Neuromuscular Research Partnership

Neuromuscular Research Partnership

The Neuromuscular Research Partnership supports the following research projects (listed in alphabetical order by investigator surname).

Characterization of a novel function for PABPN1: the product of the oculopharyngeal muscular dystrophy disease gene


François Bachand, PhD
Université de Sherbrooke

Dr. François Bachand

Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset form of the disease that, while found worldwide, affects French Canadian and Jewish populations more frequently. Symptoms include drooping eyelids, difficulty swallowing, and limb weakness. The genetic mutation responsible for OPMD is known, but nothing is known about the underlying mechanism by which the mutation causes OPMD. Dr. Bachand and his team are investigating the function of the responsible gene, called PABPN1. Their work could address why OPMD is limited to specific muscles and open the way to new treatments.



Misfolding of Cu/Zn superoxide dismutase by pathological FUS and TDP43: relevance to ALS


Neil Cashman, PhD
University of British Columbia

Dr. Neil Cashman

While amyotrophic lateral sclerosis (ALS) can be caused by a variety of inherited gene mutations, the majority of cases occur sporadically. Dr. Cashman and his team believe that misfolding of copperzinc superoxide dismutase (SOD1), an enzyme that is an important antioxidant defense, may represent a common pathological pathway for both familial and sporadic ALS. They have already shown pathological TDP-43 and FUS are associated with SOD1 misfolding. Confirming a common molecular pathway in ALS that involves these proteins and the misfolded SOD1 will have important implications in the design of effective treatments in the future.



Differential role of myogenic regulatory factors in establishing muscle-specific gene expression


Jeffrey Dilworth, PhD
Ottawa Hospital Research Institute

Dr. Jeffrey Dilworth

Myogenin regulates gene expression and plays a critical role in deciding which genes to turn on in muscle cells. Dr. Dilworth is determining how this decision is made. His work will shed light on the developmental process that gives rise to muscle cells, including identifying cellular proteins that collaborate with myogenin. His work will contribute to the development of stem cell-based therapies for muscular dystrophy.



Rank/RankI/OPG: a new pathway that regulates skeletal muscle disuse, aging and disease


Jérôme Frenette, PhD
Université Laval

Dr. Jérôme Frenette

Nearly 65% of our body weight is made of bones and skeletal muscles. They control many important functions in the body, including movement, breathing, and the production of blood cells, but aging, injury, and neurodegenerative diseases can cause them to atrophy. Building on exciting advances in bone biology and disease, Dr. Frenette and his team want to bridge the physiopathology (the study of bodily disturbances caused by disease) of bones and muscles. Their early results indicate that a pathway that plays a role in bone homeostasis also features in muscle wasting and muscular diseases in some skeletal muscles, notably those essential for brief and powerful movements. Dr. Frenette and his team believe that this pathway, known as the Rank/RankL/OPG pathway, is an important actor in skeletal and possibly even cardiac diseases.



Molecular basis of ryanodine receptor regulation and function in skeletal and cardiac muscle


Anthony Gramolini, PhD
University of Toronto

Dr. Anthony Gramolini

Dr. Gramolini’s research is aimed at providing a detailed study of the mechanics of skeletal muscle function and the role played by calcium regulatory proteins in normal muscle function and skeletal muscle diseases. By understanding the ryanodine receptor (RyR) calcium release channel (which regulates the movement of calcium ions that are involved in muscle contraction and relaxation), Dr. Gramolini and his team hope to increase their knowledge of calcium release in muscle. That information could prove crucial to identifying new cellular targets for therapeutic intervention in RyR-based muscle diseases, such as central core disease and malignant hyperthermia.



Growth arrest and osteoporosis in Duchenne muscular dystrophy patients treated with glucocorticoids


Marc Grynpas, PhD
Mount Sinai Hospital, Toronto

Dr. Marc Grynpas

Children with Duchenne muscular dystrophy (DMD) are often treated with high-dose glucocorticoids, which substantially reduce mortality rates, but which also result in disordered bone health, potentially causing fractures, bone pain, and vertebral compression. While a number of factors contribute to poor bone health in children—such as nutrition, genetic factors, and growth—studies in adults are of limited use. Dr. Grynpas and his team believe that by understanding the cause of osteoporosis, growth arrest (an interruption of normal bone growth), and the signaling pathways in bone, they can develop an approach to prevent and treat disordered bone health in DMD, thereby alleviating the additional burden that it causes.



Post-transcriptional Regulation of Utrophin in Skeletal Muscle: Implications for new therapeutic strategies for Duchenne muscular dystrophy


Bernard Jasmin, PhD
University of Ottawa

Dr. Bernard Jasmin

Duchenne muscular dystrophy (DMD) is the most prevalent inherited neuromuscular disorder, but there is still no effective cure or treatment for the disease. Resulting in mutations or deletions in the X-linked (or male) dystrophin gene, DMD prevents the production of full-length dystrophin, the protein that is crucial to muscle function. One possible therapy is the use of utrophin, a protein similar to dystrophin that might compensate for the lack of the other protein. Building on his previous research on the subject, Dr. Jasmin seeks to decipher the mechanisms involved in controlling utrophin in normal and DMD muscle fibres, information that one day might form the basis for the design of pharmacological intervention that increases the expression of utrophin in DMD muscle fibres.



