Place and experiences of risk among young drug users in downtown Vancouver

Illicit drug use is associated with severe harms and immense social suffering among youth. Previous ethnographic work has shown how social-structural and cultural processes present within specific urban locales intersect to push young people who engage in drug use towards ‘risk’, until it becomes difficult or impossible for them to avoid transitioning into increasingly ‘risky’ behaviours. However, there have been relatively few in-depth investigations of drug-using contexts or ‘scenes’ that focus exclusively on the meanings, understandings and everyday lived experiences of young drug users themselves. Danya Fast’s research explores young people’s understandings of the social-structural and physical landscapes of the downtown Vancouver drug scene, and how various locales (e.g. neighbourhoods, alleyways, service locations, residences), shape experiences of ‘safety’ and ‘risk’ among drug-using youth. Her approach emphasizes the influence of place on health, where place is understood to encompass both physical and social spaces. An important goal of this research will be the identification of elements in the physical and social environment that shape risk and structural interventions that alter context and, by consequence, facilitate safer spaces for work, rest and recreation for youth. Ms. Fast’s project will result in a more comprehensive and culturally sensitive account of young drug users’ everyday experiences in the context of the downtown Vancouver drug scene, and will also be used to inform ongoing epidemiological research with drug-using youth. Moreover, Ms. Fast’s project will contribute to the development of an ongoing ethno-epidemiological research program that has been identified as an important emergent area within Human Immunodeficiency Virus research, due to its unique ability to inform the development of interventions designed to reduce drug-related harms.

Knowledge representation in Health Research: the Canadian Influenza Research Network model

The Public Health Agency of Canada estimates that influenza infection currently results in an average of 20,000 hospitalizations and 4,000 deaths each year. Therefore, an influenza pandemic would have severe health, economic and social consequences. The Public Health Agency of Canada/Canadian Institutes of Health Research Influenza Research Network (PCIRN) was developed to identify research gaps in the country's pandemic influenza preparedness initiative. To facilitate the initiative, research will be done at various sites across the country, supported by a common information technology (IT) group. An essential mission of the IT support group is to develop standards ensuring proper communication and knowledge transmission amongst the different members of the network. Currently, differences in interpretation of the 'meaning' of data or semantic heterogeneity pose a significant challenge to combine information from multiple heterogeneous sources. In order to efficiently integrate information generated by the various centres constituting the network, a consistent representation of data must be adopted.

Mélanie Courtot's research centres on the development of a model to unambiguously interpret influenza data. Working in collaboration with Dr. Scheuermann, leader of the BioHealthBase project, the equivalent of the PCIRN network in the United States, Ms. Courtot will develop a guideline outlining the minimum information required, and derive a data model that captures the necessary elements and the semantic relationships between them, which will allow for the integration of Canadian and American data, thereby assisting in the development of a North American influenza data network. Establishment of standards for unambiguous data representation and investigation modeling will improve the integration and re-use of information produced, and ultimately increase the quality and re-usability of that information and decrease the cost of health care.

The role of immune cells and the inflammatory response in tumor cell metastasis

In recent years, there has been a marked improvement in the clinical classification of individual cancer sub-types based on their detailed genetic and pathophysiological analysis. While this has had a tremendous impact on determining patient diagnosis, current treatments used to block the spread of tumour cells have largely been unsuccessful, and metastasis (the spread of tumour cells from a primary tumour to secondary sites), remains responsible for 90 percent of cancer deaths. Notably, the number of cancer cells that have the capacity to reach the bloodstream correlates with primary tumour size, and when diagnosed with cancer, patients can expect to have between 100,000 and more than one million circulating tumour cells in their blood. This apparent inefficiency of tumour cells to get out of the bloodstream and proliferate may be an important avenue for therapy, as maintaining and/or enhancing this inefficiency could be a key step in blocking the spread of cancer. Recently, Spencer Freeman has been investigating this possibility. His research has provided general information on how tumour cells adhere to and migrate out of the blood vasculature, and he has identified Rap1 and integrin as critical regulators of tumour cell adhesion. Moreover, Mr. Freeman and colleagues have been able to block this pathway using antibodies and genetic approaches, which has reduced the ability of tumour cells to adhere to and migrate out of the vasculature in vitro as well as in animal models. In his current research project, Mr. Freeman is investigating the underlying mechanism, in particular the signalling events, which mediate communication between tumour cells, circulating blood leukocytes and vascular endothelial cells. The results of his research will improve our understanding of the genetic axis and physical steps that tumour cells use in order to first colonize distant sites. In turn, this knowledge may lead to improved cancer treatments against metastatic disease.

