While there has been significant research conducted about how bacteria and viruses cause disease, in comparison, relatively little is known about eukaryotic pathogenic processes – specifically, the disease-causing mechanisms of parasitic protozoans, which are single-celled, nucleated organisms. Dr. Michael Grigg is investigating the protozoan parasite Toxoplasma gondii, a common eukaryotic pathogen capable of infecting essentially any nucleated cell in most warm-blooded species. This highly successful parasite currently infects close to one-third of the human population. There are only three main strains of the parasite in nature and each line causes profoundly different disease in animals. Toxoplasma is known to stimulate a variety of immunological responses in infected hosts. Hosts are unable to clear the parasite, resulting in a life-long infection. Dr. Grigg is studying the immunological and molecular interactions that modulate Toxoplasma pathogenesis in an animal model of the disease, and identifying the virulence factors that are essential to the success of particular strains of the pathogen. From his work, he hopes to uncover new mechanisms and principles of pathogenesis.
Research Pillar: Biomedical
Molecular study of interaction between mycobacterium tuberculosis and the macrophage endosomal compartment: An approach to identify mycobacterial virulence factors
Much of the resurgence of tuberculosis during the past decade can be attributed to the fast spread of new bacterial strains that are resistant to the conventional anti-tuberculosis drugs. New therapeutic strategies are urgently needed, requiring a better understanding of the interaction of the causal agent, Mycobacterium tuberculosis, with the host cells. Monocyte/macrophages are the principal targets for mycobacterium. These cells possess a powerful intracellular killing mechanism and play an essential role in the clearance of bacteria. However, one of the major features of tuberculosis pathogenesis is the residency of bacteria in an intracellular vacuole that evades intracellular killing. Mycobacterium tuberculosis interacts with specific cell surface molecules, acting as “”an entrance gate”” and ultimately producing factors that inhibit the intracellular killing. Dr. Zakaria Hmama’s research focuses on the molecular mechanisms regulating the entry of the bacteria into macrophages and the resistance to intracellular killing. Such studies will provide a rational basis for the development of new drug strategies.
Epidemiology, genetics and molecular biology of a virulence-associated bacteriophage of Chalamydia pneumoniae
Dr. Karuna P. Karunakaran is exploring a mystery around how Chlamydia pneumoniae (an infectious bacteria) is implicated in atherosclerosis (hardening of the inside of the arteries). While a strong link has been established between C. pneumoniae and atherosclerosis, 60 to 80 per cent of the adult population is infected with the bacteria with no apparent ill effects. One explanation may be that some strains of the bacteria are more capable of causing vascular disease than others, due to genetic variation. In fact, one strain of C. pneumoniae has been shown to contain a bacteriophage, a virus that infects bacteria and integrates itself into the genetic code. Preliminary studies have indicated a strong association between vascular disease and the presence of this strain. Karuna is studying the biology of the implicated bacteriophage, and hopes to identify the strains of C. pneumoniae that may cause vascular disease. This may lead to effective design of a vaccine to combat vascular disease caused by infectious bacteria.
Genes regulated by the androgen receptor in prostate cancer cells
Dawn Bradley’s research focuses on the key role of the male hormone androgen in prostate cancer, the second leading cause of death for men with cancer in North America. Prostate tumours initially need androgen to grow and proliferate, but tumours can progress to the point where they survive without androgen. Conventional treatments are ineffective when prostate tumours become androgen-independent. Bradley is investigating the process by which the androgen receptor regulates various genes. Using microarrays, a technology that allows thousands of genes to be examined in a single experiment, she hopes to identify genes that are regulated by the androgen receptor and other genes that progress to androgen-independence. Her research will improve understanding of how prostate cancer cells become androgen-independent and provide potential targets for anti-cancer therapies.
Cytoskeletal modulation and developmental regulation of Kv15 surface expression
Potassium channels comprise a group of transmembrane proteins in cells that typically allow preferential passage of K+ from the inside of the cell to its external environment. In excitable tissues such as neurons and myocytes, these channels functionally hyperpolarize the cell, serving to retard electrical conduction and excitability. In the heart, K+ channels such as Kv1.5 are of paramount importance in cardiomyocyte repolarization and governing the duration of the action potential. Since cardiac arrhythmias arise from abnormal cardiac excitability, the control of cardiac K+ channel modulation constitutes a promising site of clinical therapeutic intervention. It has been proposed that disruption of the actin cytoskeleton leads to an increased surface activity of cloned Kv1.5 channels in human embryonic kidney (HEK) cells. To investigate this hypothesis and its physiological importance, I propose to investigate cytoskeletal disruption in cardiomyocytes as well as HEK cells, examining its effect on levels of gating current in Kv1.5 and the distributions of a-actinin-2 and Kv1.5. In addition, it has been speculated that repolarizing K+ currents underlie the basis of alterations in cardiac action potential configuration occurring during post-natal development. I further propose to examine the possible postnatal changes in Kv1.5 expression contributing to this developmental dependence.
