During pregnancy, approximately 15 per cent of women experience depression requiring medical intervention. Although these conditions are often treated with Serotonin Reuptake Inhibitor (SRI) antidepressants, these drugs are reported to increase the risks of adverse infant outcomes, including preterm birth, small for gestational age (SGA) birth, respiratory distress, and some congenital heart malformations. Infant outcomes are also influenced by other factors, including socioeconomic status, and research has shown that mothers of lower socioeconomic status are at increased risk of preterm birth, SGA birth, stillbirth, and neonatal and infant death. To complicate things further, data shows that mothers of low socioeconomic status are significantly more likely to experience depression during pregnancy and are significantly more likely to use one or more psychotropic medications (including antidepressants) to manage mental illness during pregnancy than women of higher income. The relationships between prenatal depression, socioeconomic status, use of antidepressants, and infant outcomes are complex and poorly understood.
Dr. Gillian Hanley will systematically address questions about the role socioeconomic status plays in maternal depression, antidepressant use, and infant developmental outcomes during the first year of life. She has hypothesized that maternal socioeconomic status accounts for an increased risk of adverse infant outcomes previously attributed to antidepressant exposure during pregnancy. For this study, Dr. Hanley will link a number of BC population-level administrative datasets to build the most comprehensive source of data on pregnant women of its kind in the world. This dataset will include all pregnancies and births in British Columbia between 2002 and 2009 (approximately 300,000 infants) and will provide sufficient sample size to detect differences in rare outcomes, such as congenital anomalies and neonatal/infant death. In this project, socioeconomic status will be studied as a predictor of antenatal maternal depression, antidepressant use, and infant developmental health.
These results will illuminate complex relationships between prenatal depression, antidepressant use, and infant outcomes. Given that it is ethically and medically unadvisable to undertake a randomized trial of prenatal antidepressant exposure, this population-based study will provide an unprecedented opportunity to examine key influences on infant health. Dr. Hanley's findings should help clinicians and mothers make more informed treatment decisions for their health and that of their infants.
Polybrominated diphenyl ethers (PBDEs) and perfluorocarbons (PFC) are chemicals that are used as flame retardants and surfactants in a wide variety of consumer products. In animal studies, both chemical groups have been shown to have toxic effects on the thyroid and have the potential to affect fetal brain development. A small but growing body of evidence suggests similar thyroid effects may occur in humans; however, the links between these chemicals and thyroid disruption in early pregnancy, the most critical window of exposure, are still unclear. The specific effects of prenatal PBDE and PFC exposures on neurodevelopment in humans are largely unknown. Disturbingly, both chemicals are present in the blood of the entire Canadian population, including children and newborns, and the most important sources of these chemicals are poorly understood. The post-doctoral research of Dr. Glenys Webster will help fill these gaps by 1) identifying the main sources of PBDEs in maternal blood, 2) exploring whether maternal PBDE levels are associated with maternal thyroid hormone levels in early pregnancy, a time when thyroid hormones play a critical role in fetal brain development, and 3) examining the relationships between maternal PBDE and PFC levels and neurodevelopmental outcomes in one- to three-year-old children, as measured by cognition, motor function and behavior. Dr. Webster’s work will use data from two existing pregnancy cohorts in Vancouver and Cincinnati, and will link the sources of chemical exposure to chemical levels in blood to maternal thyroid effects to child neurodevelopmental effects, all within the same study populations. Understanding the public health implications of population-wide exposures to PBDEs and PFCs will provide key information for ongoing risk assessment and risk management strategies in Canada and will support the development of effective chemical regulation policies to protect public health.
