58,000 people live with HIV/AIDS in Canada. British Columbia houses 20% of national infections. The BC Centre for Excellence in HIV/AIDS (BCCfE) estimates that there are 2,000 HIV+ people in BC who are eligible for HIV treatment and not accessing it, either because they are unaware of their infection or not appropriately linked to care. It is believed that a large percentage of these individuals may be Aboriginal, given their disproportionate risk of acquiring HIV, and limited access to treatment. As HAART access is expanded to HIV-positive communities throughout BC, additional research is necessary to understand Aboriginal risk factors for acquiring HIV, to explain their limited access to HIV treatment and care, and to understand their elevated mortality while receiving HAART. Overall, my PhD research seeks to answer the question: How do social, sexual and drug-using networks influence Aboriginal risk for HIV acquisition, HIV treatment access and HAART outcomes. I will explore three hypotheses: 1) Socio-demographic and economic status, injection drug use and risky sexual behavior, are primary risk factors for HIV infection among Aboriginals in BC; 2) Socio-cultural beliefs and drug addiction perpetuate limited treatment access among Aboriginals in BC; 3) Lifestyle issues influence poor treatment outcomes among Aboriginals on HAART in BC. I intend to employ social, sexual and drug-use networking techniques that have been pre-validated for HIV/AIDS epidemiological study. An initial pool of consenting HIV-positive Aboriginal adults on HAART (n=30) will be asked to recruit up to 10 people from their sexual and/or drug use network, defined as someone with whom they have had sex and/or done injection drugs with, within the preceding 2 months. A maximum of 300 participants will be recruited through this technique (n=300). Mathematical modelling techniques will be used to analyze the impacts of sexual and drug use networks on Aboriginals’ HIV risk behavior, treatmenta access and treatment outcomes. This research will be coordinated from the British Columbia Centre for Excellence in HIV/AIDS, and carried out at the Vancouver Native Health Society.
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Protective factors associated with preventing injection drug use initiation among at-risk youth in Vancouver, British Columbia
Street youth – 15- to 24-year-olds without a permanent residence – are at considerable risk for acquiring HIV and hepatitis C due to participation in high-risk activities such as injection drug use (IDU) and sex trade work. In comparison to their older counterparts, street youth who use injection drugs are at greater risk for blood-borne infections because of their lack of experience: they are more likely to share needles and other drug equipment, and they are more likely to initially require a friend or acquaintance to inject them, decreasing their control over the use of clean equipment. In addition to the risk for HIV and hepatitis C infection, initiation of IDU at a young age is associated with participation in sex trade work, binge drug use events, criminal activity, and long term injection drug use. While most research concerned with IDU in street youth populations examines high-risk behaviours for HIV and hepatitis C infection, few studies have investigated factors that prevent street youth from initiating IDU. Catharine Chambers’ research aims to determine why certain street youth are resilient to IDU initiation and, for those youth who have experimented with injection drugs, why they initiated IDU and what can potentially prevent them from transitioning into regular users. She hypothesizes that stable relationships with primary caregivers, social support networks separate from the street community, and absence of criminal activity may provide resilience from IDU initiation. Chambers’ findings will inform the development and implementation of prevention programs to reduce initiation of injection drug use among Vancouver’s street youth. Ultimately, this could reduce the prevalence of blood-borne infections, HIV and hepatitis C, in these high-risk groups.
Investigating syringe-sharing among at-risk youth, and analyzing coverage of and access to youth-targeted needle exchange programs
Street youth often carry a heavy burden: trauma, sexual and physical violence, lack of education, homelessness, and mental illness all contribute to the difficulties that many young street people face. Studies have shown that street youth are also one of the groups at most risk of progressing from non-injection drug use to injection drug use, including crystal methamphetamine use. Because they often engage in high-risk sexual activities and drug use, street youth are also particularly susceptible to being infected with and spreading blood-borne diseases like HIV and Hepatitis C. Young women in this group, some of whom are involved in the sex trade, are at particularly high risk of contracting these diseases. Health authorities in Vancouver have recognized this problem and responded by expanding and decentralizing needle exchange programs that target street youth. However, little is currently known about the effect that these programs have had on the risk behaviours and drug use patterns of street-based youth. Given that street youth who inject are often hard to reach, there are concerns that this population may not have adequate access to critical HIV prevention programs such as needle exchange. Daniel Werb is investigating the factors associated with syringe sharing among street youth, such as crystal methamphetamine use, unstable housing, involvement in sex trade work, historical sexual abuse, and depression. He will also investigate the reach of youth-oriented needle exchange programs in Vancouver and determine their effectiveness in harm reduction. Werb’s findings will help health authorities understand this at-risk population better, and contribute to the development of effective programs that support the health of street youth who inject drugs.
