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.
Research Pillar: Biomedical
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.
A dynamic structural description of the cyclic nucleotide receptor region of pacemaker ion channels
Rhythmic electrical impulses that drive beating of the heart and sleep waves in the brain are controlled by natural pacemakers called ion channels. Pacemaker channels act as electrical switches, and they switch on faster when they bind natural chemical messenger molecules called cyclic nucleotides (CNs). This is thought to involve temporary structural changes in the region of the channel molecule that interacts with the CNs. By modifying the structure of the CN-binding region in the channel and observing how this affects switching, Dr. Edgar Young is studying what structural features of the channels help or hinder this process. Gaining a better understanding of the structural changes that allow switching may lead to the development of new drugs to control pacemaker acceleration, which could alleviate problems such as accelerated heartbeats or epileptic seizures.
Protein traffic at nascent neuronal contacts
Neuronal impulses in the brain are transmitted across synapses, which control brain function by facilitating the firing of neurons (excitatory synapses) or restricting it (inhibitory synapses). An imbalance in this process is thought to underlie several neurological diseases, including Alzheimer’s disease, mental retardation, autism, schizophrenia and epilepsy. Dr. Alaa El-Husseini was previously funded by MSFHR to support his research into the study of a post-synaptic density protein (PSD-95) that stimulates the formation and maturing of the synapses that release glutamate, a key neurotransmitter. He has also determined that this protein affects the balance of excitatory and inhibitory contacts induced by neuroligins, a family of cell adhesion molecules. Dr. El-Husseini’s current research focuses on how these proteins assemble at the synapse, uncovering the molecular mechanisms that govern the trafficking and function of these proteins to determine how their manipulation may affect synaptic balance.
The endothelium: Function and dysfunction
The interior lining of blood vessels is known as the endothelium. Endothelial cells, which make up this inside layer of all blood vessels, are remarkably responsive to changes that occur in the blood and tissues, both under normal conditions and in disease states, sending signals back to the blood and tissues to organize a response. Endothelial cells initiate and direct the growth of new blood vessels within a tissue that is not receiving a sufficient supply of oxygen and nutrients. This growth of new blood vessels can be either beneficial or detrimental to a person’s health. When blocked blood vessels are contributing to the lack of sufficient blood supply (e.g. hardening of the arteries or diabetes), the body’s creation of new blood vessels can prevent tissue damage and promote healing. However, new blood vessels also required for cancer growth by providing the tumour with the oxygen and nutrients it needs. Dr. Aly Karsan is studying several molecules on the surface of endothelial cells to determine how they regulate the growth of new blood vessels. With greater knowledge about the molecular processes underpinning blood vessel growth, he hopes to identify new ways to either promote or restrict these processes to combat a variety of diseases.
Reduction in microsporidian parasites
Microsporidia are a group of parasites that can only reproduce by invading and taking over an animal cell. They are highly dependent on their host cell for nutrients and energy, which has allowed them to discard genes for many metabolic proteins and evolve unique ways to carry out other essential activities. For example, microsporidian genomes are among the smallest of any complex cell. As the genomes shrink, critical information controlling gene expression has been squeezed from its conventional location. The mitochondria—known as the powerhouse of the cell—is also reduced nearly beyond recognition in form and function. In both these systems, the microsporidia do things differently from other cells, including the host animal cell in which they reside. Dr. Patrick Keeling is studying the effects of a shrunken genome and mitochondria in microsporidia, investigating how these reductions affect the way the parasite expresses its genes and targets proteins for function. Fully understanding these unique characteristics is important because, as with other parasites, such features could be exploited as targets for therapy.
Gene and cell therapy approaches to treat diabetes
Transplantation of pancreatic islets has proven to be effective in controlling blood glucose levels in subjects with type 1 diabetes. The results of this procedure have demonstrated the potential to treat diabetes by transplanting as little as a teaspoon of insulin-producing cells into a diabetic patient. However, the promise of this procedure is currently restricted by two major challenges: transplantation is dependent upon the availability of tissue from recently deceased individuals; it also requires the use of chronic immunosuppression in the recipient, which carries the risk of side effects. Dr. Timothy Kieffer is investigating a variety of approaches to achieve the results of islet transplantation without relying on donor tissue. Ideally, he hopes to develop a therapy that uses the patient’s own cells and stimulates either the regrowth of insulin-producing beta cells, or the generation of new cells from adult stem cells. His team is also looking at ways to genetically modify the body’s gut cells to produce insulin or other anti-diabetic factors automatically in response to eating a meal.