Single Channel analysis of the mechanism basis of Zn 2+ and H+ medical block of Kv1.5
A goal that scientists have long hoped for — the ability to design drugs based specifically on the known properties of their targets — motivated Daniel Kwan’s Masters research. In order to develop such target-specific drugs, the molecular structure of potential targets needs to be well-defined. Daniel contributed to this goal by combining techniques in electrophysiology, cell biology and molecular biology to study Kv1.5, a protein controlling the movement of potassium ions from heart muscle cells. The protein acts as a pathway for ions to pass through cell membranes. Results from the research show that zinc ions and protons can block these pathways by causing a reduction in the channels available. Daniel also examined how nickel ion affects these channels and results from this study point to a possible link between zinc and epileptic seizures. These findings could help in developing drugs to block the channels as a treatment for diseases such as irregular heartbeat and epilepsy
Identification of caspase modifiers via genetic selection in yeast
Elaine Law’s Masters research literally related to matters of life and death. Elaine investigated apoptosis – the process of programmed cell death. Apoptosis plays a critical role in normal body function by eliminating unwanted and potentially dangerous cells as part of tissue renewal. However, too much cell death can lead to strokes and neurodegenerative disorders such as Alzheimer’s Disease and Huntington’s disease, while too little cell death has been associated with many forms of cancer and autoimmune diseases. Using yeast as a host and advanced genetic techniques, Elaine studied caspases, a group of proteins that play a key role in cell death. She developed a genetic selection system in yeast for identifying caspase modifiers: proteins that either activate or inhibit caspases. Her research improves understanding of cell death and provides insights about genes that contribute to abnormal patterns of cell death leading to cancer.
Identification of Notch4-Modulated Genes in Vascular endothelia Cells
Graeme McLean’s research focuses on angiogenesis, the process by which a person’s existing blood vessels sprout extensions from themselves to enhance blood flow or nutrient delivery. The process is critical in embryo development, wound healing and inflammation. Defects in angiogenesis can interfere with wound healing and contribute to conditions such as rheumatoid arthritis. Abnormal patterns of angiogenesis also contribute to the growth of cancerous tumours that are capable of co-opting the process to increase their blood supply. In addition, the ability to increase blood flow to the heart is crucial to the survival of heart attack victims. McLean is studying Notch4, a protein in endothelial cells that line the blood vessel wall and participates in the regulation of angiogenesis. Investigating how this protein works will lead to a better understanding of angiogenesis and provide insights into correcting defects in the process.
Calcium Homeostasis and Basal Entry in Vascular Smooth Muscle
Much research has been devoted to understanding how calcium enters stimulated vascular smooth muscle and causes muscle contraction. Defects in this process have been linked to diseases such as hypertension and peripheral vascular disease. But little research has been done on calcium entry in unstimulated muscle. Damon’s research suggests that a significant amount of calcium enters muscle even in the absence of a contraction-inducing stimulus. By investigating the pathways through which calcium enters vascular smooth muscle and skeletal muscle, Mr. Poburko aims to identify the specific role of calcium entry in causing diseases such as muscular dystrophy and chronic hypertension. Ultimately the research may point to new drug therapy targets for the diseases.
The role of cystine transport by the xCT protein in maintaining the brain antioxidant glutathione
Andy Shih’s Masters research focuses on preventing damage to cells in the central nervous system after a traumatic injury. Following such an injury to the brain or spinal cord, free radicals (oxidants) accumulate and damage almost all molecules in a cell by stealing electrons. Toxic damage to neural tissues worsens progressively over hours or days due to an imbalance between free radicals and antioxidants that normally protect the cells. Shih is examining the effectiveness of increasing antioxidants to prevent cellular damage, with a particular focus on glutathione, a potent antioxidant. He hopes this work will lead to new treatments for brain and spinal cord injuries. Shih also sees potential benefits from the research for many other diseases, including stroke, epilepsy and neurodegenerative disease.