Natural killer (NK) cells are a subset of white blood cells and are part of the innate immune system. Their activation, unlike that of the adaptive immune system, does not require exposure to a foreign substance. NK cells are considered a first line of immune defense in the body, as they can recognize and destroy altered cells such as virus-infected or tumour cells. On the surface of normal cells there are receptor molecules called MHC class-I, which are recognized by receptors on the surface of NK cells. The interaction of NK receptors and MHC class-I prevents NK cells from destroying normal cells. NK cells are able to destroy virus-infected cells and cancer cells because in these cells, MHC class-I molecules are often not expressed (shut off). In both human and mouse, the repertoire of receptors varies among different NK cells. To better understand how NK genes are regulated, Arefeh Rouhi is studying the mechanisms that control these variations among NK cells. Ultimately, this knowledge may lead to ways to use the body’s own immune system to protect against infections and malignancy.
Research Pillar: Biomedical
Immunomodulation using the modified transporter associated with antigen processing (TAP)
The immune system constantly monitors all cells in the body to identify and eliminate any cell that becomes infected or cancerous. A key component of the immune system is a transporter called TAP, which resides inside the cell on the membrane of a compartment called the endoplasmic reticulum (ER). Normally, TAP imports protein fragments called peptides into the ER, after which they are displayed on the cell surface and examined by immune system cells. If the immune system recognizes peptides derived from a virus or tumour, the cell is destroyed. In many cancer cells, TAP is present in very low levels, so viral or tumour peptides do not get into the ER for identification. As a result, the T cells that recognize and kill aberrant cells are not activated and diseased cells continue to grow. At the opposite end of the immunity spectrum, T cells may identify cells from a donor organ as being foreign to the host’s body and kill these cells, resulting in transplant rejection. Robyn Seipp is investigating whether different forms of TAP can be used to improve the immune system’s ability to recognize and respond appropriately to both tumour cells and donor cells from a transplanted organ. The results may be used to improve cancer treatments and reduce transplant rejection.
Effect of glucagon-like peptide-1 on islet transplantation
More than two million Canadians and 135 million people worldwide have diabetes, a chronic medical condition characterized by a lack of insulin to regulate blood sugar levels (Type 1), or insensitivity to insulin (Type 2). Transplanting islets, the cells in the pancreas that produce insulin, can cure Type 1 diabetes. But use of this therapy is limited because of the huge volume of islet tissue required to treat all Type 1 diabetics. As a result, most continue to rely on insulin injections to help control blood glucose. Glucagon-like peptide-1 (GLP-1) is produced in the intestine and has numerous anti-diabetic effects. Clinical trials are currently investigating GLP-1 as a treatment for Type 2 diabetes. Other recent studies show GLP-1 also enhances the growth of islet tissue. Rhonda Wideman is investigating the effects of GLP-1 on the growth and survival of transplanted islets to determine if GLP-1 reduces the amount of islets needed to cure Type 1 diabetes in transplant recipients. If so, more islet tissue could be produced and more patients could be treated with this procedure.
Development of a non-viral DNA cancer vaccine by combining liposome-mediated gene and immunostimulatory oligonucleotide delivery technologies
Vaccines offer a promising approach to prevent and treat cancer. Vaccines have the potential to overcome the failed immune response to cancer cells by priming the immune system to recognize and destroy these cells. But two issues hamper the success of generating cancer vaccines: the difficulty in identifying an appropriate tumour associated antigen (TAA) that would induce an anti-tumour response; and the availability of a safe but potent adjuvant (partner) therapy to boost the immune response against the antigen. Kaley Wilson is researching ways to overcome these obstacles and allow the creation of a non-viral DNA cancer vaccine. To accomplish this, she is using two lipid, or fat-based delivery systems to introduce TAA and adjuvant therapies into tumour cells. The combination of these two lipid-based technologies could support the development of a vaccine targeting a variety of cancers.