Developing an innovative antibody-based nanopharmaceutical for treating cancer

Rituximab is an anti-CD20 monoclonal antibody (mAb), approved for use in combination with standard chemotherapeutic agents for treatment of patients with CD20-positive B cell lymphomas. Although it provides significant benefits for lymphoma patients, it is not curative, and for several specific forms of lymphoma, rituximab offers little or no benefit. To date, the mechanism(s) underlying the anti-tumour activity of this mAb in vivo are not clear. However, one area of particular interest is in activities that involve clustering of the CD20 molecule on the cell surface. Clustering of CD20 has been shown to elicit changes in cell signalling pathways that promote cell death, while enhancing sensitivity of lymphoma cell lines to cytotoxic agents. By better understanding this mechanism of antibody-induced tumour death it will be possible to determine the clinical basis for insensitivity to rituximab. Jesse Popov’s research is exploring this mechanism of activity by comparing a novel, highly active multivalent form of rituximab that he has developed, to the activity of rituximab. The results of his research will provide for improvements on the novel mAb he has developed and may also provide a possible therapeutic alternative to rituximab. Importantly, this novel agent can be made with any therapeutic antibody, not just rituximab, which means that it has the potential to be used for treating virtually any type of cancer. Such improvements over current therapies translate directly into a higher quality of life for cancer patients.

Developing New Non-Invasive Optical Techniques for Detecting and Diagnosing Cancer

While cancer continues to affect thousands of Canadians, when detected at an early stage patients have a better chance of survival. Therefore, the development of sensitive diagnostic tools to enable early cancer detection and diagnosis is important. Dr. Anthony Lee is focusing his research efforts on the design and development of high resolution, non-invasive, in vivo optical imaging tools that will allow clinicians to perform so called ‘optical biopsies’ to detect and diagnose lung and skin cancers while the patient is being examined. Lung cancer is the leading cause of cancer mortality. The only reliable way to definitively diagnose the disease is to perform a lung biopsy for histological inspection by a pathologist. This technique is invasive and is associated with numerous problems. Dr. Lee’s Optical Coherence Tomography (OCT), is a technique that shows promise as a non-invasive diagnostic tool for lung cancer. Part of his project will be dedicated to developing a new OCT instrument designed specifically for use in patients’ lungs. OCT is similar in principle to ultrasound except that it uses light rather than sound as the imaging signal. It has higher resolution than ultrasound and sufficient penetration into tissue to examine the lung epithelial lining, where most cancers originate. The endoscopic probe being designed can image large segments of the bronchial tree in high resolution. Additionally, Dr. Lee is developing a Multiphoton Microscopy (MPM), instrument for use in diagnosing skin cancer, the most commonly diagnosed form of cancer. MPM has microscopic resolution and will be able to create 3-dimensional volumetric images of tissue. The results of Dr. Lee’s work will provide improved diagnostic tools to replace traditional biopsies which are time and resource intensive. Moreover, if cancer diagnoses can be confirmed in situ, immediate treatment becomes a possibility and may eliminate the need for subsequent patient visits.

Perceptual and attentional abnormalities in autism – understanding impaired discrimination of the eyes

Autism is a pervasive developmental disorder involving impairments in social interaction, verbal and non-verbal communication, a lack of imaginative play, and repetitive and restricted solitary activities. A critical goal of autism research is the identification of biological, behavioural and cognitive markers that will help researchers determine the links between genes and autism and aid in the development of effective diagnostic tools, as well as improve upon existing intervention and treatment programs. Of note, abnormal perceptual processing is currently a candidate marker of autism. There is mounting evidence to suggest that people with autism show specific perceptual abnormalities, and that these abnormalities may play a causal role in deficits in social processing. For example, research suggests that individuals with autism show abnormal perception of faces, with a reduced ability to discriminate visual changes to the eye area of a face, as compared with normal perception of changes to the nose and mouth. However, it is unclear whether these abnormalities are due to a deficit in perceiving visual information from the eyes, or a lack of attention to this visual information. Elina Birmingham’s research involves the use of eye tracking and a new methodology called the moving window technique, to measure the focus of attention in children with autism while they undertake visual face exploration. Her research will provide insight into several key questions regarding perceptual and attentional abnormalities as indicators of autism in children. The results of her study will contribute to the goal of identifying markers of autism, and as such may have important implications for treatment and intervention methods.

Influence of aging on candidate neuropsychiatric disease genes measured using differential coexpression

Aging and developmental change represent body wide changes in genes. Because many genes change as people age, the relationships between genes also often change, a phenomenon called differential coexpression (of RNA levels). Studying differential coexpression has uncovered changes that cause disease. However, knowledge gaps remain with respect to relationships between disease and aging in neurological diseases, for example. Many diseases have a specific age of onset, schizophrenia for example, typically strikes in early adulthood. This suggests that in multi-gene disorders, where interactions between genes play a role, rewiring may occur between susceptibility genes at the age of disease onset. Dr. Gillis’s current research project builds on his earlier work which showed that aging is associated with numerous changes in coexpression, and that genes known to be associated with specific diseases change their relationships with age in healthy individuals. His current project involves studying how the relationships between candidate genes – differential coexpression – in schizophrenia and Alzheimer’s Disease, change as a function of age. By understanding how networks of gene interactions might be rewired in diseases, we can identify candidate genes that would be missed otherwise, and beneficially influence the design of treatments and diagnostics.

