A stem cell can both self-renew and divide to form differentiated daughter cells. In adult tissues, stem cells have the ability to generate mature cells of a particular tissue through differentiation, and to do so multiple times. Such cells were recently identified in a mammary gland, and demonstrated their capacity to regenerate their structures in other breast tissues. This was an important discovery, as it is speculated that these stem cells are central to the development of breast cancer. Because stem cells are relatively long-lived compared to other cells, they have a greater opportunity to accumulate mutations leading to cancer. Also, these cells have a pre-existing capacity for self-renewal and unlimited replication. The idea that stem cells are inherent to malignant transformation has wide-stretching implications for therapeutics, particularly with regards to drug resistance. Angela Beckett is studying the growth and differentiation of normal breast stem cells, which will provide knowledge about what drives malignant transformation and how to prevent cancer initiation. By obtaining basic information on stem cell regulation, this research is taking an important step in designing novel therapeutic approaches to their malignant counterparts, cancer stem cells.
Research Pillar: Biomedical
Characterizing the role of granzyme B in atherosclerosis and hair loss in apolipoprotein E knockout mice
Cardiovascular disease is the leading cause of death in Canada. Atherosclerosis is a cardiovascular disease, in which the inside of blood vessels contain fatty growths known as plaques. Over time, these plaques become unstable and can break, resulting in blockage of blood vessels. This can lead to heart attacks, strokes and limb loss. Wendy Boivin’s research explores what makes a plaque develop, grow, and become less stable. She is focusing on a protein called Granzyme B, which is known to cause plaques. What is unknown is which of two possible approaches Granzyme B uses to induce plaque formation and atherosclerosis: either by entering blood vessel cells and killing them, or by breaking down structural proteins in the blood vessel. Wendy Boivin is studying the role of perforin, a protein that is required for Granzyme B to enter into blood vessel cells. By conducting a study that observes what happens when perforin is removed from blood vessels, she can pinpoint the pathway Granzyme B uses to cause atherosclerosis. Ultimately, this study may contribute to new therapeutic targets for combating this disease.
Characterizing the Molecular Mechanisms of Adaptor Proteins AP-3 and AP-1B Function: An Integrated Analysis
The cell consists of many different compartments, each of which carries out a special function. A network of transport pathways moves molecules between these compartments to reach their proper location. This process, called vesicular transport, is central to the cell’s ability to grow, divide and communicate with its external environment. Receptors are dependent on vesicular transport for reaching the cell surface, where they bind factors that are essential for the cell such as hormones and nutrients. An enormous number of human diseases, including cancer, diabetes and Alzheimer’s disease, result from defects in vesicular transport. A specialized group of proteins called adaptors coordinate the wide variety of transport events within the cell. Each adaptor recognizes its own set of molecules for transport and initiates the pathway that will take them to their final destination. Adaptors cannot work by themselves; many regulators cooperate with these complexes, guiding them to the correct location and activating them for cargo binding. Helen Burston is identifying the molecules that cooperate with Adaptor Protein Complex 3 (AP-3), an adaptor required for the formation and function of lysosomes, which are required for immunity, blood clotting, and brain function. This research will help develop a better understanding of defects in neurological function and immunity.
The Role of Granzyme B in Aortic Aneurysms
An aneurysm is a permanent dilation, or ballooning, of a blood vessel or an artery to 1.5 times its normal diameter. It is usually a complication of atherosclerosis, a form of cardiovascular disease where the interior walls of blood vessels are blocked by a fatty substance called plaque. While most aneurysms are small, slow growing and rarely rupture, some are large, fast growing and at higher risk of rupturing. Aneurysm formation can result in hemorrhaging and death if not immediately repaired – the mortality rate after a rupture is 80-90 per cent. Aneurysms in the brain (cerebral aneurysms) can rupture and cause bleeding within the brain, resulting in a stroke. Ciara Chamberlain is studying a protease, Granzyme B, which is made and released by certain types of immune cells. Granzyme B may play a role in aortic aneurysms by breaking down structural proteins and causing thinning of the blood vessel wall. Building upon work in this area already conducted at the James Hogg iCAPTURE Centre, this research seeks to provide definitive evidence about the therapeutic potential for Granzyme B inhibition for the prevention of aneurysms in patients with mild or advanced atherosclerosis.
Discovery of immunogenic Salmonella peptides by immunoproteomics
Salmonella bacteria can contaminate food, causing Salmonellosis, a disease with symptoms such as diarrhea and abdominal cramps. Although treatable with antibiotics, the incidence and severity of Salmonellosis has increased over the last ten years, partially due to increased antibiotic resistance by some strains of the bacteria. Consequently, other methods of treatment or prevention are needed to better control these infections. Queenie Chan is investigating the potential to develop a vaccine for Salmonellosis. Vaccine design varies in difficulty, depending on the nature of the infectious agent. In the case of Salmonellosis, dendritic cells take up bacteria in the body and break the protein components down into small pieces (peptides) on the surface of the cells. These fragments retain the identity of the original bacteria. In theory, injecting bacterial fragments identical to those found on the surface of dendritic cells will prompt an immune response against the bacteria, without an actual infection. Chan is using an instrument called a mass spectrometer to simultaneously assess hundreds of these peptide fragments to determine which peptides elicit an immune response. Chan hopes these peptides will provide the foundation for creating a vaccine against Salmonellosis, thereby avoiding the use of antibiotic drugs that help perpetuate the growth of antibiotic-resistant bacteria.