The emergence of broad-spectrum antibiotic resistance is leading to the appearance of an increasing number of multi-resistant pathogenic bacteria, or “”superbugs.”” During the past decade, the superbug Methicillin-Resistant Staphylococcus Aureus (MRSA) has become a major cause of drug-resistant infectious disease. MRSA strains are resistant to all beta-lactam antibiotics, including the commonly prescribed penicillins and cephalosporins. The rapid emergence of community-acquired MRSA strains affecting previously healthy individuals outside the healthcare environment is particularly distressing, as it presents an urgent public health threat. The objective of Dr. Solmaz Sobhanifar’s research project is to investigate antibiotic resistance mechanisms in MRSA. Dr. Sobhanifar is specifically studying beta-lactam sensor/signal transducer proteins, BlaR1 and MecR1, which sense beta-lactam antibiotic levels. Understanding the structures of BlaR1 and MecR1 and how their mechanisms of action permit survival of MRSA during antibiotic treatment would considerably assist drug-design efforts. Dr. Sobhanifar is using x-ray crystallography and NMR spectroscopy to conduct the first detailed molecular structural analysis of these important drug resistance signaling proteins. Obtaining the necessary quantity of materials for structural investigation has proven notoriously challenging, so a “”cell-free”” protein expression approach will be used to obtain sufficient levels of BlaR1 and MecR1 for structural studies. This approach also facilitates selective amino acid labeling, which is important for x-ray- and NMR-based investigations. In partnership with the Centre for Drug Research and Development at UBC, the acquired structural and biochemical data will be used, in conjunction with unique small molecule and natural product chemical libraries, to screen and optimize novel lead inhibitors against BlaR1/MecR1-induced antibiotic resistance in MRSA. This will hopefully provide new therapeutic approaches to manage MRSA in the future.
Sex workers in Vancouver have been found to be highly vulnerable to a variety of negative health and safety outcomes, including high rates of occupational and historical violence, a high prevalence of HIV (approximately 25 percent within street-based sex workers in Vancouver), and limited access and use of health services. In order to mitigate some of the HIV and sexually transmitted infection (STI) risk in this population, researchers at the Gender and Sexual Health Initiative at the BC Centre for Excellence in HIV/AIDS are looking into understanding some of the larger structural and environmental determinants of HIV/STI risk. Dr. Kathleen Deering is studying a sample of sex workers in Metropolitan Vancouver to investigate the intersecting relationships between different social, environmental and structural factors, such as the availability and access to health services, neighbourhood of residence, and locations and venues of sex work. She will be measuring health and safety outcomes of these women (such as HIV/STI risks, including inconsistent condom use, number of sex partners and sex partnering patterns, and occupational and intimate partner violence) and the geographic distribution of these outcomes over time. This project will access data from a five-year longitudinal cohort of women in sex work in Vancouver, including 500 women and 250 youth sex workers who are 14 to 24 years of age. Participants will fill out a detailed survey and be asked to provide blood and urine samples for HIV and STI testing at the start and every six months for the five-year duration of the study. Dr. Deering will be using these data, combined with social epidemiology methods and Geographic Information Systems (GIS) mapping technology to help understand how social, structural and environmental factors impact risk patterns for HIV/STI and health services use and access. She will also be exploring the use of complex adaptive systems approaches as a novel and key methodological/analytical approach for examining multiple intersecting levels of risk. The results of this research will lead to important recommendations relating to changes in public health policy and the development of effective safer-environment interventions to improve the health and safety of women in sex work in Canadian settings. Results will be communicated to community members, the local and provincial government, and the study population through ongoing partnerships.
Chronic myelogenous leukemia (CML) is a cancer of the white blood cells. The disease starts when genetic changes in blood stem cells (hematopoietic stem cells, or HSCs) cause them to become malignant (leukemic stem cells) and grow uncontrollably. Normally, HSCs make all the white and red blood cells that function to protect our bodies from infections and to carry oxygen and nutrients to other cells in the body. In CML, leukemic stem cells crowd out all other cells in the bone marrow, leading to illness and eventually, if uncontrolled, death in the patient.
Dr. Kevin Lin's research group recently discovered that the Ahi-1 gene plays an important role in CML. The gene contributes to leukemic stem cell activity and can influence how these cells become resistant to current drug therapy. The goal of Dr. Lin’s research is to understand exactly how Ahi-1 contributes to CML disease development in HSCs and leukemic stem cells. Using a new mouse model that is deficient in this gene, he will examine what happens to the development and function of HSCs when Ahi-1 is absent. The findings from this project will contribute to our understanding of the biology of normal hematopoietic stem cells and malignant leukemia stem cells. This new knowledge will then be applied to develop better diagnostics and eventually better treatments for patients suffering from CML.
