Infectious diseases are responsible for roughly a third of annual deaths worldwide and contribute greatly to productivity loss. Antimicrobial resistance and newly emerging diseases are both cause for significant concern. With the advent of microbial whole-genome sequencing, there has been renewed optimism that computational analyses of microbial genomes will allow for faster identification of promising new therapeutic targets, which can then be further investigated with laboratory studies. At the moment, however, current computational practices are not accurate enough to be truly effective. Dr. Fiona Brinkman is interested in improving computational methods used to identify new potential bacterial vaccine components or drug/diagnostic targets. She is focusing in particular on improving identification methods for two regions: bacterial cell surface and secreted proteins, since they are the most accessible targets; and clusters of genes called genomic islands, which appear to disproportionately contain virulence genes and so could aid investigations of bacterial pathogenicity. Her research group is also studying the evolution of microbial virulence, both from the pathogen and host perspective, using bioinformatic approaches supported by laboratory studies. This work aims to develop methods and insights that may accelerate the identification of promising new targets from pathogen genomes. With the ability to analyze multiple infectious disease-causing microbes in parallel, this research has the potential to have a wide reaching impact on efforts to control multiple infectious diseases.
Research Pillar: Biomedical
Toxicology of Natural Products and Synthetic Drugs
Adverse drug reactions are a major health risk that contributes to increasing health care costs and strain on the system. They are the sixth leading cause of death in the United States, and statistics indicate that the situation would be similar in Canada. There are many types of adverse drug reactions. Liver toxicity (poisoning) leading to fatal liver failure is one of the most common. In most cases, the mechanisms that cause drug induced liver toxicity are not well-known and even less is known about the effects of natural products (herbal products or dietary supplements) on liver function. With the ever increasing demand of herbal products by consumers, there is an urgent need to conduct detailed and systematic scientific investigations on their hepatic metabolic effects. Dr. Chang’s work is aimed at characterizing the effect of natural products and synthetic drugs on liver function and determining how they are able to give rise to damage in liver cells. A better understanding of the mechanisms will contribute to a safer and more rational use of natural/herbal products and synthetic drugs.
Transcriptional regulation of genes in health and disease
The human genome contains all the genes, and their regulatory instructions, required to develop the human body and determine how it deals with the outside environment. Now that the genomes of many species have been sequenced, a major focus of genomics is to identify all gene regulatory elements within DNA sequences. How these building blocks of life work together to build a complex human body – with its different organs, tissues, and cell types – is not well understood. Although most human cells carry the entire genome, each cell is functionally different, suggesting that not all genes are equally expressed.
Gene expression – the full use of information in a gene – is regulated in several ways, including by transcription. Specific regulatory proteins called transcription factors bind to targeted DNA sequences in the genome. This kind of activity can control cells by switching gene expression on and off. To better understand transcription regulation in genes, and thereby better understand gene expression, binding sites for transcription factors have to be identified. It is a fundamental step in the analysis of gene expression, which is tightly regulated so that genes are only expressed in specific cells, at specific developmental stages, and at appropriate levels to ensure correct physiological function.
Dr. Jack Chen’s work investigates the properties of transcription factor binding sites (TFBSs) and determines how these properties can assist with effective genome-wide TFBS identification. Using the nematode C. elegans as the model organism, he will combine experimental and computational approaches to characterize the properties of TFBSs that distinguish functional DNA sequences from nonfunctional ones. This study may pave road for a deep understanding of transcription in C. elegans, which will in turn shed light on both healthy and dysfunctional transcription in humans.
Dopamine modulation of prefrontal cortex network dynamics
Schizophrenia is a debilitating condition characterized by cognitive deficits in the realm of working memory, attention and executive function. While these deficits are a core feature of the illness, they are not adequately treated by anti-psychotic medications. The working memory deficits in schizophrenia are thought to involve dysfunction of the dopamine system in the a region of brain called the prefrontal cortex. Dr. Jeremy Seamans is working to understand the neural mechanisms that support working memory in the prefrontal cortex and how these mechanisms are modulated (affected) by dopamine levels. Using computer models, he has been able to link certain phenomena to actions of dopamine at the level of individual neurons and in the synapses between neurons. New computer simulation results suggested an even richer dynamic for how dopamine modulates activity in the prefrontal cortex. By testing the predictions of the computer simulations in a rat model, he will move from describing the known effects of dopamine on single neurons to detailing its impact on large-scale networks of neurons involved in working memory. The work has relevance not only to the theoretical question of how working memory information is coded and modulated but also may provide insight into how variations in the levels and actions of dopamine in the prefrontal cortex produces cognitive dysfunction in schizophrenia.
