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National
Brain Repair Program
Mission
The mission of NeuroScience Canada’s Brain Repair Program™ is to accelerate “transformative” research to discovery and to the development of new treatments and therapies for neurological and psychiatric diseases and disorders. We achieve this by funding teams of investigators from various disciplines and institutions that have the best chance of producing rapid progress in repairing the brain.
Brain Repair
Brain Repair is a new field of interdisciplinary, collaborative research aimed at exploring the brain’s ability to be repaired, or to repair itself. This field of research is relevant not only to neurological conditions such as stroke, Alzheimer’s and Parkinson’s disease, but also to mental illness and addiction, the latter increasingly recognized as resulting from chemical and molecular imbalances in the brain that may be amenable to repair strategies.
Escalating knowledge and new technologies across disciplines are identifying common mechanisms regulating processes for repair, restructuring, remodelling and recovery of brain function. The challenge is to coordinate the strands of new knowledge and translate them into repair and recovery strategies that could be applicable to many diseases and disorders of the brain and nervous system.
First Brain Repair Program competition
In November 2003, NeuroScience Canada launched the Brain Repair Program with the goal of fast-tracking excellent and innovative brain repair research. In 2004, three teams of researchers were awarded $1.5 million over three years, plus up to an additional $20,000 per year for networking activities. Their research covers the range of neurological and psychiatric disorders, as well as spinal cord injury and chronic pain.
The three teams from the first Brain Repair Program competition have now completed their three-year grants. Funding from NeuroScience Canada has enabled them to make a number of key breakthroughs:
Novel approaches to central nervous system white matter repair
Findings
Stem cells are an exciting new source of cells to repair the injured brain and nervous system. The team found that stem cells isolated from the dermis, the layer of skin under the epidermis, can generate nervous system cells that when placed into mice with a spinal cord injury, will restore limb function and movement. The next phase of the project will be to test whether human skin cells can repair the acute and chronically injured spinal cord in animals, the final step prior to clinical trials.
Impact
Stem cells from skin can be readily isolated, and these cells from a person with a spinal cord injury will not be rejected as would cells from other people. Skin stem cells are therefore an exciting and promising novel source of accessible cells for the treatment of nerve injuries.
Team
Team leader: Dr. Freda Miller, University of Toronto
Members: Dr. David Kaplan, University of Toronto; Dr. Wolfram Tetzlaff, University of British Columbia; Dr. Samuel Weiss, University of Calgary
Publications
September 5, 2007 Journal of Neuroscience –
Skin-Derived Precursors Generate Myelinating Schwann Cells That Promote Remyelination and Functional Recovery after Contusion Spinal Cord Injury
June 14, 2006 Journal of Neuroscience –
SKPs generate myelinating Schwann cells for the injured and dysmyelinated nervous system
December 8, 2005 Neuron –
P63 Is an Essential Proapoptotic Protein during Neural Development
Transforming research on chronic pain
November 16, 2008
NeuroScience Canada researchers discover novel therapy for chronic pain
Findings
Imagine being unable to wear a shirt or to allow a gentle breeze to blow across your face because these harmless stimuli cause you excruciating pain. This is the type of situation that the millions of individuals worldwide try to live with every day. This is neuropathic pain -- the most debilitating of all pain states. Neuropathic pain often arises from injury to a nerve in the body or may complicate a wide variety of conditions, such as cancer, AIDS and diabetes. This type of pain is nearly always resistant to known treatments, even strong narcotics. This team has made a major step forward by establishing that malfunctioning in the spinal cord causes neuropathic pain. They discovered that a type of cell in the spinal cord – the microglia – previously thought to be only involved in responses to viral or bacterial infections become activated after injury to nerves in the body. These activated microglia emit chemical signals that stimulate nerve cells in spinal cord pain pathways and cause them to send messages to the brain even if the skin is only harmlessly stimulated. The brain then interprets these messages as pain not harmless stimulation.
Impact
The team discovered cell types, molecules and genes involved in neuropathic pain. This new knowledge will lead to a range of advances not only in treatment but also in the diagnosis of neuropathic pain in those suffering.
Team
Team leader: Dr. Michael W. Salter, University of Toronto
Members: Dr. Karen D. Davis, University of Toronto; Dr. Yves De Koninck, Université Laval; Dr. Jeffrey Mogil, McGill University; Dr. Min Zhuo, University of Toronto
Publications
September 27, 2007 Molecular Pain -
Transformation of the output of spinal lamina I neurons after nerve injury and microglia stimulation underlying neuropathic pain
November 15, 2006 Pain -
Spinal microglia and neuropathic pain in young rats
December 15, 2005 Nature -
BDNF from Microglia Causes the Shift in Neuronal Anion Gradient Underlying Neuropathic Pain
Novel therapeutic strategies to repair brain abnormalities in psychiatric disorders
Findings
Communication between brain cells is essential for normal brain function. Disruption of this process has been proposed as the root cause of many psychiatric disorders including addiction, schizophrenia, autism and mental retardation. Most of the current drug therapies for these disorders work in an unspecific manner, repairing the communication in the whole brain. While lessening symptoms, they often lead to a host of negative side effects. This team completed a Proof of Principle study for developing a novel method for treating these disorders, whereby drugs can target the specific processes in brain cells in need of repair, and restore the normal brain function, with no obvious negative side effects.
