Normal nervous system function requires the generation of an enormous diversity of neurons during development. Differences in the identity and function of neurons depend upon differences in the repertoire of genes that the neuron expresses. Differential expression of these genes is controlled by intrinsic factors—the complement of transcription factors that exist within the neurons— and by extrinsic factors, signals secreted by other cells. Alterations in either of these factors have been implicated in many developmental, psychiatric and degenerative diseases. Dr. Douglas Allan is investigating how these intrinsic and extrinsic signals interact in neurons to selectively turn on the expression of different repertoires of genes in different neurons, so that the neurons attain their appropriate form and function. He is using the fruit fly, Drosophila melanogaster, as a model organism to study these mechanisms, because of the battery of powerful molecular genetic experimental tools available in this organism. Since the basic mechanisms of neuronal development are shared by fruit flies and humans, his work is relevant to understanding how human neurons develop and how disruption of these signals can cause disease.
Program: Scholar
Examination of the role of cadherin/beta-catenin adhesion complexes in the development and maintenance of synaptic junctions
Synapses of the central nervous system—junctions across which a nerve impulse passes from neuron to neuron—are highly-specialized regions of cell-to-cell contact. Deficiencies in synaptic function are central in many psychiatric and neurodegenerative diseases such as schizophrenia, Alzheimer’s, Parkinson’s and Huntington’s disease. Cell adhesion molecules, localized at synapses, are believed to have an important role in the regulation of synapse formation, maintenance and function. Dr. Shernaz Bamji has previously shown that cadherin and beta-catenin adhesion complexes act to recruit and tether synaptic vesicles to presynaptic compartments, and that transient disruptions of these adhesion complexes are important for the sprouting of new synapses. She is now further investigating the cellular and molecular mechanisms by which synaptic cell adhesion molecules regulate the formation, stability, and elimination of CNS synapses. . Understanding the underpinnings of these mechanisms may lead to the identification of new targets for therapeutic intervention in psychiatric and neurodegenerative diseases.
Structural and functional characterization of the vibrio cholerae toxin-coregulated pilus
Vibrio cholerae is a bacteria that infects the human small intestine to cause the potentially fatal diarrheal disease cholera. This disease, which is spread through contaminated drinking water, represents a major health threat in developing countries, with young children being most vulnerable. The toxin co-regulated pili (TCP) on the surface of V. cholerae are important components in the bacteria’s ability to cause disease in the host. TCP are hairlike filaments that hold the bacteria together in aggregates or microcolonies, protecting them from the host immune response and concentrating the toxin they secrete. The TCP are also the route through which the V. cholerae bacteria is itself infected by a virus called CTX-phi, which enables V. cholerae to produce cholera toxin. Dr. Lisa Craig is determining the molecular structure of the TCP and delineating the regions of this filament that are involved in microcolony formation and in binding to CTX-phi. The information obtained from her studies may lead to vaccines, therapeutics and diagnostics for combating this deadly disease.
Neuromechanical determinants of the metabolic cost of healthy and pathological gait
Walking is a vital means of mobility for most people. While walking is easy for healthy people, for individuals who have suffered a stroke and have partial paralysis of one side of their body (hemiparesis), walking can be difficult. Often, these people will avoid walking, because their gait requires nearly twice the metabolic energy of healthy gait. These increased energy demands may partially explain why stroke patients tend to walk slowly and avoid carrying heavy loads, impairing their daily activities. Dr. Max Donelan’s research aims to advance our understanding of the fundamental principles that underlie locomotion physiology and to apply these principles to directly improve human health. Across the range of his research, he uses a combination of mathematical modeling and empirical experimentation, which involves techniques from biomechanics, energetics and neurophysiology. To study the metabolic cost of gait after stroke, Dr. Donelan is determining the important mechanisms that make normal walking easy and energy-efficient, and how these mechanisms are compromised in individuals with stroke-related paralysis. The results of his research will guide the design of rehabilitation strategies and devices aimed at lowering metabolic cost and increasing patient mobility.
Molecular basis of tenascin elasticity and mechanotransduction
Tenascin is an important family of proteins found in the extracellular matrix of tissues—the filamentous structure that is attached to the outer cell surface and provides anchorage, traction, and positional recognition to the cell, and plays important roles in regulating the interactions between cells and the extracellular matrix. It is also known that tenascin mutations are linked to disorders that affect the mechanical properties of skin tissues and joints. However, little is known about the mechanical properties of tenascins and how they are regulated to adapt tissues to withstand force. To study tenascin, Dr. Hongbin Li is stretching single molecules of the protein and examining its mechanical response. He will also evaluate the consequences of disease-causing mutations on the mechanical behaviour of tenascins. These studies will provide new insight into the molecular basis of tenascin mechanics, and help to pinpoint the cause of tenascin-related connective disorders. They may also offer useful information in developing tissue engineering strategies for skeletal repair.
