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.
The number of Canadians older than 65 is steadily increasing, a trend that will continue over the next few decades. The prevalence of age-related disorders such as dementia is also increasing, along with the related need for personal care and treatment. Cognitive impairment adversely affects quality of life in late adulthood, limiting independence and survival. To examine these important health issues, Dr. Stuart MacDonald is studying factors related to age-related declines in cognitive performance. Part of his research employs existing data from a Swedish study (the Kungsholmen Project; http://www.kungsholmenproject.se/) to examine patterns and identify early predictors of cognitive decline. As the average age of the Swedish population far exceeds that of Canada, research on the Kungsholmen data may provide important insights that can help inform Canadian healthcare policy and prevention strategies.
Dr. MacDonald is also researching how performance for select measures of memory and intelligence is influenced by cognitive training across a period of weeks, as well as regular aerobic exercise (walking three times per week for 30 minutes) over a period of months. Dr. MacDonald's goal is to clearly demarcate the stages and transitions of cognitive decline from mild age-related impairment to more severe dementia deficits. This will help identify early warning signs of cognitive impairment from a broad range of predictors. The findings could lead to more effective prevention based on knowledge of these risk factors, including campaigns to promote health-smart behavior.
The nature of the relationship between a healthcare provider and an individual receiving care has an impact on the success of psychotherapy and drug therapy. A strong professional working relationship can not only enhance the effect of psychological and psychiatric interventions, but can be therapeutic in and of itself. This has even been found in the treatment of very serious psychiatric conditions such as bipolar disorder and schizophrenia. Researchers have estimated that as least 30% of the effectiveness of psychotherapy and drug therapy can be accounted for by the quality of the professional relationship between an individual and his/her mental healthcare provider. There is a lack of understanding about the factors that are most important for developing a solid working relationship from the perspective of the individuals receiving the mental health services. Expanding upon research he conducted as a MSFHR trainee, Dr. Robinder (Rob) Paul Bedi is exploring this area. He is interviewing individuals currently receiving mental health services and analyzing the variables that they identify. The result: identifying the most common factors found to be essential in the development of positive therapeutic relationships. Bedi’s research aims to help mental healthcare providers develop strong working relationships with the individuals they treat, resulting in improved overall effectiveness of the mental health services that individuals receive.
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 “mark” 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.
Peer victimization — the experience of being a target of a peer’s hurtful teasing and aggressive behaviour — has major implications for adolescents’ mental health. It’s estimated that 15 to 27 per cent of adolescents are victimized by their peers and approximately 10 per cent of students face severe or chronic victimization by peers. Chronic and frequent victimization experiences can lead to increased levels of depression and anxiety among victimized adolescents and put them at risk for becoming more aggressive over time. Breaking the cycle of peer victimization is a priority; however less is known about the protective factors that will reduce levels of harmful outcomes associated with peer victimization. Rachel Yeung is investigating the associations between peer victimization and emotional and behavioural problems among adolescents across a four-year period. She is examining whether emotional support from parents, peers and teachers can moderate and protect against these harmful outcomes. Yeung will use data taken from a longitudinal Healthy Youth Survey, which followed 664 adolescents in an urban community via individual interviews. Yeung’s findings can support the importance of building existing support systems and fostering new relationships with parents, peers and teachers to prevent long term and negative mental health problems associated with peer victimization. This will also provide a basis for the development of effective prevention programs that aim to break the cycle of peer victimization and its harmful outcomes among older adolescents.
Rett syndrome is a severe neurodevelopmental disease that affects approximately one in 10,000 girls. Progressive symptoms begin at a very young age and worsen through childhood. These include loss of speech, purposeful hand use, ability to walk, and the development of seizures. In 85 per cent of cases, the cause of Rett syndrome has been traced to mutations of a protein known as MeCP2. Dr. Toyotaka Ishibashi is studying the relationship at the cell level among the MeCP2 protein, DNA and chromatin (a complex of DNA and protein that regulates the binding of the MeCP2 protein to DNA). Despite some research carried out in recent years, details of the interaction of MeCP2 with chromatin remain largely unknown. Toyotaka is investigating how MeCP2 works in normal cells, which is critical for later study of how gene mutations interfere with the normal function of the protein to cause the symptoms of Rett syndrome. Ultimately, Toyotaka hopes to clarify the role of the MeCP2’s nucleosome — the most elementary structure involved in regulating the protein’s activity — to provide potential cellular targets for drug targeting and new prospects for the development of clinical therapies.