Impact
Results from this investigation can lead to the development of drugs that have no side effects, thereby giving a better quality of life to patients affected by neurological and psychiatric disorders such as addiction, Alzheimer’s disease, autism, mental retardation and schizophrenia.
Team
Team leader: Dr. Yu Tian Wang, University of British Columbia
Members: Dr. Stephen S.G. Ferguson, University of Western Ontario; Dr. Alaa El-Husseini, University of British Columbia; Dr. Ridha Joober, McGill University; Dr. Anthony G. Phillips, University of British Columbia
Publications
June 25, 2007 Nature NeuroScience -
Hippocampal long-term depression mediates acute stress-induced spatial memory retrieval impairment
February 16, 2006 Neuron –
A Preformed Complex of Postsynaptic Proteins Is Involved in Excitatory Synapse Development
November 25, 2005 Science –
Nucleus Accumbens Long-Term Depression and the Expression of Behavioral Sensitization
Second Brain Repair Program competition
Thanks to the generosity of the T. Robert Beamish family, which made a $1.5-million commitment through the WB Family Foundation, NeuroScience Canada was able to launch the second Brain Repair Program competition in 2006. Through this process, two additional teams were selected for funding in June 2007.
Mitochondrial dysfunction and neuronal demise: Insights provided by Parkinson’s disease genes
Mitochondrial dysfunction and neuronal demise: Insights provided by Parkinson’s disease genes
This research project, led by Dr. Louis-Eric Trudeau from Université de Montréal, focuses on Parkinson’s disease. In Parkinson’s, brain cells called neurons containing the neurotransmitter dopamine degenerate, leading to a dramatic and irreversible perturbation of the function of brain systems involved in motor control. Although the causes of this disease are not yet completely understood, the last few years have witnessed the discovery of a number of genetic dysfunctions leading to the production of abnormal proteins in the brain of affected individuals.
The goal of Dr. Trudeau and his team is to attempt to explain why these genetic perturbations lead to the death of dopamine-containing neurons. The major lead followed by this team, is that all of these abnormal proteins end up, one way or another, affecting tiny but abundant organelles called mitochondria, found inside neurons. Dysfunction of these mitochondria would then lead to perturbations of neuronal physiology and to the generation of cell death signals. Similar signals are thought to be activated in other neurodegenerative diseases. To tackle this challenging objective, the team unites two investigators that are specialized in the molecular biology of neurodegenerative diseases (Dr. Edward Fon, Montreal Neurological Institute; and Dr. David S. Park, University of Ottawa), one investigator specialized in the genetics of neuronal development (Dr. Yong Rao, Centre for Research in Neuroscience, McGill University Health Center), one mitochondria scientist (Dr. Heidi McBride, Ottawa Heart Research Institute) and one expert in the physiology of dopamine neurons (Dr. Louis-Eric Trudeau, Université de Montréal).
This multidisciplinary team of scientists will combine their efforts with the objective of identifying mechanisms that will become novel targets for the development of new treatments for Parkinson’s disease, but also for a number of other degenerative diseases including Alzheimer’s and stroke that also implicate the abnormal demise of neurons in the brain.
During the first year of their grant, the team will tackle a number of objectives aimed at evaluating the impact of various Parkinson’s disease gene mutations on the function of intracellular organelles called mitochondria, and on the function of neurons, and in particular, dopamine-secreting neurons in the brain. The team will focus its initial efforts on the LRRK2, DJ-1, Pink1 and Parkin genes. Experiments will be performed in mouse neurons as well as in the fly. Drs. Yong and Park will develop new approaches to knockdown the function of these genes in the fly and develop behavioural assays to monitor the functional impact. Drs. Park and McBride will expand on their recent efforts to develop approaches to monitor multiple readouts of mitochondrial function. Drs. Fon, Trudeau and Schlossmacher will concentrate their initial efforts on the Parkin gene and will evaluate the impact of its gene deletion on mitochondrial function and dopamine neuron physiology as well as study the proteins that it interacts with and the regulation of its expression. These studies should lead to major progress in our understanding of the causes of brain damage in the context of Parkinson’s disease and other neurodegenerative disorders.
Second Year Progress
The most important fndings by the team are those showing that alterations in the Parkin and DJ-1 familial Parkinson’s genes change the shape and structure of mitochondria. Since the shape and internal structure is important for energy generation by mitochondria, the team will next determine how mutations and changes in Parkin and DJ-1 that occur in families alter how mitochondria function. They also found that mutations in Parkin affect the ability of nerve cells to secrete dopamine. A second important result, published in the prestigious journal Proceedings of the National Academy of Sciences, showed that the Pink1 gene is required for the survival of nerve cells in the brain. Finally, the team is identifying proteins in the body’s cells that regulate how Parkin, DJ-1, and Pink1 function, as a frst step towards identifying novel drugs for the treatment of Parkinson’s.