Effects of exercise on structural and functional plasticity in the aging hippocampus
In the past 10 years we have come to adopt a more dynamic view of the brain. While we used to believe that the adult brain did not produce new neurons, we now know that new neurons are produced continually through out our lives, a process known as neurogenesis. In conjunction with neurogenesis, both new and existing cells also possess the capacity to alter the number and types of connections they make with other cells, a process called synaptogenesis. These processes can dramatically affect our cognitive processing capacities, and current research indicates that abnormalities in either neurogenesis and/or synaptogenesis are linked to a variety of neurological disorders ranging from those normally associated with adulthood (i.e. Alzheimer’s disease. Major depression, and Schizophrenia), to those that are more developmental in nature (i.e. Fetal Alcohol Syndrome, Fragile-X Syndrome, Rett’s Syndrome. Dr. Brian Christie’s research has targeted how exercise can facilitate learning performance, synaptic plasticity, neurogenesis and synaptogenesis in the brain. He has shown that exercise can induce long-term structural and functional changes in the connections between brain cells. His current work will provide greater detail about the mechanisms underlying the marked effects of exercise, particularly in the aging brain. A deeper understanding of these mechanisms may ultimately result in new approaches for establishing, maintaining, and even enhancing brain cells and their connections as we age.
Microfluidic Instrumentation for Single-Cell Chemical Genetics
Healthy cell behavior, cell differentiation and disease progression are all governed by complex protein interactions and regulatory networks across different cells. Unraveling the specific, time-dependent chain of events within cells has proven challenging for several reasons. First, diversity in cell types and the cumulative effects of past cell history mean that cells may vary in their response to chemical environments. Additionally, conventional methods of cell analysis are generally restricted to averaging measurements of large populations of cells, or analyzing cell response at a single point in time. Because these ensemble measurements and snapshots obscure persistent and time-dependent behaviour, deciphering the underlying molecular mechanisms of cellular response is difficult. A deeper understanding of such pathways is essential to the advancement of fundamental biological research, to the diagnoses of disease, and to the development of medical interventions. New technologies are needed to enable continuous monitoring of large numbers of single cells, subject to precisely-controlled sequences of chemical stimuli. Recent developments in micro-fabrication technology has led to micro-scale cell culture “chips”, with features similar to electronic micro circuits. Thousands of microscopic channels and valves can be tightly integrated into powerful biomedical sample processing devices the size of an iPod. Dr. Carl Hansen will focus on maximizing these state-of-the-art systems to develop new instrumentation capable of rapidly analyzing thousands of isolated single cells exposed to precisely defined and time-varying chemical conditions and drugs. Experimentation at the single cell level will accelerate fundamental biomedical research and will ultimately improve both our understanding of, and our ability to treat, disease. The ability to precisely manipulate and interrogate single cells will find broad application in health research fields including cancer biology, regenerative medicine, and drug development.
Exploring and exploiting the protein psoriasin as a new target for breast cancer therapies
Ductal carcinoma in situ (DCIS) is a precursor to invasive breast cancer, and the protein psoriasin is one of the most highly expressed genes in DCIS. Psoriasin is present at abnormally high levels in many pre-invasive breast cancer cells and in a smaller subgroup of invasive breast cancer cells. Recent research has shown that the interaction of psoriasin with the signaling protein Jab1 may be a keystone of the signal network of the breast cancer cell, and that psoriasin binding can cause Jab1 to stimulate the development of invasive and metastatic breast cancer cells. Inhibiting protein-protein interactions is an exciting new approach in the search for targeted cancer therapeutics, and the psoriasin-Jab1 interaction is a promising new target for the treatment of breast cancer. Dr. Fraser Hof’s work deals with fundamental questions about the interactions of proteins and small molecules and with the applied design of small molecule therapeutics. His proposal is to design and develop novel drug molecules to block this psoriasin-Jab1 interaction, first to validate the target and then to guide subsequent drug development. A drug that inhibits this interaction may offer a novel therapy to directly target pre-invasive breast cancer and prevent the development of invasive breast cancer. This therapy may also hold promise as a new approach to target the small subgroup of invasive breast cancers where psoriasin is also present, as this subgroup is typically not eligible for current targeted therapies such as tamoxifen and herceptin.
