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Brain Repair Program
Mission of the Brain Repair Program
The mission of NeuroScience Canada’s Brain Repair Program™ was to accelerate “transformative” research to discovery and to the development of new treatments and therapies for neurological and psychiatric diseases and disorders. We achieved this by funding teams of investigators from various disciplines and institutions that had 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
Converging research efforts have recently identified five genes that are associated with familial Parkinson’s Disease (PD), a condition associated with severe motor dysfunction and loss of dopamine-producing cells in the brain. These genes include α-synuclein, Parkin, DJ-1, Pink1, LRRK2. It is striking that all of them have been linked directly or indirectly with the function of mitochondria, small ubiquitous intracellular organelles found in all cells. A research group, led by Dr. Louis-Eric Trudeau from the Université de Montréal and including researchers from McGill University (Dr. Ted Fon, Dr Yong Rao) and from the University of Ottawa (Dr. David Park, Dr. Heidi McBride and Dr. Michael Schlossmacher) undertook collaborative projects to systematically examine PD genes and their control of mitochondrial function and neuronal physiology and survival.
The team focused their attention on the impact of LRRK2, DJ-1, Pink1 and Parkin gene mutations on the function of mitochondria and on the function of neurons, and, in particular dopamine-secreting neurons in the brain. Experiments were performed in mouse neurons as well as in the fly, Drosophila, a unique and powerful model system. Drs. Yong and Park have been developing new approaches to knockdown the function of these genes in the fly and developing behavioural assays to monitor the functional impact. Drs. Park and McBride have been expanding on their recent efforts to develop approaches to monitor multiple readouts of mitochondrial function. Drs. Fon, Trudeau and Schlossmacher have been concentrating their initial efforts on the Parkin gene and are evaluating the impact of its gene deletion on mitochondrial function and dopamine neuron physiology as well as studying the proteins that it interacts with and the regulation of its expression. These studies have led to exciting observations, many of which have now been published in international journals, with many other publications to come during the upcoming year.
After three years of fruitful collaboration, the group has achieved great progress in its objectives to evaluate the impact of LRRK2, DJ-1, Pink1 and Parkin genes mutations on the function of mitochondria and on the function of neurons and in particular dopamine-secreting cells of the brain.
Publications
The Journal of Neuroscience, December 15, 2010
Neuronal Apoptosis Induced by Endoplasmic Reticulum Stress Is Regulated by ATF4–CHOP-Mediated Induction of
the Bcl-2 Homology 3-Only Member PUMA
Human Molecular Genetics, July 2010, Vol. 19
Loss of the Parkinson’s disease-linked gene DJ-1 perturbs mitochondrial dynamics
Nature Cell Biology, Volume 12 | Number 6 | June 2010 -
The role of Cdk5-mediated apurinic/apyrimidinic endonuclease 1 phosphorylation in neuronal death
Harnessing beneficial aspects of neuroinflammation for regenerating the central nervous system
This research project, led by Dr. V. Wee Yong from the University of Calgary, focused 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 postulated that a well-regulated immune reactivity in the CNS can enable repair of the nervous system.
This research team 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 sought 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.
Dr. Yong and his team have made significant progress. Using worldwide MS prevalence data and assessing 11 risk factors, they have found that the lack of ultraviolet B radiation (and the corresponding deficiency of vitamin D) is the single most important risk factor for the development of MS.
They have extended the knowledge of the immunologic mechanisms by which vitamin D improves wellbeing in MS and have uncovered new insights into vitamin D: that vitamin D is a protective agent against injury to axons and neurons
The team has also uncovered potential new medications for MS and other neurological conditions: crocin, dipyridamole and atipamezole. The last is very interesting because it uniquely acts on neurons to increase their defense mechanisms, even when there is widespread inflammation
In human MS patients, measurements of the optic nerve using optical coherence tomography (OCT) provide evidence for the continued loss of axons in MS, and that the rate differs across the subgroups of MS. Dr. Yong’s team are now enrolling MS patients for a pilot trial of neuroprotection by minocycline in MS using the optic nerve and OCT as models.
The team has also continued to refine the discovery that amphotericin B, an anti-fungal agent, activates microglia/macrophage, and that amphotericin B can be used safely in mice to promote recovery from a demyelinating injury. This could represent a new means to promote repair from demyelinating conditions in humans. By stimulating microglia with M-CSF, they have found that this promotes clearance of Aβ toxic deposits in the brain of mice with Alzheimer disease pathology. Remarkably, once weekly M-CSF treatment is effective in halting progression of Alzheimer symptoms in mice, even when treatment is initiated late in disease when amyloid plaques are already well entrenched
Dr. Hubert van Tol Travel Fellowship
The neuroscience community lost a brilliant scientist when Dr. Hubert van Tol died suddenly in a bicycle accident on April 20, 2006. Dr. van Tol was an internationally recognized and respected neuroscientist who received numerous awards and greatly advanced the entire field of molecular neurobiology. To honour him, his family set up the Dr. Hubert van Tol Fund at NeuroScience Canada, through which the Dr. Hubert van Tol Travel Fellowship was established. The fund has received more than $30,000 in donations since it was established. The fellowship enables PhD students and postdoctoral fellows performing research as part of a Brain Repair Program team to attend major international conferences, symposia or training courses outside of Canada. This is consistent with Dr. van Tol’s belief in the importance of international experiences. A list of the recipients can be found under the Award recipients section.