White blood cells are the key elements of the immune system that keep our bodies healthy. Normally these cells circulate in the bloodstream, but upon infection or injury, the cells exit from blood vessels and enter the damaged tissue to promote healing. Proteins on the cell surface, called cell adhesion molecules, take white blood cells to the afflicted site. These molecules are tightly regulated to ensure they only allow cell migration into damaged tissues. When regulation fails, cell adhesion molecules may promote inflammatory diseases such as arthritis, inflammatory bowel disease and atherosclerosis or metastasis (transfer from one organ or body part to another) of cancer. Kelly Brown is studying CD44, a cell adhesion molecule found in mice and humans on virtually all cell types. Kelly is investigating CD44 on particular white blood cells called monocytes. Once in damaged tissues, these cells eliminate pathogens and alert the rest of the immune system. She is examining the changes that occur in CD44 when monocytes are activated and how the regulation of CD44 contributes to monocyte function during an inflammatory response. Kelly ultimately hopes to learn how to block or promote CD44, which could lead to new treatments for inflammatory diseases and cancer.
Program: Trainee
Abnormal response to vasoactive agents in pulmonary hypertension
Pulmonary hypertension (PHT) is a life-threatening disease; people with PHT experience shortness of breath, chest pain and fainting and live an average of 2.5 years after diagnosis. The disease involves increased production of endothelins in the lungs, which constrict blood vessels in the lungs. Endothelin is a potent vasoconstrictor (constrictor of blood vessels). Xing Cheng is investigating how certain substances produced in the lungs with PHT influence the ability of endothelin to constrict blood vessels. She is also examining how anti-inflammatory drugs that inhibit the formation of these substances affect production of endothelin. Her research will help identify drug combinations that may reverse the cardiovascular abnormalities causing pulmonary hypertension.
Contribution of granzyme B-induced cell death to atherosclerotic plaque rupture
Jonathan Choy brings previous research experience in the mechanisms of controlled cell death to his work at the Cardiovascular Research Laboratory in the McDonald Research Laboratories at St. Paul’s Hospital. His research focuses on atherosclerotic plaques in the vascular system—also known as hardening of the arteries—caused by a buildup of lipids on the innermost portion of the arteries. Advanced plaques tend to break down and rupture, and can lead to blood clots and heart attack. Jonathan is specifically studying the role of granzyme B—a protein normally used by the immune system to kill abnormal and infected cells—in causing plaque rupture. He is investigating whether granzyme B destroys structural cells in the plaques, thereby reducing the integrity of this part of the vessel wall. Understanding the processes that alter the structural integrity of the atherosclerotic plaques could enable control of some of the events that lead to heart attacks.
Phylogeny of the Ichthyosporea
The Ichthyosporea are a group of single-celled parasites that infect a variety of animals, including humans. The group has only very recently been identified on the basis of some preliminary genetic data, and appears to have evolved from animals and fungi. Very little is known about these parasites, and genetic data is needed to understand their evolution and how they function. Audrey de Koning is determining the DNA sequences of some common genes in several Ichthyosporeans and comparing these sequences to the genes of other organisms. This will allow her to identify similar genetic patterns and learn more about how Ichthyosporeans evolved. She is also generating a large number of DNA sequences for expressed genes-genes that have had their coded information converted into the structures present and operating in a cell-in a representative member of the Ichthyosporea. This will give a broad picture of how these parasites function, and may uncover weaknesses that can be exploited to develop new disease treatments.
Contribution of genes other than the CFTR gene to disease severity in Cystic Fibrosis
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.
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.