Cancer screening behaviours, sexuality, and acculturation: decreasing disparities in Chinese Canadian women
The Chinese are one of the fastest-growing ethnic groups in Canada, comprising about four per cent of the population in 2001. Research has consistently found that compared to individuals of European descent, people of Chinese descent have much lower rates of health-seeking behaviours (actions taken in order to maintain or improve health). For example, Chinese women in BC have twice the risk of cervical cancer compared to Euro-Canadian women, mainly because of poor screening behaviours. Culture is believed to be an important factor contributing to low Pap testing rates among Chinese women. By Western standards, traditional Chinese sexual attitudes and behaviours are conservative: sexual activity is strongly discouraged before marriage and it is taboo to talk about sex openly. One way to study culture is to consider what happens when individuals move to a new country and encounter a new culture. Acculturation is the process whereby values of the new culture (Mainstream culture) are incorporated into one’s self-identity and culture of origin (Heritage culture). Recently, a pilot test was conducted among university students investigating the role of acculturation in the relationship between sexuality-related beliefs and behaviours and Pap testing. Among the Chinese women, high Mainstream acculturation was significantly related to more accurate sexual knowledge and better sexual response, and high Heritage acculturation was significantly related to less Pap testing behaviour. Jane Woo is building on the pilot study to further explore these relationships. Following validation that the findings among university students can be extended to women in the general population, she will conduct focus groups to understand women’s experiences related to their sexuality and reproductive health behaviours. A greater understanding of the factors that affect health-seeking behaviours among Chinese women will contribute to the development of more equitable, culturally-sensitive health care services to all Canadians.
Integrating gene expression data, interaction network information and evolutionary analysis to investigate mammalian innate immunity at the systems level
The immune response is the set of defenses our bodies mount to counter harmful microbes. The innate immune response is our first line of defense, providing protection until the adaptive immune response is activated. Unfortunately, the innate immune response can also be a double-edged sword. It can spin out of control and cause an overwhelming immune response called sepsis, which is responsible for 200,000 deaths every year in the US. The innate immune response is initiated and regulated by complex signalling pathways of genes in our cells. These pathways identify which type of microbe is invading (bacteria or viruses, for example) and mounts appropriate responses. Dr. David Lynn is investigating the genes involved in the innate immune response, how they are turned on and off in particular infections, and what goes wrong in cases of sepsis. This work generates vast quantities of data, requiring computer-based approaches (bioinformatics) to understand and handle such large datasets. Lynn’s work integrates gene expression data with information about how genes and proteins are interconnected in our cells in signalling networks or pathways – providing new information about gene interconnections influence their regulation. He is also investigating the same networks and pathways in other species such as mouse and cow, determining the differences and similarities in their innate immune response. Lynn’s work will help identify potential therapeutic or drug targets that could help safely boost the immune response. It will also highlight cases where important immunological differences make animal models unsuitable for research on human immunity.
Pathogenomics of innate immunity: analysis of the roles of TNIP1, DUSP16, and TANK in toll-like receptor signalling, innate immunity and inflammation, using novel gene-knockout mice
When disease-causing microorganisms breach the body’s external defences, protective mechanisms of innate immunity are rapidly activated. These are essential to control and clear the infection, but can also contribute to tissue damage. Uncontrolled or inappropriate activation of innate immunity can cause chronic inflammatory disorders, such as arthritis, or result in a highly-dangerous state of acute inflammation, known as sepsis. Thus, a detailed knowledge of innate immunity is critical for understanding the mechanisms regulating inflammation and the causes of human inflammatory diseases. It is also essential if we are to develop therapies that artificially boost innate immunity to cure infections, without inducing damaging inflammation. Activation of innate immunity is critically dependent on several classes of receptor-proteins, which detect infections by selectively binding microbial compounds. Toll-like receptors (TLRs) are one of the most important classes of such proteins, activating a cascade of events that is an essential part of the early phases of innate immune response. Previous research has identified a set of genes, believed to be important regulators of TLR signalling, innate immunity and inflammation. As part of a large, multinational research program, Dr. Anastasiya Nyzhnyk is focusing on three of these genes: TNIP1, DUSP16 and TANK. Using mouse models and human cell lines, she is analyzing how the inactivation of these genes affects TLR signalling, and studying the resulting molecular, cellular, and physiological effects. Her work is expected to expand knowledge about early immune responses to infection, and may lead to a better understanding of the causes of inflammatory diseases and suggest new strategies for their therapy
Redefining community resilience: community perspectives on the intersection of gender, mental health and adaptive capacity in the context of the Mountain Pine Beetle disaster
Much of British Columbia’s forests have been infested with the mountain pine beetle (MPB), an epidemic that is predicted to result in the loss of more than 80 per cent of the province’s pine forests by 2013. The MPB is also expected to result in the widespread loss of jobs, shifts in traditional resource cultures of affected communities, and an increased risk of forest fires and other natural disasters (e.g. slides, flooding). Gender is recognized as one of the most critical determinants of disaster-related vulnerability. Women and children are disproportionately affected by disasters, reporting higher rates of stress-related health problems (e.g., post-traumatic stress, anxiety, depression), an increased risk of sexual and domestic violence, greater economic marginalization, and substantial increases in their work. They are also less likely to be involved in community-based planning and decision-making processes. Dr. Robin Cox is analyzing individual and collective stressors associated with MPB in four forestry-dependent communities: Barriere/Louis Creek, Clearwater, Quesnel and Wells. She is piloting a community-based research strategy intended to engage affected residents in each community in a series of workshops and focus group interviews. The focus of these events is to identify and elaborate community-based definitions and strategies of resilience that reflect the specific cultural, social, and political contexts of participants. The proposed study will contribute to the development of knowledge around community resilience that integrates a gender perspective, and will lead to the development of policies and procedures that are relevant and responsive to different communities affected by MPB.