Vaccines are important in protecting our bodies against potentially deadly infectious diseases. The vaccines developed in the past 200 years have clearly had a great impact on human health by preventing many infectious diseases and eradicating others, such as smallpox. Despite this success, strategies for developing new and better vaccines are urgently needed. Current vaccine technologies are still inadequate to counter persistent infectious disease threats like human immunodeficiency virus (HIV), tuberculosis, and malaria. This is partly due to the limited ability of our body to mount a robust immune response to these vaccines, particularly for immuno-compromised individuals such as children, elders, and individuals on immunosuppressive treatments such as post-transplant patients or patients with autoimmune diseases. Further, during epidemics, vaccine production capacity is often limited. Dr. Jacqueline Lai will be developing/optimizing strategies that will deliver safer, more stable and effective vaccines painlessly through the skin. Dr. Lai will be exploring the use of novel vaccine formulations and delivery technologies. The laboratory in which she will train has previously shown that a DNA adjuvant – a chemical that can modulate the response to a vaccine – enhances vaccination responses when rubbed onto the skin at the time of vaccination. The use of adjuvants may increase the efficacy of small vaccine doses, resulting in the immunization of more individuals with existing vaccine production capacity. As part of her research, she will be developing new DNA adjuvant formulations and administration strategies to explore the possibility of further enhancing vaccine responses. The second part of Dr. Lai’s research involves the evaluation of new vaccine delivery technologies. As the skin serves to protect us from the environment, the outer-most layer of the skin forms a tight barrier that prevents the penetration of most substances, including DNA adjuvants. To circumvent the limited penetration of adjuvants and vaccines through the skin, she will test new hollow microneedles, designed by collaborating material engineers, which allow for the painless delivery of vaccines directly into the skin. In addition, she will evaluate vaccines encapsulated in biodegradable materials to increase the stability and efficacy of the vaccine formulations and to obviate the need for refrigeration of the vaccine during distribution.
Osteoarthritis occurs when cartilage (the gristle that lines the ends of the bones) is damaged. It is the most common form of hip arthritis and is responsible for more than 90 percent of hip replacements. Recently, subtle deformities of the hip have been linked to hip osteoarthritis, and it is now believed that these deformities, combined with certain types of physical activities, such as hockey, soccer and bicycling, are one of the major causes of damage to the hip. Since the deformities have been observed in young adults, it may be possible to detect and treat osteoarthritis at an earlier stage, or prevent its development. Dr. Chuck Ratzlaff’s research will demonstrate how physical activity and one or more subtle deformities of the hip can cause cartilage damage and eventually osteoarthritis. He will determine the frequency of deformities in the Caucasian population in comparison to the Chinese population, which is thought to have a lower frequency of osteoarthritis. He will also determine how physical activity over one’s lifetime contributes to osteoarthritis. For this study, participants with and without hip pain from both Caucasian and Chinese populations will attend a two-hour assessment session consisting of a physical examination, a hip x-ray, and a questionnaire on physical activity. He will use new magnetic resonance imaging (MRI) techniques to see how the physical motion and the deformity combine to damage cartilage. This research program will generate the new knowledge needed for major breakthroughs in the prevention, detection and treatment of hip osteoarthritis. Given an aging population and the increased prevalence of chronic diseases in Canada, physical activity is an important intervention for health. Knowledge of how to modify and perform physical activities, and identification of susceptible individuals, will lead to inexpensive and practical recommendations that maximize the benefits of physical activity without increasing the risks of joint disease. It may also lead to identification of a subset of people that will benefit from minor hip surgery to correct the subtle deformity, thus preventing the later development of hip osteoarthritis and its associated burden of suffering and other costs to the individual and society.
Beyond playing an important role in nutrition, carbohydrate building blocks and their biochemistry have been described as the "last frontier of cell and molecular biology." It is easy to see why their study has remained a great challenge: even a simple chain with only six sugar links has over a trillion possible arrangements. This vast structural diversity is reflected in the role of polysaccharides (sugar chains) as the "language of the cell," in that specific arrangements of carbohydrate messages act like dual receivers and transmitters of cell-signaling events. These signals may contribute to friendly cell-cell interactions, lead immune responses, or help to disguise human pathogens from immune detection. Because of the central importance of polysaccharides in signaling events, characterizing the cellular mechanisms responsible for the synthesis, breakdown, and recognition of cell-surface polysaccharides are of vast importance in understanding how the cell works.
