Cystic fibrosis (CF) is a severe genetic disorder caused by one gene: the cystic fibrosis transmembrane regulator gene (CFTR). Inheriting the gene from both parents leads to CF. People with CF experience chronic respiratory infections that cause lung damage and ultimately lead to lung failure and death. Lung damage in CF is not fully understood and cannot be completely explained by the CFTR gene defect. There are considerable differences in the severity and progression of lung disease, for example, among patients with the same mutation in the CF gene. Some may require lung transplantation by their teenage years, while others may not experience severe lung disease until adulthood. Daisy Frangolias is looking specifically at two types of genes: ones that are involved in fighting lung infections, and those that are involved in initiating and controlling the inflammatory response to the bacteria that cause lung infections. Her findings will increase the understanding of the relationship between the CF gene disorder and other genes in defining the long-term progression of CF, and may provide therapeutic targets for reducing lung damage.
Research Pillar: Biomedical
Identification of novel apoptosis-related genes and pathways in cancers using bioinformatics approaches
Programmed cell death occurs when cells respond to internal or external signals by initiating a process that results in their own death. While this process is necessary for the normal development of organisms, errors in the process can cause diseases such as cancer or neurodegenerative illnesses. Erin Pleasance is working to identify new genes that are expressed (activated) in programmed cell death and determine their role in diseases such as cancer. Using specialized equipment at the BC Cancer Agency’s Genome Sciences Centre, she is studying the fruit fly to find genes whose role in cell death has not yet been defined. The fruit fly is a useful model because the proteins and mechanisms involved in its cell death correspond to those in mammals and can be used to help identify cancer-causing genes in humans. Learning how to inhibit genes that prevent cell death may lead to the development of new anti-cancer drugs that stop cell growth.
Novel enzyme inhibitors for the prevention of metastatic Cancer
Carbohydrate molecules exist on the surface of all cells in the body, and control the movement of various compounds-viruses, bacteria, hormones, toxins and drugs-in and out of cells. Metastasis-the spread of malignant cancer cells-is linked to changes in the carbohydrate molecules on the surface of cancer cells. A particular enzyme helps produce mutations in these carbohydrate molecules. In earlier research, Nag Kumar showed that some compounds from a plant (used to treat type-2 diabetes in the Ayurvedic medicine system) inhibit this enzyme. Now he is using this lead compound to develop potent inhibitors of this enzyme. His goal is to interfere with the synthesis of the large carbohydrate molecules on the cell surface, and use the new enzyme inhibitors to develop anti-cancer drugs that can prevent cancer.
Role of PI3-kinase family in phagocytosis and phagosome maturation
Successful host defense against microorganisms relies heavily upon a population of immune cells called macrophages. These cells are capable of ingesting and destroying pathogens such as bacteria and yeasts. Jimmy Lee’s research will investigate the cellular mechanisms involved when macrophages ingest and destroy pathogens. Specifically, he is studying a protein family called PI(3)K, which is responsible for activating many cellular activities and is believed to enable macrophages to ingest microorganisms. He aims to identify the specific PI(3)K protein involved in this process. This research will increase the understanding of how the body responds to infection and may lead to the design of specific therapeutic approaches to fight infections.
AMPR receptor trafficking and membrane surface expression in models of cerebral ischemia (stroke)
A common consequence of stroke or heart attack is brain cell death. Studies indicate that an increase in AMPA, a type of neurotransmitter receptor on the surface of brain cells, may be one of the critical causes leading to brain cell death during a stroke. Yitao Liu is investigating the mechanisms that lead to an increase of AMPA receptors on the surface of brain cells. He hopes his work contributes to a better understanding of how brain cells die following a stroke and suggest ways to limit the activity of AMPA receptors and decrease brain cell death.