Harnessing beneficial aspects of neuroinflammation for regenerating the central nervous system
This research project focuses on the immune system, which is comprised of two major components, the innate and adaptive systems. Innate immunity is the first immune component to sense and respond to an injury. Indeed, a well-regulated innate immune response is a normal physiological process that is essential for functions such as wound healing and defense against foreign substances. Within the central nervous system (CNS), microglia are the resident cell population belonging to the innate immune system. Under conditions of CNS injury, another innate immune cell type, the macrophage, accesses the brain and spinal cord. The initial emphasis was on the role that such activated innate immune cells play in promoting the disease process in conditions such as stroke, multiple sclerosis and spinal cord injury. Only more recently is there attention on the contribution of the innate immune system in improving the well being of the CNS. Indeed, this research team postulates that a well-regulated immune reactivity in the CNS can enable repair of the nervous system.
This research project, led by Dr. V. Wee Yong from the University of Calgary, is composed of: Dr. Luanne Metz, University of Calgary; Dr. Christopher Power, University of Alberta; Dr. Peter Stys, University of Calgary; Dr. Fiona Costello, University of Calgary; and Dr. Serge Rivest, Université Laval. They seek to define the conditions under which physiologic neuroinflammation enables recovery, and to harness the beneficial aspects of innate neuroinflammation to allow the regeneration of the CNS from insults. This approach is transformational, as it promises to deliver new means to enabling CNS regeneration. These experiments are relevant to promoting recovery from several neurological disorders, including stroke, multiple sclerosis, spinal cord injury, and Alzheimer’s disease.
During the first year of their grant, the team will seek to fine-tune the inflammatory response so that the detrimental aspects of inflammation on the nervous system can be inhibited; at the same time, it is hoped that the beneficial sides of inflammation and their positive effects on the nervous system can be promoted. In Year 1, the collaboration between the laboratories of Drs. Power, Rivest and Yong will generate different subsets of inflammatory cells and these will be tested on neurons in culture and in a slice preparation of the spinal cord through collaboration with Dr. Stys. Whether inflammatory cells ultimately injure axons through a phenomenon referred to as excitotoxicity will be investigated. These experiments address the role of particular immune subsets on neural integrity and they seek neuroprotective strategies to prevent harm to neurons and nerves. To extend from these nerve studies, the clinical team of Drs. Costello and Metz will study patients with inflammation of the optic nerve using an ophthalmologic device, optical coherence tomography (OCT).
Year 1 will involve setting up the OCT unit and getting staff trained. Moreover, Drs. Costello and Metz will initiate the longitudinal follow-up of multiple sclerosis (MS) patients in a study that will last years, in order to define the relationship between optic nerve inflammation, loss of nerve fibers, and possible recovery. These clinical studies will set the background to plan trials not only for neuroprotection but also for repair, since a third component of Dr. Yong’s team is to enhance remyelination (repair of myelin) in models of demyelination. In this regard, Year 1 will also see the initiation of collaboration between Drs. Stys, Rivest, Power and Yong on repair strategies. Of note is that the beneficial properties of a normally functioning immune system will be tapped to foster repair. Overall, and given the increasing recognition that inflammation plays a vital role in injury and recovery, the experiments are relevant not only to inflammatory processes such as MS and stroke, but also in normal aging.
Second Year Progress
Dr. Yong and his team have identifed new agents that protect the brain from injury, particularly that of ultraviolet radiation and Vitamin D (Sloka et al., submitted). They have found a very close correlation between the amount of ultraviolet radiation incident upon areas of the earth, and the reduced risk for multiple sclerosis. Of particular interest is their discovery that Vitamin D prevents harmful cells of the immune system called T lymphocytes from destroying nerve cells. They also found that benefcial cells of the immune system regulatory called T cell (Treg) can protect the brains of mice from injury caused by infammatory insults if the mice had been exposed during early life to a bacterial pathogen (Ellestad et al., J Immunol, in press). Moreover, in the context of spinal cord injury in mice, they have determined that yet another infammatory cell type called neutrophils, plays helpful roles in coordinating benefcial growth factor responses within the injured tissue (Stirling et al., 2009). In a second line of research, they have pursued several approaches to foster the repair of myelin, the insulation of nerve cells that is damaged in MS which causes the symptoms of the disease. They have identifed drugs that cause activation of microglia, the "scavenger" cells in the brain necessary to remove the debris that accumulates upon injury before repair can occur. Future experiments will determine if these drugs will repair the injured mouse spinal cord, and if so, commence a human clinical trial with these drugs already approved for use in people. Another series of experiments to harness the benefts of infammation has involved a mouse model of Alzheimer’s disease. These mice overexpress the Aß protein that is then deposited in the brain to produce neuropathological wwAlzheimer’s disease. The treatment of these mice with macrophage colony stimulating factor (MCSF), which results in the recruitment of microglia in the brain to clear the toxic Aß deposits, ameliorates neuropathology and behavioral changes (Boissonneault et al., 2009). Finally, their clinical research continues to proceed well. They have found a new way to evaluate the extent of disease in MS, using an eye exam to measure changes in the nerve cells in the eye. They are enrolling patients in a study to evaluate whether this exam can be used in clinical trials to evaluate new treatments for MS.