing viral vaccines provide immunity against a number of important infectious diseases. The technologies used to develop these vaccines generally work best against viruses that do not mutate very much in nature. However, conventional vaccine design approaches have proven inadequate for viruses such as HIV-1 that continuously evolve in order to evade our immune defenses. Thus, new vaccine design strategies are needed to tackle viruses like HIV.
Dr. Ralph Pantophlet’s research program is developing novel strategies for the design of vaccines that will induce broad immunity to HIV infection. Specifically, Pantophlet seeks to better understand molecular and immunological conditions that impact the elicitation of antibodies with the capacity to block the infectivity of a wide variety of HIV strains. This research focuses on these types of antibodies, dubbed “broadly neutralizing antibodies,” because of their demonstrable ability to block HIV infection in animal models. Another component of this program of research will be systematic studies to define neutralizing antibody target sites on HIV and investigate exposure of these sites at the molecular level. As part of the proposed research program, knowledge gained from the studies outlined above will be incorporated into the design of formulations to elicit target site-specific broadly neutralizing antibodies upon immunization. Thus, insight gained from this work is expected to advance HIV vaccine design efforts and be of significant interest to the field.
Although the focus will be on HIV, knowledge gained from this work may be applicable to other viruses for which conventional vaccine design approaches are also not optimal. Examples include hepatitis C virus, which like HIV is highly mutable and for which a vaccine has yet to be developed, and influenza, for which better vaccines are urgently being sought due to the constant threat of the emergence of a pandemic strain.
Keywords: HIV, vaccine, neutralizing antibody, immunogen design, vaccine immunology, B cell epitope, adjuvant, glycoprotein, T cell epitope, animal model
Dr. Laura Sly’s research program aims to improve our understanding of inflammatory bowel disease pathology and to identify and validate novel therapeutic approaches that will improve patient care. Her team has been investigating the role of SH2-containing Inositol Phosphatase (SHIP) in intestinal inflammation. SHIP is a protein that regulates enzymes involved in immune cell signaling. Sly’s research has shown that SHIP-deficient macrophages are hyper-responsive to IL-4, which drives them to an alternatively activated or M2 phenotype.
Using mice as a genetic model of M2 macrophages, Sly reported that M2 macrophages are protective against induced intestinal inflammation. Since then, her team has characterized a complimentary genetic model of M1-polarized macrophages and has identified key anti-inflammatory mediators that may be responsible for protection. Future investigations will focus on whether adoptive transfer of polarized macrophages or targeting macrophage polarization in situ can reduce intestinal inflammation in pre-clinical models of inflammatory bowel diseases.
Sly’s team has also developed a new mouse model of intestinal inflammation that shares key pathological features with Crohn’s disease. They have reported that SHIP-deficient mice develop spontaneous, discontinuous ileal inflammation accompanied by excessive collagen deposition and muscle thickening. Current research goals include targeting macrophage polarization or polarized macrophage products to reduce intestinal inflammation in pre-clinical models of inflammatory bowel disease, and identifying cell types and biochemical mechanisms that contribute to intestinal inflammation in SHIP-deficient mice. Together, these studies will identify cellular and biochemical targets and investigate new immunotherapeutic approaches that may useful in reducing intestinal inflammation in people with inflammatory bowel diseases.
Medical advances have played a fundamental role in dramatically increasing life expectancy in Canada and around the world. This has created challenges for the health-care system as a number of diseases exhibit increased incidence with age. Two examples include Alzheimer’s disease (AD) and cancer; cancer is now the leading cause of death in Canada. Continued research into the causes and progression of the disease is sure to provide advances in our ability to treat and eventually prevent the disease, with great benefit to our society and economy. The overall goal of Dr. Tim Storr’s biomedical research program is to develop new chemical tools to diagnose and treat the disease.
Storr’s team is focusing their research efforts in two areas: metal-overload diseases, and cancer. Many metal ions are essential to our existence, yet under certain conditions can become toxic. The team is currently studying the role of excess metal ions in the development of AD and Wilson’s disease (WD). The increased incidence of AD, and the lack of effective treatment strategies, underscores the pressing need for research into the causes, and the development of new therapeutic options. Storr’s team is investigating a new approach to AD treatment in which drug molecules are activated in the presence of excess metal ions, allowing for selective therapy. At the same time they are applying this treatment strategy to WD, a genetic metal overload disease in which excess metal ions accumulate in the liver. The overall goal is to bring forward new treatments for metal overload diseases that are generated at the site of need and only when excess metal ions are present.
Storr’s team is also applying chemical tools to cancer by developing imaging agents that allow for the early detection of the disease, and the ability to monitor treatment regimens. This information is key to a successful patient outcome, and the group is currently investigating differences in the energy needs of normal and cancerous tissue. Working at the interface of chemistry, biology, and medicine, this research promotes investigation across disciplines towards the design and testing of innovative disease treatments.
Pathogenic bacteria, such as P. aeruginosa, E. coli, and K. pneumonia, can cause serious infectious diseases such as pneumonia, urinary tract infections, and diarrhea. These bacteria are becoming resistant to many of our commonly used antibiotics and have been spreading rapidly over the past decade. Antibiotic-resistant bacteria are a serious threat to Canadian and global health, and new strategies are needed to combat them.
Groups of enzymes called beta-lactamases confer antibiotic resistance to the bacteria by allowing them to destroy beta-lactam antibiotics such as penicillin. Moreover, ongoing changes in bacterial beta-lactamase genes in nature are producing more potent enzymes to destroy our newest antibiotics.
Dr. Nobuhiko Tokuriki’s research will study the ways that beta-lactamase enzymes change. His team will combine experiments in the laboratory to identify mechanisms of change with detailed studies of enzyme function so they can develop ways to block their activity. The information obtained in this research will ultimately be used to develop novel, persistent, and sustainable antibiotics and inhibitors against pathogenic bacteria.
Cancer deaths are driven by two key biological processes: metastasis and treatment resistance. Although these processes are extensively studied as unrelated occurrences, evidence of shared signaling networks suggests common genetic or adaptive events. These pathways will change a therapy-responsive tumour to a resistant and lethal tumour. This occurs in prostate cancer where strategies used to kill tumours induce adaptive responses promoting the emergence of treatment-resistant tumours prone to metastasize. There is limited study of linkages between metastasis and treatment resistance, and Dr. Amina Zoubeidi’s research program will address an important knowledge gap in our understanding of aggressive tumour behavior in prostate cancer. The hope is that this research will translate into novel therapeutic development for prostate and other human cancers.
Zoubeidi’s work will be facilitated by her recent development of novel cell lines and xenograft models of prostate cancer that are resistant to a new generation of the AR pathway inhibitor drugs MDV3100 and abiraterone. These drugs, while recently introduced as therapeutics for patients with castration-resistant prostate cancer, offer survival gains of only four months and promote MDV- or abi-resistance. Zoubeidi has observed that MDV-resistant tumours metastasize whereas the castration-resistant tumours from which they were derived are non-metastatic. These observations suggest that tumours acquire metastatic traits in parallel with drug resistance.
Zoubeidi’s research program will focus on identifying common molecular mechanisms that elicit both metastasis and resistance to this new generation of prostate cancer drugs. Because tumour invasion and resistance dictate treatment outcome, pathways identified with this approach will represent relevant targets that can be inhibited singularly or jointly as more effective therapy. The research program is organized under three themes: the role of sustained AR activation in these processes; mechanisms associated with acquired EMT and their abilities to elicit treatment resistance; and the emergence of cancer cell “stem-ness” as a common mechanism driving treatment resistance and metastasis.