Unleashing the research potential of a population-based data system: integrating community-centred, life-course, linked-data, and longitudinal approaches to monitoring child health and development
Early Child Development (ECD) – the development of physical, social-emotional, and language-cognitive capacities in the early years – is recognised as having life-long effects on health, well-being, behaviour, and skill acquisition. Population-based ECD research is essential for understanding the capacity of our future population. British Columbia is at the forefront of population-based research in ECD, thanks to a rich database created by the Human Early Learning Partnership (HELP) at the University of British Columbia. Here, health scientists can access population-based data on children’s health and development, and link these data to other administrative and research databases, such as Statistics Canada’s neighbourhood-level census file. Making use of these state-of-the-art data resources, Dr. Jennifer Lloyd is exploring the pathways of early developmental experiences to later educational outcomes, the relationship between children’s developmental trajectories and their neighbourhoods of residence, and the patterns in which children’s health and development present themselves as gradients when assessed against the socioeconomic characteristics of their residential neighbourhoods.. Lloyd’s research will explore inequalities in children’s developmental trajectories in an unprecedented fashion in British Columbia. In terms of policy and practice, her research stands to influence health delivery systems by providing evidence to guide public health and social policies and program development, and to assist in reducing gaps in existing patterns of children’s development and educational outcomes in British Columbia and beyond.
Novel characterization of a G-protein coupled receptor, Autocrine Motility Factor Receptor (AMFR): an endoplasmic reticulum-localized E3 ubiquitin ligase
The endoplasmic reticulum is a membrane network within cells involved in the synthesis, modification, and transport of cellular materials. Endoplasmic Reticulum Associated Protein Degradation (ERAD) is a cellular process that identifies unneeded or misfolded proteins of the endoplasmic reticulum and modifies the protein by attaching to it a ubiquitin protein. This ubiquitination process serves to mark the protein for destruction – a key process that helps prevent a range of diseases. Autocrine motility factor receptor (AMFR) is a transmembrane protein expressed on the cell surface and in a smooth subdomain of the endoplasmic reticulum (SER). AMFR has a critical function in the ubiquitination process, binding to the regulatory protein autocrine motility factor (AMF). Overexpression of AMF and AMFR occurs in a number of malignancies and participates in cancer cell migration during cancer progression and metastasis. It has been observed that AMF is secreted by tumour cells and acts as a protein messenger to other cells. However, its mechanisms remain unknown. Maria Abramow-Newerly is determining the signalling pathways used by AFMR following its binding to AMF, working to identify critical proteins and factors that may all tightly regulate AMFR expression and distribution within normal and cancer cell lines. In particular, she is focusing on characterizing AMFR as a G-protein coupled receptor, a family of proteins that serve as important drug targets for a number of diseases. Abramow-Newerly’s studies may contribute to the future design of drugs that specifically target components in the AMFR-signalling pathway to reduce cancer cell migration and metastasis
Formation, stabilization, and dynamic modulation of GABAergic inhibitory synapses in the central nervous system
In the central nervous system (CNS), the chemical synapse is the major site of communication between neurons (nerve cells). There are two main types of synapses in the CNS: excitatory glutamate synapses and inhibitory gamma-aminobutyric acid (GABA) synapses. Dysfunction of GABA synapses has been identified in disorders such as autism, schizophrenia, and depression. GABA synapses are also the main targets for drugs to treat epilepsy and anxiety. The protein neuroligin is a molecule that directs a neuron to form a synapse at the place where it comes in contact with another neuron. A specific type of neuroligin, Neuroligin-2, builds GABA synapses. However, little is known about why and how Neuroligin-2 is specific for building GABA synapses. Frederick Dobie was previously funded by MSFHR for his research in protein transport in neurons. He is now studying proteins involved in synaptogenesis (the process of building a synapse). To better understand how GABA synapses are formed, he is looking at regions of Neuroligin-2 that are important for this function. He is also studying how GABA synapses can change over time, responding to the specific needs of the neuron to fit into a fully-functioning brain. He is watching the growth and maturation of synapses over a period of several days, observing in real-time the strikingly dynamic appearance, disappearance, and movement of synapses. By understanding the biology underlying GABA synapses, Dobie hopes his work will ultimately lead to the advancement of therapies for a wide range of debilitating developmental, neurological, and psychiatric disorders.