Dr. Michael Suits is working to understand how infection by Streptococcus pneumoniae, a human pathogen that is one of the world's leading causes of death, causes infection by recognizing and manipulating the carbohydrate building blocks present on many of our cell surfaces. Certain strains of S. pneumoniae have evolved resistance to antibiotics, are not recognized by human immune defenses even following vaccination, and have the capacity to act in lethal synergy with the Influenza virus. As part of a concerted attack, S. pneumoniae releases proteins, which help the microbe to attach to host cells and short circuit the carbohydrate messages being transmitted. Dr. Suits is directing his research attention towards a pair of carbohydrate-modifying enzymes produced by S. pneumoniae.
Using powerful X-rays to investigate these key enzymes in very precise detail, Dr. Suits hopes to determine how these enzymes interact with an important type of carbohydrate found on the surface of human cells. Additionally, he will use molecular biology tools to "knock out" S. pneumoniae genes encoding important carbohydrate modifying enzymes and then examine how this influences bacterial growth and the ability to cause infection. These research results will help identify potential targets for therapeutic intervention, and provide a platform to develop compounds to inhibit carbohydrate-modifying enzymes.
An increasingly large number of individuals are facing homelessness and inadequate housing (i.e. living in a shelter, on the street or other places not intended for human habitation) in Canada. Annually, it is estimated that 150,000 to 300,000 individuals experience homelessness across the country. In addition, a much larger number of individuals are vulnerably housed (i.e. individuals with low or moderate income who spend more than 50 percent of their income on housing and are at risk of becoming homeless). Housing is a significant determinant of health. Compared to the general population, homeless and vulnerably housed individuals (HVHIs) have been found to be at a substantially increased risk for physical and mental illness, substance use, injuries, assaults and mortality. Furthermore, HVHIs are socially marginalized and frequently experience barriers to health care and social services. Dr. Anne Gadermann will be examining the dynamics of homelessness and housing vulnerability over time, risk and protective factors associated with onset and exiting of homelessness, and whether changes in housing status are associated with changes in physical and mental health status and quality of life. To conduct her research, Dr. Gadermann will be analyzing data from the Health and Housing in Transition study, a longitudinal multi-site cohort study of HVHIs. In this study, a representative sample of more than 1,100 HVHIs has been interviewed annually over a three-year period in Vancouver, Ottawa and Toronto. At each time point, the interview surveys assessed a wide number of variables, including demographic characteristics, housing history and quality of living conditions, physical and mental health status, family history, substance use problems, quality of life, social support, risk behaviours, health care and social service utilization, contact with the legal system, and life events. Furthermore, the interview data have been linked to health insurance databases to provide information on respondents’ health care utilization. Given the increase of homelessness and vulnerable housing in Canada, there is a greater need and demand for research evidence that can complement and expand existing policies, services and programs. The proposed research project is uniquely situated to provide such research evidence, and a special focus will be given to the dissemination of the findings in order to maximize the impact of the research findings on public policies, services and programs related to housing and health.
Cancer is one of the leading causes of death among Canadians, and therefore the identification of new cancer therapies is of great importance. To that end, researchers have found that the structurally diverse defence chemicals provided by sessile marine organisms offer great potential in the fight against cancer. In fact, in the past decade more than 30 natural products isolated from marine sources have entered preclinical and clinical trials as potential treatments for cancer. However, it is rarely ecologically or economically feasible to obtain the active ingredient by harvesting the natural source. Fortunately, synthetic organic chemistry – where molecules are fabricated in the laboratory through a series of chemical transformations – can serve as an alternative source of these compounds. Eleutherobin was originally isolated from a rare soft coral located of the coast of Western Australia in 1997, and in preliminary tests it has shown many promising anti-cancer properties. In fact, taxol, a member of the same class of agents, has already been used to treat more than one million patients suffering from advanced breast and ovarian cancers. Over the past two years, Jeffrey Mowat has spearheaded research centered on the development of a concise synthesis of eleutherobin and analogues of this substance as candidates for cancer treatment. However, so far, eleutherobin's preclinical evaluation has been hampered by lack of material from the natural source or chemical synthesis. Mr. Mowat's current research project addresses this situation through the development of a synthetic strategy that would significantly reduce the number of steps required to access eleutherobin and facilitate its preclinical evaluation. His research also provides a venue for the construction of analogues of eleutherobin, the biological evaluation of which may well lead to the discovery of new, improved antimitotic drugs for cancer therapy.