Endoplasmic reticulum-plasma membrane contact sites: Regulation of ER structure and cell growth
Lipids play important roles in all cells, separating the cell from the outside environment and serving to divide the cell into distinct compartments called organelles. In order to carry out their critical biological processes, organelles need to contact and communicate with each other. The disruption of these contacts can result in defective movement of lipids, and the accumulation of lipids is a factor in diseases such as atherosclerosis, Alzheimer’s disease, type 2 diabetes and motorneuron diseases. The endoplasmic reticulum is an organelle that is made up of a network of membranes within cells, involved in the synthesis, modification, and transport of cellular materials. Communication of the endoplasmic reticulum with other organelles is especially important to the cell, because it is the site of many metabolic activities, including making lipids and proteins. Dr. Christopher Loewen is working to determine how the endoplasmic reticulum contacts and communicates with other cell compartments, particularly with regards to lipid synthesis. By studying these contacts, he hopes to shed light on both normal and dysfunctional communication, potentially uncovering new ways to fight lipid accumulation.
Characterization of the influence of covalent histone modifications on DNA methylation in mammalian cells using a novel genomic targeting system
Normally, cells in the body grow, divide, and die in an orderly manner, under the direction of their DNA, the genetic blueprint of life. However, damage to the DNA in a single cell can disrupt this regulated process, prompting the cell to begin dividing uncontrollably and becoming cancerous. A subset of cell growth regulating proteins – those encoded by the tumour suppressor genes – normally act to inhibit cell growth. In many cancer cells, these proteins are no longer produced, not because the genes that encode them have become mutated, but because they have been shut off, or “silenced”. Gene silencing frequently involves methylation, a specific chemical change in the genes’ DNA. However, the cause of methylation and its associated gene silencing cascades remain unclear. Dr. Lorincz is determining the underlying cause of DNA methylation, using a novel mouse cell model system that he has developed. The knowledge gained from this work may lead to the development of pharmaceuticals that inhibit DNA methylation and, in turn, provide new agents for the treatment of those cancers arising from aberrant methylation of tumour suppressor genes.
Methods and tools for integrative meta-analysis of neuroscience micro array data
Dozens of neuroscience laboratories around the world are using gene expression microarrays, a technology that simultaneously monitors the activities of thousands of genes in a sample of brain tissue or cells. While the specific goals of each study may vary, a common theme is increasing our understanding what happens to the brain when it is diseased (as in Alzheimer’s disease or schizophrenia) or damaged by injury (such as stroke). These studies each generate huge amounts of data, with the potential for new discoveries arising from the compilation and comparison of results across laboratories. However, there have been few efforts to date to provide advanced analytic capabilities that can span data sets, and none that address the specific needs of neuroscience. Dr. Paul Pavlidis is developing methods, databases and software to gather, integrate and compare the vast amount of data compiled from neuroscience-related gene expression data. The tools he is developing will allow brain researchers to submit their own data, compare it to published data or that of their collaborators, and combine microarray data with other types of gene expression data. This work will help researchers share data and collaborate in studies that target diseases of brain function.
Algorithms for RNA structural interaction prediction and antisense RNA design
Until recently, RNA was only considered to be a carrier of information from DNA to proteins. Because the functional roles of RNAs were largely unknown, their structural properties received limited attention. However, with the recent discovery of regulatory RNAs – RNAs that control the activity of genes – interest in the functionality of RNA has surged. Understanding their structure is a key starting point in determining how RNA molecules function. Dr. Cenk Sahinalp is using new approaches to increase the reliability of his previously-developed mathematical frameworks and corresponding algorithms for accurately predicting individual RNA structure and the joint structure of interacting RNA molecules. This includes the development of algorithms for designing RNAs that help regulate the expression of select genes. His long term goal is to help inform the development of artificial RNAs that might be used as therapies for disease.
Developing and using inhibitors to examine the role of O-GlcNac post-translational modification of proteins on glucohomeostasis and beta-cell adaptation
Type 2 diabetes develops when our bodies are unable to properly regulate blood glucose levels. Normally, blood glucose levels are carefully maintained at optimal levels through the finely-orchestrated action of pancreatic beta cells, as well as insulin-responsive tissues. These tissues must be able to sense and rapidly respond to changes in glucose levels; when this system is disrupted, type 2 diabetes develops. Researchers know that glucose is central in regulating insulin synthesis and secretion, but how this occurs remains only partly understood. Dr. David Vocadlo is studying the role of a single sugar unit known as O-GIcNAc, which is installed by the enzyme OGTase and removed by the enzyme O-GlcNAcase, that is believed to act as a glucose sensing mechanism that triggers cells to adapt to their nutrient environment. While this mechanism is generally seen as an important process in maintaining health, disruption of this process can lead to extended periods of abnormal O-GIcNAc levels, and may cause some diabetes-related health problems. By developing and using inhibitors of both the O-GlcNAcase and OGTase enzymes, how O-GIcNAc acts in nutrient sensing will be addressed. Dr. Vocadlo’s research may prove useful in correcting problems in glucose sensing among type 2 diabetes patients.