Escherichia coli (E. coli) bacteria cause much disease and death worldwide. However, little is known about the mechanisms these bacteria and others use to cause disease in their hosts. Specific virulence factors – strategies and molecules that enable the bacteria to cause infection – are needed for disease to develop. The bacteria inject these virulence factors into host cells, which affect normal cellular processes. Dr. Mark Wickham is using two pathogens, E. coli and Citrobacter rodentium, as a model to research how pathogens produce disease at the molecular and cellular levels. Understanding how this process occurs will address a gap in current knowledge, thus improving health and health services, and the research results could be applicable to other disease-causing organisms.
Research Pillar: Biomedical
Dendritic cells in autoimmunity and cancer
Dendritic cells play a vital role in regulating the immune response. They are the only cells capable of activating T cells that have not previously been exposed to a particular antigen (immune threat) to recognize and mount an attack on these foreign proteins. This process ensures an appropriate immune response against potentially harmful antigens. Dendritic cells are also thought to have the ability to instruct the immune system to ignore certain antigens, establishing a state of immune tolerance in the body. When the balance between immune activation and immune tolerance is disrupted, the result may be the development of autoimmune disorders in which the immune system attacks body tissue or cancer in which tumour cell growth goes unchecked. Dr. Cheryl Helgason is studying the biology of dendritic cells and the mechanisms by which they interact with T cells to activate an immune response or to establish immune tolerance. Such research could suggest ways of manipulating immune function to develop new methods of treating cancers, autoimmunity and other diseases involving immune dysfunction.
Bioinformatic approaches to cancer research
Genes – the functional units of DNA – are involved in all aspects of normal human development and human disease. Although most cells have a core set of active genes, selective activation of other genes is necessary to produce different types of specialized cells, such as muscle cells, nerve cells and skin cells. Malfunction in the normal pattern of gene activation is implicated in many diseases, including cancer. Dr. Jones uses sophisticated computational techniques to analyze the activation of genes involved in the formation and development of mammalian organs and tissues and to explore genes that are activated in specific cell types such as muscle and neural cells. His goal is to develop software that will allow researchers to predict the behaviour of genes by indicating when they are switched “on” or “off”. Besides improved understanding of normal growth and development, this research will help clarify the changes in activation patterns that give rise to cancer, potentially leading to new ways of detecting cancer risk and the earliest stages of cancer onset.
Genetic modifiers of pulmonary disease severity in cystic fibrosis
Cystic fibrosis is a severe genetic disorder caused by a single gene called the cystic fibrosis transmembrane regulator (CFTR). The disease is characterized by chronic and persistent respiratory infections, which progressively damage and eventually destroy lung function. Research has shown that cystic fibrosis patients with the same alteration in the CFTR gene may each follow a very different clinical course: with one patient having very mild lung disease and infrequent lung infections, while another will have frequent lung infections and significantly decreased lung function. Dr. Andrew Sandford is investigating genes other the CFTR gene that may play a role in causing lung disease to progress more quickly in some cystic fibrosis patients than in others. It is thought that cystic fibrosis patients may also have compromised immune function. For this reason, Dr. Sandford is looking for genes involved in fighting infections and in controlling the inflammatory response to the bacteria and viruses that attack the lungs.
Regulation and role of granzyme B in Atheromatous Diseases
Atherosclerosis – hardening of arteries – is caused by buildup of plaque inside artery walls. This constricts blood flow and elevates blood pressure, and is the leading cause of heart attacks, stroke and lower limb loss due to poor circulation. There is evidence that immune cells provoke a tightly-regulated form of cell death known as apoptosis (programmed cell death) in atherosclerotic blood vessel walls, which contributes to progression of the disease. While the mechanisms are not clearly understood, the result is a change in the architecture of blood vessel walls that leads to additional plaque build-up and also to plaque instability. The latter increases the danger of pieces of plaque breaking off and potentially lodging in and blocking blood flow in smaller vessels. In previous work, Dr. David Granville and his research team have found that an enzyme used by the immune system to kill abnormal and infected cells is released in atherosclerotic blood vessels. Dr. Granville is studying the role of this enzyme – granzyme B – in vessel wall restructuring and cell death associated with atherosclerosis and transplant vascular disease. Findings from this research may reveal new opportunities for intervening to prevent or treat these vascular disorders.
