Viruses are responsible for many of the world's most serious diseases. In Canada, viral infections remain the single most common reason that people seek medical attention. In order to spread infection, many viruses replicate themselves in the nucleus of their host cells. To accomplish this, they must transport their genome into the nucleus – a process known as nuclear trafficking. Today, many aspects of this viral replication and initial entry into cells are well understood at the molecular level. However, very little is known about how viruses deliver their genetic material into the nucleus. Interrupting the trip into the nucleus could prevent the virus from spreading. A detailed description of this process is an important step to developing anti-viral therapy.
Dr. Nelly Panté studies the mechanism by which viruses deliver their genomes into the nucleus of their host cells. In particular, she is focusing on two common and important viruses: Influenza A and Hepatitis B virus. To investigate the trafficking of these viruses, Panté uses a combination of structural, functional, biochemical, and genetic approaches. As well, she uses high-resolution electron microscopy to track the virus’ movement and entry into host cell nuclei. This work is critical for complete understanding of viral infections – not only for targeting viral illnesses, but also for their potential application in gene-delivery technology, such as in anti-cancer gene therapy.
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 today’s 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 Jan’s laboratory. He uses a unique IRES found in an insect virus called the cricket paralysis virus (CrPV). Jan’s 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 – taking advantage of a viral mechanism against itself.
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 protein’s 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.
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. Viau’s 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.
The prevalence of obesity is increasing dramatically, and is occuring at an increasing rate among children. Obesity is a major risk factor for numerous diseases including diabetes, heart disease, high blood pressure, stroke, arthritis, and some forms of cancer. Inherited factors strongly affect an individual’s risk for becoming obese, especially in an environment with little exercise and diets high in fat and sugar. However, many of these genetic factors are not yet known.
Dr. Susanne Clee’s research seeks to identify one of these genetic factors. She is conducting genetic studies on mouse strains that differ in their risk of developing obesity when fed a high fat diet. Clee will progressively zero in on new candidate genes by comparing the suspected region’s DNA sequence between obese and non-obese mice, and identifying specific changes in genes that could lead to the development of obesity. At the same time, Clee will use these mouse strains to study the biology of how obesity develops. By comparing mice that become obese when fed a high fat diet compared to mice that resist obesity, she will be able to describe how the body's processes are altered as individuals become obese.
By identifying new genetic factors that cause mouse strains to become more obese, Clee hopes to gain a more specific understanding of how obesity develops. This knowledge will lead to new ways to treat or prevent this disease and to identify those individuals more at-risk of developing obesity.
Electrical disturbances in the heart are a serious health threat for many people. For example, cardiac atrial arrhythmias (a type of irregular heart beat) affect 4% of people aged 60 and older, and have an associated fivefold increase in stroke. As our population ages, this incidence is expected to increase up to 2.5 times over the next half century. Cardiac membrane proteins called ion channels control the flow of sodium and potassium in and out of heart cells, regulating both the cardiac electrical impulses and the contractions associated with the heart beating. Dr. Christopher Ahern is interested in drugs that interact with the sodium ion channel to correct atrial arrhythmias. Although these drugs are widely prescribed, scientists still don’t fully understand exactly how they work. More critical is that these drugs can become lethally toxic in cases where the arrhythmia co-exists with other common heart problems, such as an enlarged heart. This dangerous shortcoming seriously limits their use for many people who could otherwise benefit from their therapeutic effects. There is a need for better anti-arrhythmic therapies – ideally, designer drugs for atrial arrythmias that exploit the positive attributes of current therapies while minimizing their negative side-effects. Dr. Ahern is using new chemical methods that are providing much more detailed information about how these drugs bind to and interact with the sodium channel. Using these new methods in combination with computational approaches that bypass previous limitations with the research, his team will take a fresh look at drug binding and ion channel function with the goal of designing safer anti-arrhythmic drugs
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 – and largely avoidable – 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 – 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.
Syphilis, caused by the bacterium Treponema pallidum, is a chronic bacterial infection with a global distribution. Although this sexually transmitted disease is 100 per cent curable with penicillin, syphilis remains a health threat, with an annual incidence rate of 12 million active infections. In BC, new cases are being reported at almost double the national rate. Unchecked, the infection can damage every tissue and organ in the body, including the brain. Equally troubling, syphilis infection drastically increases vulnerability to HIV infection. Treponema pallidum is a highly invasive pathogen; following attachment to host cells, the organism invades the tissue barrier and enters the circulatory system, resulting in widespread bacterial dissemination. Little is currently known about the mechanisms this bacterium uses to initiate and establish infection.
Dr. Caroline Cameron has the only laboratory in Canada conducting basic research on this bacterium. She is using cutting-edge proteomic technologies to study two molecules that enable the bacterium to attach itself to host cells lining the bloodstream – a critical step in the development of infection. By understanding these mechanisms, Cameron hopes to identify potential ways that scientists could interfere with adhesion and disrupt the infection process. Ultimately, her work could lead to development of a vaccine to prevent syphilis.
A recent report from the World Health Organization revealed that about 1.5 million people died from TB in 2006. In addition, another 200,000 people with HIV died from HIV-associated TB. Current strategies aim to reduce the annual death toll from TB to less than 1 million worldwide by 2015, as set out in the United Nations Millennium Development Goals. Infection by the Mycobacterium tuberculosis microorganism causes TB. The current global strategy for TB control is based on reducing the spread of infection through massive vaccination campaigns with the BCG (bacille Calmette-Guérin) vaccine, and treatment of individuals with active disease using multi-drug combinations. However, there are challenges to this approach, including inefficiency of the BCG vaccine, the emergence of drug resistant strains of Mycobacterium tuberculosis (Mtb) and the difficulty in delivering a treatment that requires multiple drugs over periods of six months or more.
Until recently, little was known about how Mtb alters the host immune system to cause infection. Through Dr. Zakaria Hmama’s work as an MSFHR Scholar over the past six years, important new knowledge has been developed regarding the sub-cellular and molecular mechanisms of host/pathogen interactions. His research over the next five years will focus on gene manipulation technologies to upgrade the current BCG vaccine with recent immunological concepts to maximize its protective properties. Hmama is also investigating an important virulence factor identified by his lab as a potential drug target for TB treatment.
Tuberculosis kills more than two million people worldwide every year. More than one-third of the world’s 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 bacterium’s survival. Compounds that inhibit Mtb’s 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 KshA’s three-dimensional structure and synthesizing potential inhibitors for the enzyme. By investigating the mechanisms of this promising new enzyme target in tuberculosis, Capyk’s studies may help lay the foundation for the development of new classes of therapeutics to treat this deadly disease.
