One of the major challenges of neuroscience is the lack of regeneration of the mammalian central nervous system when it is injured. Extensive effort has been devoted to promote growth of regenerating axons (fibres that sent impulses from one neuron to another) across the lesion site. Since 55 per cent of spinal cord injuries are incomplete, in many cases a portion of axonal connections between brain neurons remain intact. These intact connections can be induced to form collateral branches, or sprouts, that cross the spinal cord midline and stimulate the other side, leading to some locomotion recovery. Finding ways to enhance this sprouting is a promising strategy to improve recovery in patients with incomplete spinal cord injuries. Ana Le Meur is using mathematical modelling to complement experiments to gain knowledge about the mechanisms regulating sprouting of neuronal connections. By generating a comprehensive model of collateral sprouting, this research will take an important step toward enhancing recovery after spinal cord injury.
Year: 2006
Structural and Functional Studies of Peripheral Components of the Sec Translocase Supercomplex
The delivery of proteins to their correct cellular location is a fundamental aspect of cell biology. For many proteins, reaching a final destination involves crossing membranes, a process known as translocation. Understanding the mechanisms that nature has evolved to translocate proteins across membranes is an important aspect to learning more about the function and dysfunction of this key process. A useful model for studying protein translocation is the evolutionarily-conserved Sec system of Gram negative bacteria (such as E. coli), which exports proteins across and into the inner membrane. The Sec translocase of Gram negative bacteria also serves as the primary conduit for the secretion of virulence factors (toxins and adhesions) in Gram negative bacteria, making it an excellent target for the design of novel antibiotics. David Oliver’s research will expand our understanding of the Sec system and how proteins cross membranes. His work will contribute to improved and possibly novel strategies for protein production for biotechnological and pharmaceutical purposes, as well as to new insights into diseases linked to defects in protein targeting and trafficking.
A Cell-Based Therapy for Type 1 Diabetes
Type 1 diabetes is a debilitating condition ultimately leading to severe, life-threatening complications that arise as a result of inadequate insulin secretion from the pancreas. Type 1 diabetes results from the destruction of insulin-producing cells by the affected person’s own immune system, requiring multiple daily insulin injections. While there has been much progress in the field of islet transplantation as a potential cure for type 1 diabetes, the limited availability of donor tissue and the requirement for lifelong immune suppression has led researchers to examine other potential methods for replacing insulin. Michael Riedel is investigating the potential to create cells capable of secreting insulin in response to a meal. With the goals of yielding insulin-producing cells, he is working with genes that encode the key proteins that are critical for the formation of pancreatic islets during development. Michael is also exploring another approach that involves looking for novel compounds to create insulin-producing cells and investigating their therapeutic potential. If successful, the creation of insulin-secreting cells could provide an additional source of replacement cells to combat type 1 diabetes.
Uncovering cytoplasmic domains of NMDA receptors important for basal and activity-dependent trafficking to synapses
Glutamate receptors are important for excitatory transmission between neurons and for basic neural function, and the NMDA-type glutamate receptor is widely expressed in the brain. Studies investigating the role of NMDA-type glutamate receptors have implicated their function in schizophrenia, pain, ischemia, addiction, synaptic plasticity and learning and memory. The majority of NMDA receptors cluster at synapses: interactions of certain regions of the receptor with proteins in the cell govern their transport and localization to the synapse. The number of NMDA receptors at synapses, and the composition of the subunits that make up the receptors, are important elements of the overall function of the nervous system. MSFHR funded Jacqueline Rose for her PhD work, where she used the microscopic worm C. elegans as a model to analyze how mutations in Presenilin genes affect learning and memory. Now, Jackie is researching the molecular mechanisms underlying the transport of NMDA-type glutamate receptors to synapses, and determining how this affects plasticity, thought to underlie memory and learning, at the cellular level. By developing specific mutations that will prevent certain proteins from interacting with particular NMDA-type glutamate receptor subunits, she hopes to shed further light on the receptor regions necessary for glutamate receptors to move to synapses during activity-dependent plasticity.
Mapping the combinatorial code that generates bipolar cell diversity in the retina and identification of candidate human ocular disease genes
The retina is a thin sensory structure that lines the inside of the eye. Visual information is captured in the retina by cells called photoreceptors which convert the energy of light into electrical signals. Prior to the transmission of signals to the brain, visual information is processed through a class of cells found in the inner retina, the retinal interneurons. These retinal cells integrate and modulate the signals received by photoreceptors and relay the processed information via ganglion cells to the brain. Without retinal interneurons, we would be unable to process visual information and consequently, we would be unable to see. Very little is known about the birth and development of the bipolar cell class of retinal interneurons or the contribution of this cell class to visual disorders. Recent work has determined that visual pathway dysfunction is one of the leading causes of visual impairment, highlighting the need for biomedical research in this area. Erin Star’s research is focused on deciphering the molecular mechanisms that generate and regulate the formation of the bipolar cell class of retinal interneurons. Knowledge gained through this research will contribute to our understanding of fundamental retinal biology, and it is anticipated that ultimately this research will provide the insight necessary to address and effectively treat inherited disorders of the visual system.