Leptin regulation of glucose homeostasis
More than two million Canadians have diabetes, a chronic metabolic disorder caused by the inability of the body to produce or properly use insulin. Obesity is a risk factor for developing type 2 diabetes, the most common form of the disease. Dr. Timothy Kieffer has uncovered links between leptin – a hormone that affects how the body manages and stores fat – and insulin producing beta cells of the pancreas, plus the liver, one of insulin’s target tissues. His research suggests there may be a defect in the interaction between leptin, fat, beta cells and liver cells. Using genetic engineering approaches, Dr. Kieffer is investigating the role of leptin in the development of diabetes and obesity, in the hopes of eventually developing novel therapeutic strategies to combat these debilitating diseases.
Mammalian organelle-membrane Type Na+/H+ exchangers
The cell is the basic unit of structure and function in the body. Many of the functions of cells are performed by particular subcellular structures called “organelles”. Acidity (pH balance) is important for organelle function and disruptions in this environment can lead to uncoordinated communication between brain cells, compromised immunity and uncontrolled cell growth or death. Dr. Masayuki Numata is studying the mechanisms for pH regulation in cells. Dr. Masayuki Numata and his research team have isolated ion transporter proteins that may regulate acidity inside organelles. Using biochemical, cell biological, genetic and immunological techniques, he is investigating how these transporters are delivered to the right destination when they are needed and how they are regulated by different factors. The research could ultimately increase understanding of the mechanisms by which brain cells transmit signals to each other and how disruptions in these signaling pathways cause damage leading to Alzheimer’s disease and other neurodegenerative disorders.
Regulation of NMDA receptors and excitotoxicity
Glutamate mediates signaling between neurons (nerve cells) by binding to protein receptors. Over-activation of one type of glutamate receptor, NMDA, can result in damage to neurons. Dr. Lynn Raymond is researching how neuronal activity and cell proteins regulate NMDA receptors, with the goal of better understanding how irregularities or disruptions in regulatory pathways are implicated in damage associated with neurological disease. Dr. Raymond is especially interested in Huntington’s Disease. This inherited neurological disorder causes progressive neurological damage in specific brain regions leading to movement abnormalities, personality changes, psychiatric disorders and memory loss. Studies have suggested that over-activation of NMDA receptors plays a major role in this selective destruction of brain cells. Dr. Raymond is investigating interactions between mutant huntingtin (the protein produced by the Huntington’s Disease gene) and NMDA receptors to gain a more detailed understanding of the causes of neuronal death in Huntington’s Disease – research that may help in the development of new therapies for this incurable disease.
Synaptic and non-synaptic modulation of neuronal excitability
Neurons (nerve cells) communicate through a process in which one cell stimulates another with an electric pulse transmitted by secreting special chemicals called neurotransmitters into the synapse (gap) between the cells. Learning and memory are influenced by changes in the strength of these synaptic connections and by alterations in the excitability of neurons (how readily they produce an electrochemical response). Abnormalities in the regulation of neuronal excitability give rise to neurological diseases including epilepsy and psychiatric diseases such as schizophrenia. Dr. Brian MacVicar is studying two aspects of synaptic transmission: mechanisms that regulate neuronal excitability and mechanisms that influence synaptic plasticity (the ability of neurons to adapt the way they communicate with each other). In one series of experiments, he is examining cells that surround neurons in the brain to determine if they influence neuronal activity through the regulation of blood flow or other mechanisms. He is also studying how past synaptic experience modifies activity in dendrites, the part of the neuron that receives synaptic transmissions. This research into how brain activity is regulated will contribute to improved understanding of many aspects of neuroscience, including stroke, mental illness and learning and memory.
Molecular controls of embryonic facial patterning
The transformation of the embryo from a mass of undifferentiated cells into a fully formed, functioning organism is a complex process. In early embryonic development, discrete buds of cells fuse to create a face. If proper fusion fails to occurs, the result is severe developmental abnormalities including cleft lip with or without cleft palate. The embryonic segments that form the face are similar in chickens and mammals. Using the chicken embryo as a model, Dr. Joy Richman is studying how the jaw is formed and what goes awry in the process to cause cleft lip. By investigating the mechanisms that designate which embryonic facial bud will develop as a particular facial feature and how appropriate growth is initiated at key times to form a face, Dr. Richman will identify genes and gene signaling pathways that underlie normal and abnormal development of the face and jaw. Such information is critical for improved treatment and prevention strategies for defects such as cleft lip.