Year: 2006

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.

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.

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.

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.

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.