Molecular mechanism of genomic instability and telomere shortening in Dog-1 mutants
BRCA1 is a breast cancer susceptibility gene found in more than 80 per cent of families in which six or more family members have had breast cancer. A protein that interacts with this gene is very similar to a specialized enzyme, called a helicase, in the worm. Iris Cheung and her colleagues have demonstrated that the helicase is required to prevent the loss of DNA that is rich in guanine (one of the four components of DNA). Without the enzyme, DNA is lost in multiple sites in the worm genome, resulting in genetic instability and opening the door for normal cells to develop into tumour cells. Iris Cheung is researching how the prevention of genetic mutations in the worm may provide clues to how mutations arise and are prevented in the gene known to cause breast cancer. Findings may help improve researchers’ understanding of the development and properties of breast cancer, and potentially the development of new therapies.
Functional role of p33ING1 phosphorylation in cellular stress responses to DNA damage
The organization of DNA sequences within a structured framework is vital to maintain the stability of a cell’s genetic material. When DNA damage occurs and is left unrepaired, it can affect cell division and normal cellular functions and ultimately lead to cancer. Eric Campos is expanding previous knowledge generated in Dr. Gang Li’s lab around a tumour suppressing protein known as p33ING1. This protein has been found to play an important role in the cell’s response to ultraviolet radiation, enhancing the repair of UV-damaged DNA. Eric’s research focuses on the biochemical processes by which p33ING1 is activated. This work could lead to novel treatments for cancer, a disease caused by the onset of genomic instability.
Structural determination of bacterial type III secretion mechanisms
Overuse and improper use of common antibiotics have reduced their effectiveness because bacteria become resistant to the drugs. As result, there is a growing interest and need to discover new drug therapies to combat bacterial infections. A novel approach to fighting bacteria is to inhibit mechanisms that allow virulence factors to be secreted into host cells. Jason Gunawan is studying a specific secretion mechanism called the Type 111 Secretion System (TTSS), which is found in several bacteria including E.coli and salmonella strains. While there is a wealth of information about the structural components of bacterial TTSS, very little is known about how these components are assembled and how they deliver virulence factors into human cells. Jason’s research findings may contribute to the development of new antibiotics.
Computational and laboratory characterization of genomic islands of potential relevance to bacterial pathogenicity
Infectious diseases cause one-third of all human deaths worldwide. Microbiologists are beginning to get a clearer picture of some of the bacteria that cause disease, using the increasing number of genome (gene) sequences available for these microbes. In fact, a back log of genetic data is waiting to be prioritized and analyzed. The data shows transfer of genetic material between bacteria seems to be much more common than previously believed. Essentially, bacteria can exchange genes that cause disease. In addition, a significant portion of the genes associated with disease are found in clusters called “pathogenicity islands.” William Hsiao believes that focusing on these genomic islands will narrow the search for disease-causing genes in bacteria. He hopes the information will explain how some bacteria cause disease and how they differ from bacteria that do not.
Mechanistic basis of the inhibitory effect of extracellular zinc on rat Kv3.1
Zinc is a trace element that concentrates in some nerve terminals in the brain. Increased zinc concentration in the brain has been linked to epileptic seizures, which affect about 300,000 Canadians. Zinc is known to inhibit a potassium channel, Kv3.1, essential for neuronal activity, but how this occurs is not yet understood. Daniel Kwan is joint author on two papers in the international Journal of Physiology on research into a protein that controls the movement of potassium ions from heart muscle cells. Now he is extending his studies to determine how zinc binds to and inhibits the Kv3.1 channel. Ultimately, the results may lead to new treatments and drugs for brain disorders such as epilepsy.
Uncoupling dopamine and glutamine transmission in animal models of schizophrenia
Schizophrenia affects one per cent of Canadians — more than 300,000 people — causing personality and perceptual changes and thought disorders. Physical and biochemical changes in the brain are linked to schizophrenia, but the exact cause is not known. In addition to the devastating effects on patients and families, the economic burden of schizophrenia on the health care system is staggering. Unfortunately, current medications are only partially effective and result in undesirable side effects. Schizophrenia disrupts interactions between dopamine, an important neurotransmitter (messenger) in the brain and glutamine, an amino acid that is one of the building blocks of protein. Richard Swayze is investigating whether proteins critical to signalling between dopamine and glutamine systems are uncoupled in schizophrenia. He hopes this information will lead to more effective drug treatments that improve quality of life for schizophrenic patients and their families, and reduce costs to the health care system.