The brain is made up of millions of neurons that transmit signals to one another across synapses. An imbalance in the number of excitatory (glutamatergic) and inhibitory (GABAergic) synapses in the brain is believed to underlie complex neurological disorders such as autism and schizophrenia. Kimberly Gerrow was previously funded by MSFHR to investigate the molecular stages of synapse development in the hippocampus. Now, she is working to bring further understanding to the basic principles that dictate the number and strength of excitatory and inhibitory synapses in the brain. Specifically, she is investigating the role of a pre-assembled postsynaptic complex of scaffold proteins, which she hypothesizes dictates the number and strength of contacts formed between young neurons during development. She hopes her work may lead to new potential targets for therapy.
Program: Trainee
Combatting antibiotic resistance in MRSA: the structural biology of beta-lactam resistance regulation by the protease domain of Staphylococcus aureus protein BlaR1
Antibiotic resistant infections are becoming more widespread, posing serious threats to human health. For example, Staphylococcus aureus bacteria are common on the skin of healthy people, but can cause serious infections if they penetrate the skin and enter the body. The antibiotic, methicillin, effectively treats most “staph” infections, but some bacteria have developed a resistance. As a result, MRSA (methicillin-resistant staphylococcus aureus) outbreaks can be life-threatening in hospital wards, especially for patients with compromised immune systems. Even more worrisome is that new strains of MRSA that can infect and harm otherwise healthy people – called ‘community MRSA’ – are on the rise across Canada. Michael Gretes is investigating how MRSA bacteria turn their resistance genes off and on using two proteins. The first protein keeps the resistance turned off. Another protein has a scissor-like part. With no antibiotics around, the scissors are closed. When penicillin or methicillin is administered to try to kill the bacteria, the scissors receive a signal to cut the first protein, turning the antibiotic resistant genes on. Michael is x-raying protein crystals to determine how the scissor functions. This information may lead to new drugs to keep the scissors locked, which could be combined with antibiotics for patients with antibiotic resistant infections.
Identification of regulatory mutations involved in cancer by gene expression analysis and bioinformatics approaches
Regulatory DNA sequences determine the leveI, location and timing of gene expression. These sequences are important in nearly all biological processes and many disease conditions. In some cases, the onset of cancer is related to changes in these sequences, such as when gene translocation results in the production of a protein that prevents normal cell death. Expanding on his previous MSFHR-funded work, Obi Griffith will make use of public gene expression data and novel computational approaches to identify genes believed to have undergone a change in regulation leading to cancer. Once these genes have been identified, further analysis will investigate the mechanism responsible for the change in regulatory control. Then, Obi will obtain specific tumour samples and validate the predicted changes in the laboratory. Obi hopes to increase understanding of how genes are controlled under normal conditions and how the loss of this control leads to cancer. Such identified genes could make suitable targets for therapeutic intervention as well as having prognostic and diagnostic value.
Protein isoforms generated by alternative splicing: prevalence and relevance to models of cancer progression
Continuing the study that he began in his MSFHR-funded Master’s work, Malachi Griffith is examining the changes in the forms of certain genes due to alternative splicing that may be important in the progression of cancer. Alternative splicing is a phenomenon in which one gene is assembled from its component pieces in many different ways, a process which produces immense diversity and enables genes to fulfill many functions. This diversity in gene structure may also account for the differences in the severity of cancers and response to treatment observed among individuals. Malachi is studying colon and prostate cancer cells – some that are responsive to treatment, and others that are resistant. By studying differences in the structure of expressed genes between these contrasting states, he hopes to gain insight into why treatment initially appears to work well in some patients, yet becomes less effective over time. Such knowledge may lead to improved or novel treatment strategies, resulting in better outcomes for cancer patients.
British Columbia Transient Ischemic Attack Project
A transient ischemic attack (TIA) occurs when there is a temporary disruption of blood supply to the brain. Damage from a TIA is temporary and reversible, but the experience is an important warning symptom for stroke, which is a major cause of death and long-term disability. Patients have a five to ten per cent risk of having a stroke within a week of a transient ischemic attack. Patients with TIA symptoms often go to the emergency department for evaluation, but there is no universally accepted strategy for managing TIA in B.C. Emergency Departments (EDs). A major challenge has been the lack of a system for determining which patients are at high risk for having a stroke and warrant urgent investigation and treatment. Dr. Devin Harris is evaluating the effectiveness of a clinical guideline for standardizing TIA care in EDs. This evidence-based guideline is being implemented as a pilot project in six B.C. emergency departments and will then be expanded to all 92 EDs in the province. Devin is examining physician adherence to the guideline and the impact on patient outcomes. This information will be used to develop a model for predicting which patients are at high risk of stroke after TIA, leading to better preventive and treatment options.
