Cerebellar ataxia is a rare neurological disorder that causes attacks of jerky, uncoordinated movements. Walking can become increasingly difficult, and eventually the use of a wheelchair is necessary. The name is derived from the word cerebellum, which refers to the part of the brain that controls balance and coordination. The condition has no cure and is irreversible. Treatment is available to alleviate symptoms, but not all patients respond to the drug of choice, acetazolamide. Genetic screening has revealed that one type of ataxia is caused by mutations in a particular gene. Interestingly, the same gene causes inherited forms of epilepsy and migraine headache. Simon Kaja’s studies are aimed at understanding the impact of ataxia on certain neuronal pathways in the brain. Nerve cells (neurons) connect one area of the brain to another, via pathways, to send and receive information. Simon is comparing mutated pathways with their healthy counterparts to determine how the ataxia gene causes disruptions or blockages in brain cell communication necessary for normal movement. Ultimately, the goal is to help develop new, more effective treatments.
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The Effect of Chronic Exercise on Lymphatic Function in Breast Cancer Survivors with Lymphedema
A serious, chronic condition facing 28 per cent of women who have received treatment for breast cancer is breast cancer-related lymphedema (BCRL)—a painful swelling of the hand or arm. Typically resulting from the removal of a patient’s lymph nodes and/or radiation treatment, BCRL is characterized by an impaired lymphatic system, which is no longer able to properly drain fluid from tissues. In addition to pain, women with BCRL live with side effects such as restricted movement in the affected arm, increased risk of infection and reduced quality of life. Although exercise was initially believed to aggravate BCRL, current research suggests that exercise may actually help in reducing the severity of lymphedema and alleviating symptoms. MSFHR previously funded Kirstin Lane for her PhD research to develop a test that uses nuclear medicine in combination with exercise to measure lymphatic function in women with BCRL. Now, as an MSFHR Post Doctoral Fellow, Kirstin is applying this test to evaluate and compare lymphatic function in women with BCRL before and after a three-month program of supervised upper extremity exercises. The results of this research may confirm exercise as a safe, positive treatment option for BCRL. This information could be used to create exercise programs for preventing and treating the condition, thereby improving the health and quality of life for women living with BCRL.
The temporal regulation of neurogenesis during olfactory system development
Olfactory receptor neurons (ORNs) are the cells responsible for translating the odours in our external environment into the code that represents these smells in our brains. ORNs sense odours using receptors on their surface. These receptors bind the odour molecule by initiating a signalling process that results in information being transmitted to the appropriate part of the brain. Each ORN expresses only one type of receptor, and only a few out of thousands of other ORNs may express that receptor. This indicates that although all ORNs perform a similar function – sensing odours – each cell is unique. Since these cells are constantly exposed to the harsh external environment, they typically have a short life span. As a result, they are constantly replaced by new ORNS that are generated throughout life from undifferentiated cells. Thus, the olfactory system is the ideal model for understanding how an undifferentiated cell becomes a uniquely specialized neuron. Matt Larouche is seeking to define the time and place a particular ORN is produced since understanding these aspects may help explain what conditions are necessary for producing such a cell. This research will provide insight into how unique neurons are generated in the brain, and how to build specialized types of cells that can replace neurons lost due to injury. In the future, this information could be valuable for designing treatments for ailments that affect the nervous system, including strokes, paralysis and neurodegenerative diseases such as Multiple Sclerosis, Alzheimer’s or Parkinson’s diseases.
Mathematical modelling of axonal sprouting signalling
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.
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.