Identification and analysis of proteins required for tubulin homeostasis: impact on nervous system disorders and cancer

A cytoskeleton is a central component of all cells, and is made of protein filaments that assemble into networks. These networks allows cells to divide, change shape as needed and perform a multitude of other vital functions. Microtubules (MTs), are essential cytoskeletal components composed of an elementary protein called tubulin. To fulfill its cellular function, the activity and level of tubulin must be maintained optimally by a process known as homeostasis. This process is not well understood, but is known to be particularly important for nervous system function. In fact, disruption of tubulin homeostasis can lead to neurological problems such as Huntington’s disease. Furthermore, because MTs are important in the uncontrolled division of tumour cells, tubulin represents an important target for cancer treatment. To improve our understanding of the fundamental principles guiding tubulin homeostasis, Dr. Melissa Frederic has undertaken research to identify and characterize proteins associated with the function, organization and maintenance of tubulin, using mainly C. elegans, a tiny worm, and mammalian tissue culture cells as model systems. One protein that will be characterized at the molecular and cellular levels, termed HECTD1, has been identified in her lab as a likely factor influencing tubulin homeostasis; importantly, it has also been linked to neural tube defects in a mouse system where the protein was removed. At the same time, Dr. Frederic is doing genetic screens to identify proteins that effect tubulin homeostasis, including one that utilizes the anticancer drug taxol or benzyl isothiocyanate. Together, the characterization of HECTD1 and the discovery and subsequent characterization of additional proteins implicated in tubulin homeostasis, are expected to shed new light on nervous system disorders such as neurodegeneration and neural tube defects, the most common congenital malformation in humans, as well as cancer.

The role of microbiota in susceptibility to inflammatory bowel disease.

The cause of inflammatory bowel disease (IBD), including intestinal disorders characterized by chronic inflammation such as Crohn’s disease and ulcerative colitis, remains unclear. However, changes in the microbiota have been linked to IBD, including Crohn's disease and ulcerative colitis, as significant differences exist between the microbiota of IBD patients and healthy individuals. As western societies have developed, improvements in health and hygiene have altered human-microbe interactions through increased sanitation, antibiotic usage and vaccination. Concordantly, epidemiological studies have shown an alarming increase in the occurrence of immune mediated disorders, such as IBD. However, whether a change in microbiota composition precedes and contributes to onset of IBD or is a result of IBD remains to be determined. Marta Wlodarska and colleagues have previously shown that clinical levels of antibiotics will cause a shift in, but not complete ablation of the microbiota which results in a differential disease outcome by Salmonella Typhimurium infection. Her current research project expands on this work by investigating how antibiotic-induced fluctuations of the microbiota disrupt the homeostatic state of the intestinal immune system, potentially leading to increased susceptibility to IBD. Specifically, she is using clinical levels of antibiotics to shift the composition of the microbiota and evaluate how that affects the outcome and severity of C.rodentium-induced colitis. Additionally, her research should also provide an understanding of how changes in microbiota composition affect the homeostatic state of the mucosal immune system through intestinal epithelial cell-mediated cytokine secretion. Collectively, her work will increase the understanding of the interplay between the microbiota and immune responses as well as any associated impact on colitis. These issues are central to increasing our understanding of IBD in general, and may lead to the development of new diagnostic and therapeutic tools.

Seasonal plasticity in brain estrogen signaling mechanisms regulating aggression

While estradiol, a kind of estrogen, is often considered a “”female”” hormone, it is fundamentally important for both female and male brain function. It is a hormone with a wide range of effects on the brain and human behaviour. In early life, estradiol plays an important role in the growth of brain cells and in the establishment of differences between male and female brains. In adulthood, estradiol activates both male and female reproductive behaviour. Studies also implicate estradiol in the regulation of aggression, learning and memory, muscle control and the perception of pain. Furthermore, estradiol has been shown to influence depression, recovery from stroke and brain injury, Parkinson’s disease and Alzheimer’s disease. Because estradiol is involved in a vast array of brain functions, many of which are critical to human health, it is important to understand how estradiol affects brain cells. Dr. Sarah Heimovics’ research explores the degree to which there is plasticity in how estradiol affects the brain and behaviour. Specifically, she is investigating the effect of environmental factors, such as photoperiod, on estradiol signalling mechanisms the brain. Traditionally, estradiol has been understood to influence brain and behaviour genomically, via changes in gene expression over a relatively long timescale (days to weeks). However, a growing body of research suggestes that estradiol also has rapid (within 30 minutes), non-genomic effects. Dr. Heimovics will compare the role of genomic and non-genomic estradiol signalling mechanisms in the neural regulation of aggressive behaviour on short and long photoperiods. She is testing the hypothesis that non-genomic estradiol signalling is more pronounced on short photoperiod (as during the winter in BC), which may have implications relative to depression. The results of this research will contribute to the greater understanding of how estradiol acts on the brain, which is a critical issue for the health of British Columbians.