All successful viruses have evolved strategies to infect host cells and disrupt normal cell functions. However, the host can counteract these strategies by using its natural antiviral responses to detect and defend against viruses. Revealing the molecular mechanisms between the battle of the virus and host is vital in the fight against many of todayâs viruses. Some viruses use an internal ribosome entry site (IRES) to infect cells. Molecular machines in cells called ribosomes translate genes into proteins, but viruses with an IRES can hijack the ribosome to replicate their viral proteins instead. IRESs are found in a number of human viruses, including polio, hepatitis C, herpes and HIV, but there is limited understanding of how these mechanisms work. Understanding the ways in which a virus hijacks the ribosome function is the focus of Dr. Eric Janâs laboratory. He uses a unique IRES found in an insect virus called the cricket paralysis virus (CrPV). Janâs previous work was critical in delineating important CrPV IRES functions. Building on this work, he plans to map the specific IRES elements that interact with the ribosome. He will also determine how CrPV disrupts cellular function that leads to IRES activity in Drosophila (fruit fly) cells, and elucidate the host antiviral response in these cells. The study of Drosophila antiviral responses will contribute to knowledge about fundamental virus-host interactions in humans. The research could lead to new drug targets for inhibiting viral IRESs and therapies that can augment antiviral responses. An exciting future goal will be to exploit viral IRESs to prompt the destruction of virus-infected cells â taking advantage of a viral mechanism against itself.
Research Location: University of British Columbia - Point Grey
Presynaptic voltage-gated calcium channels: binding and regulation by SNARE proteins
Electrical signals are the fastest signals in our bodies. These signals are mediated by ion channels, specialized proteins that allow particular charged ions to pass through cell membranes. One class of ion channels, known as voltage-gated calcium channels, is of particular importance. They allow calcium ions to pass through the cell membrane when an appropriate electrical signal is present. In doing so, these channels play crucial roles in regulating heartbeats, in muscle contraction and in the release of hormones and neurotransmitters. The role of calcium channels in human health is significant. Mutations in the channels cause severe genetic diseases, and many drugs that are currently used to treat cardiovascular diseases, epilepsy and chronic pain target calcium channels to limit their dysfunction. Efforts to develop new drugs are hampered by the limits of what is known about the channels, particularly about their atomic structure. Dr. Filip Van Petegram is working to shed new light on the intricate workings of calcium channels that are expressed in the heart, in the brain, and in skeletal muscle. Van Petegram uses cutting edge technologies to gain a precise understanding of calcium channels. X-ray crystallography determines a proteinâs atomic structure, producing high resolution structural images that serve as excellent templates for the design of new drugs, and provide valuable information about how the channels work. Electrophysiology measures the tiny electric currents that are generated when calcium ions pass through the channels. This work will contribute to novel treatment strategies for targeting calcium channels.
Individual differences in stress coping and predisposition to disease.
Glucocorticoids are hormones that the body releases into the bloodstream in response to stress, protecting our bodies in the short term against the damaging effects of stress. Chronic oversecretion of these stress hormones can lead to various mental health disorders such as anxiety and depression. Humans show extreme differences in how they adapt or succumb to the pathological effects of stress. Sex steroids play a critical role in individual and gender-based differences in stress-induced pathology, but the basis for this in the central nervous system is not understood. Independent studies in rodents and humans show that testosterone can regulate the magnitude of the glucocorticoid and behavioural responses to stress. With this data, Dr. Victor Viau is working to determine how testosterone operates on stress-related pathways in the brain, from a physiological and chemical perspective. He is investigating how early-life exposure to testosterone determines the brain’s response to stress during adulthood, and providing insights about the underlying factors that allow the individual to manage stress in different ways. Viauâs research program is unique as it aims to determine how, where, and when stress and testosterone interact in the nervous system and at the hormonal and behavioural levels. The research will ultimately provide a fundamental framework for understanding why some individuals succumb to the psychopathological effects of stress and others persevere in the face of it.
Understanding how cationic antimicrobial peptides and lipopeptides function in order to design better antibiotics
With the ever-increasing prevalence of antibiotic resistance, it has become critical for scientists to develop alternatives to antibacterial agents and offer long term sustainable health care solutions. Bacterial resistance to common antibiotics has a dramatic impact on hospital and community health care, affecting entire hospital wards and communities. This creates significant â and largely avoidable â pressure on current health care budgets. Two types of microbe-fighting peptides are generating much interest as potential alternatives to current antibiotics: cationic antimicrobial peptides (CAPs) and anionic lipopeptides (ALs). Both types of peptides are commonly found in nature and have remained effective, displaying little to no antibiotic resistance effects. Both are believed to act by targeting and perturbing the bacterial membrane, which eventually leads to cell death â a process that is strikingly different from current antibiotics. Dr. Suzana Straus aims to find novel alternatives to current antibiotics by investigating how promising candidates from the CAP and AL peptide families function and by designing more potent versions derived from these candidates. Her work is focused on three peptides: two CAPs from amphibians and one AL called daptomycin, which is known to be effective against particular complicated skin infections. Straus is researching the structural and functional properties of these membrane-associated peptides and proteins, which is crucial in the design and development of new and effective medicines. Ultimately, her work will provide insight into which factors should be considered in the design and development of a new generation of antibiotics.
Studies of KshAB, a cholesterol-degrading oxygenase from Mycobacterium tuberculosis
Tuberculosis kills more than two million people worldwide every year. More than one-third of the worldâs population is currently infected with Mycobacterium tuberculosis (Mtb), the bacterium that causes tuberculosis. Because of its synergy with HIV infection, TB is the leading cause of death in HIV-infected individuals. Contributing to this global health crisis is the emergence of multi-drug resistant strains (MDR-TB), including extensive drug resistant strains (XDR-TB). The drug course to clear MDR-TB lasts up to two years, and XDR-TB is virtually untreatable with current therapies. These factors, combined with the high toxicities of current drugs, underline the urgent need for novel therapeutics to combat this disease. One of the major contributing factors to the prevalence and persistence of the disease is the bacterium’s ability to survive within the human macrophage, a type of scavenger cell that normally combats disease-causing bacteria. The mechanisms by which Mtb survives inside the macrophage in the immune system are largely unknown. However, a set of genes that encode (produce) a series of cholesterol-degrading enzymes in Mtb has recently been discovered as essential to the bacteriumâs survival. Compounds that inhibit Mtbâs cholesterol-degrading enzymes might be useful starting points for the design of novel therapeutics. Jenna Capyk is focusing on one of these cholesterol-degrading enzymes, known as KshA. She is studying how this enzyme works and how it is inhibited by small molecules. Her work also involves determining KshAâs three-dimensional structure and synthesizing potential inhibitors for the enzyme. By investigating the mechanisms of this promising new enzyme target in tuberculosis, Capykâs studies may help lay the foundation for the development of new classes of therapeutics to treat this deadly disease.
Protective factors associated with preventing injection drug use initiation among at-risk youth in Vancouver, British Columbia
Street youth â 15- to 24-year-olds without a permanent residence â 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 Chambersâ 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. Chambersâ 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.
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 womenâs 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.
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 bodyâs 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
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) â the development of physical, social-emotional, and language-cognitive capacities in the early years â 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 Canadaâs 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 childrenâs developmental trajectories and their neighbourhoods of residence, and the patterns in which childrenâs health and development present themselves as gradients when assessed against the socioeconomic characteristics of their residential neighbourhoods.. Lloydâs 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 â 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-Newerlyâs 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