Characterization of TRAF6 in normal and malignant hematopoietic cell processes: a focus on Myelodysplastic Syndromes
Myelodysplastic syndromes (MDS) are a family of disorders primarily associated with decreased production of blood cells in the bone marrow. The blood cells of people with MDS die before maturity, causing a shortage of functional blood cells. Patients with MDS are at a significantly increased risk of developing acute myeloid leukemia (AML). Dr. Daniel Starczynowski is studying whether genetic alterations in a protein known as TRAF6 may be implicated in both of these related diseases. This protein simultaneously regulates cell death and cell growth signaling pathways, and has been shown to be abnormally activated in some patients with MDS. He hopes that an increased understanding of the molecular events in MDS will reveal new targets for therapy.
Seizure prediction from EEG signal analysis in temporal lobe epilepsy
Epilepsy is a brain disorder characterized by abrupt and recurrent seizures caused by sudden and brief changes in the brain conditions. Affecting approximately one per cent of people worldwide, epilepsy results in an increased chance of accidental injury and death, and a decreased quality of life. Drug therapy is not always effective in controlling the recurrence of seizures, especially with temporal lobe epilepsy (TLE). The toxicities of these drugs and frequent resistance of TLE to drugs greatly decrease quality of life for patients. Therefore, it is important to investigate new techniques for the prediction of impending seizures to facilitate prompt therapy. Dr. Reza Tafreshi’s PhD work in mechanical engineering involved using statistical pattern recognition to detect and diagnose engine faults. Now he is using this knowledge to predict epileptic seizures by employing computer algorithms and analyzing brain electrical activity through scalp EEG recordings. Predicting seizure onset by a few seconds would give patients a chance to remove themselves from dangerous circumstances and allow administration of a short-acting anticonvulsant drug in a dose that would prevent the seizure. This procedure could be employed in conjunction with an advisory system to warn patients of impending seizures, leading to increased safety and better quality of life.
Moving transporters into intracellular storage: identifying new components of the early endosome retrograde sorting machinery in Saccharomyces cerevisiae
Vesicle transport is a process that underlies various molecular events, such as the movement of glucose transporters in response to insulin in muscle and fat cells. Malfunctions in these transport processes can result in a range of problems, including diabetes or problems in learning and memory formation. An important but unclear aspect of vesicle transport is how molecules are retained within specialized compartments in the cell and how they are released to the cell surface. Chris Tam’s research goal is to identify proteins that control the storage and release of molecules in yeast cells. She is doing this by conducting high-throughput genome-wide screening to uncover yeast genes that are required for the intracellular storage of the protein Chs3. As the basic cellular mechanisms that regulate vesicle transport are likely conserved in both yeast and humans, this understanding from yeast cells may provide insights into various fundamental aspects of human biology. Ultimately, this work may contribute to the development of new treatments for diabetes and diseases involving memory and learning deficits.
Peptide YY Therapy for Obesity
Obesity is a debilitating disease reaching pandemic proportions in developed countries. Several hormones are involved in regulating feeding and energy, including peptide YY (PYY), an appetite regulatory hormone. PYY is released from the gut in response to a meal, relaying signals to the brain to prevent further eating. Several research studies, including work by Suraj Unniappan, have shown that PYY causes inhibition of feeding when administered at pharmacological doses in experimental models. However, the body very rapidly clears PYY from the system, and continuous delivery of PYY results in desensitization against the peptide. This prevents prolonged and consistent effects of PYY on feeding and weight loss. Suraj’s preliminary results indicate that a fat cell-derived hormone, leptin, enhances and prolongs the appetite regulating effects of PYY. In this research, he is working to develop a combination therapy for obesity using PYY and leptin. Next, he proposes to develop a cell-based therapy for obesity using cells that, when activated by a drug, will synthesize PYY and release it in a meal-responsive manner. If this research is found to be effective in reducing food intake and promoting weight loss, it could be beneficial for treating obesity and its debilitating complications.
Stimulus-driven control in visual neglect: the role of awareness
A person’s field of vision, or visual field, includes an enormous amount of information. By means of attention and eye movements, people are able to select certain objects and location from any point in the visual field. Selection may be stimulus-driven (the properties of the object attract a person’s attention involuntarily, such as a flashing light) or goal-driven (the observer purposely turns their attention to an object). People with damage to the right parietal or parieto-temporal lobes of the brain—commonly brought on by stroke, vascular, demyelinating or infectious diseases—suffer from visual neglect, limiting their ability to select information from the visual field. They often fail to notice items in the visual field opposite to the damaged area of their brain. Interestingly, research has suggested that visual neglect in these people is a function of goal-driven selection, and that stimulus-driven selection function may remain intact. Wieske van Zoest’s research is investigating the role of stimulus-driven control in patients with visual neglect. While participants—patients and healthy controls alike—may not be aware of stimulus-driven influences in selection, direct measures (such as eye movement recording) allow for investigation of the contribution of stimulus-driven control. The proposed work may have significant practical relevance for patients, allowing them to process information if it is presented in such a way that it draws attention automatically in a stimulus-driven fashion.