Patterning and Organogenesis of the Mammalian Embryo
The development of a single cell to a multi-cellular organism, with each tissue and organ having a distinct architecture and function, is truly remarkable. Cells must co-operate and communicate with one another so they divide, migrate, form connections, change their identity, and die in co-ordinated patterns. These processes are complex, thus little is known about developing embryos and the genes that regulate their development. As an MSFHR-funded scholar, Dr. Pamela Hoodless examined how cells communicate with one another during embryonic development. This work continues, with a focus on two areas: the gut and heart. Congenital heart defects occur in about one per cent of births, making it a most common form of birth defect. With genomic technology, Dr. Hoodless can look closely at the genes involved in forming the valves and septa in the heart. She has identified two genes that control the activity of other genes, known as transcription factors, and is studying the functions of these genes in valve formation. Dr. Hoodless is also working to understand how the first stem cells of the gut are formed, and how these cells change to become other organs (liver, pancreas, stomach, etc). Identified for further study are three genes that are expressed (turned on) in these tissues, but not in the development of other body tissues. Understanding how gene regulation controls the development of the heart and gut in the embryo has far reaching implications for medical therapies, ranging from refining the repair of congenital defects to promising technologies such as stem cell therapies and tissue engineering.
The genetic basis of neuronal differentiation and neuronal circuit formation
Diseases or injuries affecting the brain frequently have devastating consequences for affected individuals. Despite progress in the last decade, many aspects of brain disease and brain development are still not understood with enough detail to develop effective diagnosis and treatment of disease and injury. Connectivity disorders result from defects in the formation of particular neuronal circuits that interfere with normal communication between neurons. They are especially challenging because they are often inherited and are influenced by more than one gene making it even more difficult to trace the underlying defects. It is suspected that connectivity defects are implicated in a variety of disorders including autism, schizophrenia, attention deficit hyperactivity disorder, obsessive–compulsive disorder and certain forms of epilepsy. In most cases, the nature of the circuitry defects is not understood. Dr. Hutter’s research is directed at identifying and describing central aspects of brain development, in particular how the formation of neuronal circuits is controlled and regulated at the molecular level. His research model is the simple invertebrate organism, C. elegans, which has many of the developmental control genes found in humans. By exploring the molecular basis of neuronal circuit formation in a simpler model organism, his work will contribute to a more detailed picture of the more complex circuitry of humans, and potentially to an improved ability to design drugs and other methods of treating connectivity disorders.
Mechanisms and consequences of aberrant repair in the lung
The World Health Organization estimates that between 100 million and 150 million people worldwide suffer from Asthma. The disease places a huge burden on the health-care system, with economic costs greater than of TB and HIV/AIDS combined. While less common than Asthma, Idiopathic Pulmonary Fibrosis (IPF) is a devastating disease since there is no cure or effective therapy. In North America and Canada there are over 200,000 patients with this disease. Of these more than 40,000 die annually. This is the same number of people that die from breast cancer annually. Currently we think that the pathology of both diseases follows a pathway similar to normal wound healing, although there is progression of the disease because the normal «braking» mechanisms do not function properly. As a consequence, too much connective tissue is produced. My research focuses on the cells that line the airways, called the epithelium and the cells that produce the connective tissue, called fibroblasts. Epithelial cells are important since they are the first cell in the lung that interacts with the air and are therefore most likely to be injured. We think that if the epithelium does not repair properly, it will signal the fibroblasts to continue making connective tissue inappropriately.