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.
Year: 2008
Total Synthesis and Structure-Activity Studies of a New Anti-Cancer Drug Based on the Natural Product, Imbricatine
With an estimated 159,900 new cancer cases and 72,200 deaths from cancer predicted to occur this year alone in Canada, the need for new cancer therapies with unique mechanisms of action is urgent. Researchers are finding a promising resource among the oceanâs estimated one to two million structurally diverse microbial species. Compounds derived from marine organisms offer great potential in the fight against cancer; in the past decade, more than 30 natural products from the ocean have entered preclinical and clinical trials as potential treatments for cancer. However, it is often not ecologically or economically feasible to extract the active ingredient by harvesting natural sources in the ocean. Synthetic organic chemistry â where molecules are engineered in the laboratory â serves as an alternative source of these compounds. Inhee Cho is focusing on the synthesis of imbricatine, a chemical originally isolated from the Pacific sea star that shows significant anti-tumour properties. The structural core of imbricatine includes tetrahydroisoquinoline, a molecular structure that is also found in many biologically active agents, including anti-tumour antibiotics and drugs that treat diseases such as asthma, Parkinson’s and other nervous system diseases. Cho is developing an efficient way to synthesize tetrahydroisoquinoine, allowing rapid access to this important class of natural products in order to obtain enough material for biological testing and chemotherapy. Choâs work may facilitate the discovery of new lead compounds with useful pharmacological properties, potentially leading to new therapies for treating cancer
Regulation of the Jun Transcription Factors in B Lymphocytes by the NEDD4 Family E3 Ubiquitin Ligase, Itch
Ubiquitin is a small protein found in all cells containing a nucleus. A key function for this protein is ubiquitylation, the process by which ubiquitin attaches to target proteins to âmarkâ them for degradation (breaking down) and removal from the cell. Ubiquitylation is an important process for maintaining proper levels of cellular proteins and removing mis-folded proteins to ensure proper cellular function and to prevent disease. E3 Ub ligases are important regulators of the ubiquitylation process because they select the specific proteins (substrates) that are to be degraded. Itch is an E3 Ub ligase that is important in the immune system, as mice deficient in Itch (Itchy mice) develop a fatal autoimmune-like disease. The Jun transcription factors, c-Jun and JunB, are found to be deregulated in the T cells of these mice, and this is believed to contribute to the disease. These proteins are also important for the proper function of B cells and their deregulation has been implicated in some B cell cancers, such as Hodgkin lymphoma. Joel Pearson is determining whether Itch also regulates the Jun proteins in B cells, and how this may contribute to the autoimmune-like disease of Itchy mice. He is also investigating whether Itch regulates the Jun proteins in B and T cell lymphomas where these proteins are expressed at unusually high levels. His hypothesis is that Itch is an important regulator of the Jun proteins in B cells. Furthermore, he believes that Itch is also an important regulator of the Jun proteins in B and T cell lymphomas where these proteins are over-expressed. Understanding how the Jun proteins are regulated in these cells is important for understanding how the autoimmune-like disease of Itch-deficient mice may arise. Deregulation of the Jun proteins also contributes to the pathogenesis of some types of B and T cell lymphomas. Because of this, understanding how they are regulated is important for understanding how these cancers arise and persist. It could also lead to the development of novel ways to treat these cancers.
Trajectories towards self-harm, suicide, and other maladaptive coping behaviours
Borderline personality disorder is a serious mental health problem characterized by heightened emotional vulnerability and difficulty modulating emotional responses. Individuals with BPD have high rates of health risk behaviours, such as suicide attempts (75 per cent), self-harm (69-80 per cent), and substance abuse (60 per cent). Despite frequent intense emotional reactions to stressful events, people with BPD lack the skills to reduce their distress through adaptive coping methods. In an effort to reduce these unpleasant emotions and feel better, persons with BPD features often resort to maladaptive coping strategies that are quick and easy to execute (e.g., self-harm, substance abuse) but have negative long-term consequences. However, not everyone with BPD engages in these risky behaviours in response to every stressor, and the specific triggers for these behaviours are largely unknown. Certain types of emotional states (e.g., shame) and life stressors (e.g., being rejected) may be particularly linked with self-destructive coping behaviours. Kristy Walters is examining the specific negative emotions or particular stressful triggers that may be strongly associated with maladaptive behaviours such as self-harm, substance abuse, or suicide. This research will also examine whether or not these relationships among emotions, stressors, and maladaptive behaviours is unique among individuals with borderline personality disorder (BPD). A better understanding of which specific emotions constitute cause for concern, or which types of negative events are more likely to result in self-destructive behaviour, will considerably improve clinicians’ ability to evaluate their client’s level of risk and better identify those clients who are in urgent need of life-saving interventions.
Assessing the impacts of social, sexual and drug-use networks on HIV-positive Aboriginals receiving highly active anti-retroviral therapy (HAART) in British Columbia
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.
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.
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. Werbâs 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 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.
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. Lynnâs work integrates gene expression data with information about how genes and proteins are interconnected in our cells in signalling networks or pathways â 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. Lynnâs 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 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