Pneumonia is an acute respiratory disease, the major cause of which is the bacterium Streptococcus pneumoniae. This bacterium is the leading cause of death from infectious disease in North America and a leading cause of death worldwide, particularly in children and the elderly. This bacterium can also cause meningitis, septicemia, and otitis media (middle ear infection). Reports indicate that 40 per cent of pneumonia cases caused by S. pneumoniae are resistant to penicillin and new multidrug resistant strains are beginning to emerge. To reduce increasing rates of antibiotic resistance and augment judicious use of the pneumococcal vaccine, alternative methods for treating S. pneumoniae infections must be found. Several proteins have been found in S. pneumoniae that are believed to contribute to its virulence. It is suspected some of these proteins destroy sugars such as glycogen in specific lung cells that normally serve to protect the lungs against infection. These damaging proteins are potential targets for preventing or slowing the infection. Dr. Alisdair Boraston will focus on two aspects of these S. pneumoniae proteins: if and how these proteins are destroying sugars and how to inhibit this activity. Biochemical studies will provide understanding about how these enzymes degrade sugars and whether any inhibitor molecules can interfere with this. Structural studies using X-ray crystallography will show structural features of the proteins that contribute to their activity and aid in the design of new inhibitors. Taken together, this information will lead to new approaches and agents to target pneumonia caused by S. pneumoniae.
Toxoplasmosis is a serious human pathogen carried by about one-third of the population. People develop toxoplasmosis either after ingesting undercooked meat that contains T. gondii cysts, or by coming into contact with cat feces from an infected animal. Once infected, healthy adults initially show a range of temporary flu-like symptoms; however, while these symptoms pass, the parasite Toxoplasma gondii remains in the body for life, with limited drug treatment available. Infection during pregnancy can cause miscarriage, neonatal death and a variety of fetal abnormalities, including developmental delays. It is also harmful to those whose immune systems are compromised, such as those with HIV/AIDS, cancer or who have had an organ transplant. Very little is known about how T. gondii causes disease. Dr. Martin Boulanger is studying the structure of host-pathogen interactions to determine the activities that allow T. gondii to attach to and invade human cells. With this information, treatments can be developed to prevent or manage Toxoplasmosis. This work will also apply to better understanding of other parasite-caused disease such as malaria and cryptosporidiosis.
Ductal carcinoma in situ (DCIS) is a precursor to invasive breast cancer, and the protein psoriasin is one of the most highly expressed genes in DCIS. Psoriasin is present at abnormally high levels in many pre-invasive breast cancer cells and in a smaller subgroup of invasive breast cancer cells. Recent research has shown that the interaction of psoriasin with the signaling protein Jab1 may be a keystone of the signal network of the breast cancer cell, and that psoriasin binding can cause Jab1 to stimulate the development of invasive and metastatic breast cancer cells. Inhibiting protein-protein interactions is an exciting new approach in the search for targeted cancer therapeutics, and the psoriasin-Jab1 interaction is a promising new target for the treatment of breast cancer. Dr. Fraser Hof’s work deals with fundamental questions about the interactions of proteins and small molecules and with the applied design of small molecule therapeutics. His proposal is to design and develop novel drug molecules to block this psoriasin-Jab1 interaction, first to validate the target and then to guide subsequent drug development. A drug that inhibits this interaction may offer a novel therapy to directly target pre-invasive breast cancer and prevent the development of invasive breast cancer. This therapy may also hold promise as a new approach to target the small subgroup of invasive breast cancers where psoriasin is also present, as this subgroup is typically not eligible for current targeted therapies such as tamoxifen and herceptin.
Attention-deficit/hyperactivity disorder (ADHD) is the most frequently encountered childhood onset disorder in primary care settings. ADHD is characterized by certain behaviours, most commonly: inattention, hyperactivity, and impulsiveness. Although preliminary research indicates that the biological roots of ADHD may involve certain areas of the brain, the link between the cognitive and behavioral manifestations of ADHD and its neural basis is poorly understood. Research shows that the midbrain’s dopamine system — a neural system associated with reward learning and reward-related behavior (reinforcement learning) — is abnormal in children with ADHD. To date, however, there has been little research regarding exactly how the disturbance of the dopamine system leads to this impaired reinforcement learning. Dr. Clay Holroyd is interested in the neurobiological mechanisms that underlie cognitive control — how people regulate their attention, thoughts, and actions in accord with high-level goals and intentions. Specifically, he is focusing on how people detect and correct their errors and, and how they learn from the consequences of their actions. Currently, ADHD research is an important component of his ongoing research program. Dr. Holroyd is investigating impaired cognitive control, error processing, and reinforcement learning in children with ADHD. Using behavioural experiments and computational modeling, he is researching whether the cognitive and behavioral impairments associated with ADHD are the result of the transmission of abnormal reinforcement learning (RL) signals from the midbrain dopamine (DA) system to the frontal areas of the brain involved in cognitive control. Developing a greater understanding of the link between the neural impairment in ADHD and learning and behavior is an important step towards creating a common and accepted model of ADHD; one that spans multiple levels of analysis, including biology, behavior and cognition. This research will provide a greater understanding of the neurobiological mechanisms that underlie cognitive and could lead to the development of new therapeutic treatments for children with ADHD.