Characterization of a new checkpoint in hematopoietic stem cell development
Blood cells are critically important to human health and a significant perturbation of blood production is life-threatening. In addition, the transformation of blood cell precursors leads to fatal leukemias, lymphomas and myeloma that remain difficult to treat and are often fatal within a few years of diagnosis. All blood cells must be produced from a common pool of self-maintaining cells called blood stem cells. Understanding the regulation of these cells and their immediate derivatives is critical because they are thought to be the origin of most blood cancers and it is the transplantation of these cells that is required to rescue the blood-forming system in patients who can benefit from treatment with an otherwise lethal dose of chemotherapy or require replacement of a defective blood-forming system. Although the use of blood stem cell transplants can be life-saving, its application is still limited. A major barrier to more widespread use is the extremely limited number of blood stem cells in the tissues where they are produced, and our inability to grow or expand these cells in tissue culture. Previous research has demonstrated that as they develop from fetal to adult cells, blood stem cells undergo an abrupt change that reduces their capacity to expand. Michael Copley’s research at the Terry Fox Lab focuses on improving our understanding in molecular terms of the mechanism that switches the ability of blood stem cells to expand that occurs shortly after birth. This could lead to the development of ways to block or reverse the switch, so that adult stem cells can be made more effective. It could also lead to an increased understanding of why different types of leukemias and other early onset blood disorders develop in children and adults.
T regulatory cells and T helper 17 cells: interactions between two distinct T cell subsets important for immune homeostasis
The immune system tries to maintain an optimal balance between immune responses to control infection and tumour growth, and reciprocal responses that prevent inflammation and autoimmune diseases. Impaired immune responses, such as those that occur with autoimmune disorders (multiple sclerosis, type 1 diabetes) and organ transplant rejection, result when a person’s immune system mistakenly attacks normal cells. Currently, patients afflicted with this condition must follow a strict regime of immunosuppressive drugs for the rest of their lives. However, these treatments seriously compromise the body’s ability to fight infection and also increase the risk of developing cancer. Sarah Crome is studying the role of a newly discovered class of cells, called T regulatory (Treg) cells in immune system response. She is studying how Treg cells suppress other immune cells and essentially act as a “brake” for the immune system. She is also examining how a subset of T cells, called T helper 17 cells, cause harmful immune responses that result in the rejection of transplanted tissues. A better understanding of these cells and the interactions and factors that regulate their differentiation and function, may lead to more effective treatments for organ transplantation and autoimmune diseases without compromising normal immune function.
The role of Na+/H+ exchangers (NHEs) in pH regulation and brain function
The regulation of pH (a measure of acidity or alkalinity) is a highly sophisticated and tightly controlled process that is extremely important for proper brain function. Abnormal fluctuations in the pH of neurons (nerve cells) may be involved in the development of many neurological disorders such as epilepsy. Sodium-proton exchangers (NHEs) are membrane proteins that play an important role in maintaining and regulating cellular pH. Two forms of these proteins in humans, NHE1 and NHE5, are found at high levels in the brain. Graham Diering is investigating the exact function of NHE5, the only NHE that occurs almost exclusively and at high levels in the brain. NHE5 has been linked to familial paroxysmal kinesigenic dyskinesia (PKD), a neurological movement disorder. However, the precise involvement of the protein in PKD, and its role in proper brain function, are unknown. Diering is researching NHE5 in different brain structures, including mature and developing tissue, and examining the protein at the cellular level to determine where it may be active in nerve cells. An enhanced knowledge of the mechanisms in nerve cells that regulate pH could increase understanding of the factors that govern brain function, both in the normal and diseased state. As well, an analysis of specific molecules involved in this process could contribute to development of diagnostic and therapeutic strategies for treatment of neurological disorders.
Elucidating the signal transduction pathways by which the host defence peptide LL-37 initiates immunomodulatory responses by bronchial epithelial cells
The immune system must strike a balance between fighting off illness and infection and damaging tissues in the body. If the balance swings too far in either direction, the results can be disastrous. Over-stimulation of the immune system can result in tissue damage, low blood pressure, organ failure and death. A good example is toxic shock syndrome, which occurs when an enormous overreaction by the immune system triggers a rapid drop in blood pressure, leading to multiple organ failure. Mortality is as high as 30 to 40 per cent Researchers recently suggested that this type of reaction may explain, in part, why the 1918 flu epidemic was so deadly. A protein called LL-37 is involved in healing wounds and growing new blood vessels, a process that is vital for repairing damaged tissue. Niall Filewod is investigating whether or not LL-37 can help calm an activated immune system. Thus diminishing the effect of excessive immune responses and protecting the body from toxic shock. If so, this research could lead to new drugs to treat conditions ranging from sepsis to arthritis that result from immune system reactions gone awry.
Heme binding and transport by the Staphylococcus aureus Isd system
Staphylococcus aureus is a bacterial pathogen that is of considerable medical concern. Though it normally lives externally on humans or animals, S. aureus causes problems when it is introduced into breaks in skin or mucosal surfaces, enabling it to invade the surrounding tissues and move into the blood stream. S. aureus poses an especially great threat in the hospital setting where it is one of the most commonly acquired bacterial infections and a serious cause of disease and death. The emergence of multidrug-resistant “superbugs” has highlighted the potential threat S. aureus poses in the health care system. There is an imperative need for new means of inhibiting the growth of S. aureus. As in many other organisms, iron is required for growth in S. aureus – an element that the bacteria must either extract or scavenge from within the human system. The majority of iron in the human body is found in heme, and many other organisms have evolved to utilize heme as an iron source. Recently, S. aureus was also shown to preferentially use heme-iron in early growth, but little is known about its heme uptake mechanism. Jason Grigg is exploring the function and structure of a set of four cell surface heme binding proteins found on S. aureus. By describing how the bacteria grows by extracting iron from its host, this research may lead to new ways to “starve” the bacteria and inhibit its pathogenesis.