Preventing Vicarious Traumatization of Mental Health Therapists: Identifying Protective Practices
As part of their work, trauma therapists must listen to detailed descriptions by patients of horrific events such as abuse, violence and disasters. Over time, the psychiatrists, psychologists, social workers and psychiatric nurses who treat seriously traumatized individuals are themselves at risk for vicarious traumatization and burnout. Richard Harrison is studying the factors that contribute to the resilience and health of trauma therapists. He will identify the individual characteristics, as well as the organizational practices, that help professionals succeed in their work and remain healthy. He hopes his work will help lessen the “costs of caring” for this group of health professionals, and prevent the loss of therapists who quit the profession because of burnout and vicarious traumatization.
Decision Making Related to Cancer Risk-Reduction Among BRCA1/2 Carriers
Women who learn through genetic testing that they are at high risk for developing hereditary breast and ovarian cancer may choose to undertake several risk-reducing strategies, including surgery, chemoprevention, and increased screening. An emerging body of research is beginning to describe high-risk women’s experiences and satisfaction upon adopting these risk-reducing strategies; however, little is known about how women come to make these decisions. Because of the highly personal nature of this decision, most health care providers attempt to support decision-making about risk-reducing strategies, rather than recommend particular courses of action. In order to support women and to develop and evaluate appropriate interventions, it is essential to understand how women arrive at these decisions. Fuchsia Howard is identifying the personal, psychological and social contextual factors that influence women’s decision-making about breast and ovarian cancer risk-reducing strategies. This research will contribute to an understanding of the impact of genetic testing for hereditary breast and ovarian cancer risk on the psychological health and quality of life of women found to be at high-risk. This understanding will inform future development of appropriate interventions within programs offering genetic services.
Cytochrome p450 2C Inhibition in Peri-transplant Ischemic Injury and Transplant Vascular Disease
Transplant vascular disease (TVD), characterized by a thickening of the arteries (arteriosclerosis), is the primary cause of chronic heart transplant rejection. TVD can be detected in up to 75 per cent of transplant recipients within only one year of transplantation. One factor that causes TVD is oxidative stress which occurs during the process of transplantation when blood flow is stopped in the donor heart prior to transplantation (ischemia), and then re-established in the recipient (reperfusion). This stress not only damages the heart but also makes it more susceptible to attack by the recipient’s immune system leading to chronic rejection. Previous research has suggested that an enzyme (CYP2C) is involved in triggering oxidative stress and heart damage during reperfusion. Arwen Hunter is investigating the process and mechanisms by which CYP2C causes cardiovascular damage. She will also investigate whether inhibition of CYP2C can suppress the amount of damage that occurs during transplantation and whether suppression of this damage can reduce chronic rejection later on. Results from these studies may lead to novel therapeutic strategies to alleviate chronic heart transplant rejection.
Socio-ecological analysis of HIV/AIDS treatment-related behaviours and health outcomes in an era of HAART: Considering individuals in the context of their communities
“Highly active antiretroviral therapy” (HAART) has led to dramatic improvements in quality of life and survival for people infected with HIV/AIDS. But these positive outcomes are not evenly distributed among HIV-infected individuals. Despite access to free medications in Canada’s publicly funded health care system, vulnerable groups such as HIV-positive women, injection drug users and socio-economically disadvantaged people have not experienced the health improvements others have. Research to date has focused largely on individual risk factors. Angela Kaida is examining how individual and community factors, such as neighbourhood income levels and the availability of HIV/AIDS services, affects the quality of treatment and health outcomes of people infected with HIV. Angela is assessing the role these factors play in delaying entry into treatment, non-adherence to treatment, and the advance of HIV/AIDS disease and death. In earlier research, Angela studied the impact of HIV/AIDS on agricultural production, food security and rural livelihoods in Malawi, and on male involvement in family planning in Uganda. The findings from her current study have the potential for application in the design of community programs and policies to improve equal access to HAART in Canada, and may be applied in global settings with high HIV prevalence.
Melanoma gene therapy by conditional replicative adenovirus targeting PUMA and p-Akt
Melanoma is a deadly form of skin cancer arising from the abnormal growth of pigment-producing cells in the skin. Melanoma is an aggressive tumour that spreads quickly to other parts of the body and is very difficult to treat because it does not respond to radiation or chemotherapy. In recent years, researchers have turned to gene therapy as a new approach to fight cancer. This approach is based on the idea that cancer is caused by defective genes. The goal is to eliminate the cancer by inserting therapeutic genes into cancer cells using a vector (a vehicle for delivering genetic material to a cell). Within melanoma cells, the expression (activation) of the cell death gene PUMA is often reduced and expression of the cell growth and survival gene Akt3 is often inappropriately increased. Using viral vectors known as CRAds, Alison Karst is focusing on reversing this pattern of gene expression in order to induce melanoma cell death. CRAD-based gene therapy holds promise for eliminating cancer cells and more effectively treating melanoma.