Peptide epitopes for the HIV-1 neutralizing antibodies 2F5 and 2G12 as anti HIV-1 vaccine candidates
Infection with the Human Immunodeficiency Virus type 1 (HIV-1) triggers a strong immune response in the body, which produces antibodies when it encounters the virus. However, the majority of antibodies naturally produced by the immune system are non-neutralizing, meaning they are unable to provide protection from the virus, or to prevent the eventual onset of AIDS. Alfredo Menendez is contributing to the search for an effective vaccine that would increase the body’s production of neutralizing antibodies. He has isolated unique peptides whose molecular structures closely mimic specific neutralizing sites on the surface of the virus. Alfredo is fine tuning these mimics to develop immunogens (substances that prompt a response from the immune system). He is investigating whether use of the peptides in a vaccine prompts a focused, strong and protective immune reaction that boosts the production of HIV-neutralizing antibodies.
Delivery of enteropathogenic Escherichia coli's receptor for intimate adherence into host epithelial cells
The bacteria Enteropathogenic E. coli (EPEC) is a major cause of infantile diarrhea, killing an estimated 100,000 children every year. (The bacteria is also closely related to enterohemorrhagic E. coli 0157:H7, which causes hamburger disease.) Most bacteria attach to existing proteins on host cells to cause disease. EPEC inserts its own protein into host cells and then attaches itself to the protein. Annick Gauthier is studying a specialized transport system—called a type III secretion system—that is believed to deliver this necessary protein from the EPEC bacteria into host cells. Her goal is to understand this fundamental mechanism, which is found only in disease-causing bacteria. Learning how this system works could provide targets for both vaccine and antibiotic development that would harm only the disease causing E. coli, and not the healthy bacteria that normally reside in the intestine.
The functional role of T-type calcium channels in cellular transformation and toxicity
Proteins called calcium channels regulate how calcium gets into nerve cells. In nerve cells, calcium channels control a variety of normal physiological responses including muscle and heart contraction, hormone secretion and the way neurons transmit, receive and store information in the central nervous system. When too much calcium enters these cells through calcium channels, a number of disorders can result, including congenital migraine, angina, epilepsy, hypertension and stroke. Michael Hildebrand is studying calcium channels called T-type channels, responsible for neuron firing, the nervous impulses that occur throughout the nervous system. Michael is investigating the structure and function of these channels to determine how they activate or inhibit calcium. He is also investigating drugs that can block specific channels to develop new treatments for epilepsy and various cardiovascular diseases.
Bioinformatic and functional analysis of retroelements involved in the regulation of human genes
Josette-Renée Landry is bringing both computer science and traditional molecular biology techniques to her research into the function of repetitive DNA sequences in the human genome (full collection of human genes). The Human Genome Project, completed in February 2001, revealed that more than 40 per cent of the human genome consists of repetitive sequences whose function remains largely unknown. Studies have suggested that some of these repeats, called retroelements, can influence how genes are expressed (turned on and off). Josette-Renée is working to further understanding of the function of retroelements by searching for repeats that appear to be involved in regulation of human genes. She will then use laboratory techniques to determine how these elements are involved in gene expression. Her work could lead to the discovery of important new gene regulatory factors. Since many genetic disorders result from aberrant gene regulation, the identification of retroelements that play a role in normal gene expression may provide insight into how regulatory mechanisms are altered in diseases such as cancer.
The roles of valvular myofibroblasts and endothelium in the development of human cardiac valvular disease
Vascular disease is the largest single cause of death in developed nations, and the incidence of cardiac valvular disease (disease in heart valves) is significant. The first cells to be adversely affected in vascular disease are endothelial cells, located on the inner lining of blood vessels. In the initial stages of vascular disease, there are modifications to the way endothelial cells regulate calcium signaling, an essential part of communication between cells. Willmann Liang is studying normal and abnormal calcium regulation in two types of heart valve cells: endothelial cells and myofibroblasts (cells involved in wound healing). Willmann aims to understand how calcium regulation in the human cardiac valve is altered with disease, and to determine how gene expressions governing the various components of calcium signaling are modified. Ultimately, the research may lead to the early prevention and treatment of valvular diseases.