Magnetic resonance imaging biomarkers in ALS


Sanjay Kalra, PhD
University of Alberta

Dr. Sanjay Kalra

After decades of clinical trials, there is no therapy with a meaningful effect on survival in ALS. Despite an increasing understanding of the complex pathogenic mechanisms, an important barrier to finding treatment is the lack of a human biomarker—or indicator—of cerebral degeneration. A biomarker would play an essential role in the evaluation of novel drugs, reduce delays in diagnosis, and provide insight into the biological factors related to the variability in the effects of ALS. Using magnetic resonance imaging (MRI), Dr. Kalra and his team intend to assess different regions of the brain, which in turn will allow correlations to be made with patient behaviour. Ultimately, Dr. Kalra hopes to test the capacity of MRI biomarkers to predict the progression of the disease while validating the biomarkers at several different stages. These are essential steps towards developing successful treatments for ALS that will increase our understanding of this terrible and diverse disorder.



Folding and aggregation of ALS-associated mutant superoxide dismutases


Elizabeth Meiering, PhD
University of Waterloo

Dr. Elizabeth Meiering

ALS is the most common cause of neurological death each year in both Canada and the United States. The major known cause of ALS is mutations in a protein called superoxide dismutase (SOD). Dr. Meiering is examining whether mutations in SOD cause it to mis-fold, leading to the formation of toxic aggregates that, in turn, give rise to ALS. Her work will contribute to a better understanding of the mechanisms of ALS and help in the development of therapies for the disease.



Identifying novel roles of calcineurin signaling in the control of complementary pathways affecting the dystrophic phenotype


Robin Michel, PhD (Concordia University)
Bernard Jasmin, PhD (University of Ottawa)

Thanks to landmark studies performed by Drs. Michel and Jasmin and their teams, we know calcineurin, an enzyme that orchestrates muscle growth, has a significant effect on utrophin, a protein that can compensate for the lack of dystrophin (another protein) in dystrophic muscle fibres. Drs. Michel and Jasmin now intend to take the next logical step to further define the role of calcineurin in rescuing damaged dystrophic muscles and identify other novel players involved in this rescue. They believe these experiments will contribute to our understanding of the biochemical and molecular regulatory events that are involved in this disease, thereby providing potential therapeutic targets and strategies to reverse its damaging effects.



Artificial zinc finger transcription factors targeting the utrophin promoter as a potential therapy for Duchenne muscular dystrophy


Josephine Nalbantoglu, PhD
McGill University

Dr. Josephine Nalbantoglu

One possible avenue for treating Duchenne muscular dystrophy (DMD) is to increase the activity of a protein called utrophin (which is similar to the protein that is missing in people with the disease, called dystrophin) so that utrophin becomes present throughout the surface membrane of muscle fibres, instead of its normal, very restricted, localization. Dr. Nalbantoglu and her team have already developed a protein called an artificial transcription factor in mice to increase the amount of mouse utrophin. This project will use the same approach to design artificial transcription factors that target the human utrophin gene to increase its amounts. This approach could eventually be used to treat DMD.



Strategies for therapy of respiratory muscle failure in muscular dystrophy


Basil Petrof, PhD
The Research Institute of McGill University Health Center

Dr. Basil Petrof

Affecting approximately 1 in 3500 males, Duchenne muscular dystrophy (DMD) is the most frequent disorder linked to the X chromosome. Patients often die of respiratory failure as the disease progressively destroys muscle (such as the diaphragm and other respiratory muscles) and prevents normal muscle repair. Dr. Petrof and his team want to better understand the factors that regulate muscle damage and repair in DMD in order to identify new therapeutic strategies for the disease. By examining the role of the immune system in balancing muscle damage and repair, they hope to determine whether manipulating an individual’s innate immunity could provide a way of treating respiratory muscle failure that is caused by DMD.



Development of better and more effective treatment for patients affected by hyperkalemic periodic paralysis (HyperKPP)


Jean-Marc Renaud, PhD
University of Ottawa

Dr. Jean-Marc Renaud

Characterized by periods of uncontrolled muscle contractions in the limbs, hyperkalemic periodic paralysis (HyperKPP) can leave patients confined to bed for hours or even days. While these contractions and paralysis may cease after the age of 30, patients continue to suffer muscle weakness, making walking difficult or even impossible. Currently, none of the treatments for HyperKPP are fully effective, but Dr. Renaud hopes to document the mechanism of the disease in order to develop new and more effective therapeutic approaches.

“Our ultimate objective is to find a better treatment that would eliminate the HyperKPP symptoms and this constitutes the direct benefit of our research. At the same time, there are many other neuromuscular diseases that are related to defect in ion channels. Understanding the mechanisms of HyperKPP, will indirectly help understanding the mechanism of other Chanelopathies as well as helping find better treatment.”



Therapeutic properties of the innate immune response by microglia


Serge Rivest, PhD
Université Laval

Dr. Serge Rivest

Microglia are the main immune cells of the central nervous system. They accumulate in degenerating regions of the brain, producing a wide variety of inflammatory molecules that may have beneficial or detrimental effects. Dr. Rivest and his team are investigating whether these cells can be activated to create a kind of natural immunotherapy that more effectively clears pathogens, cell debris, and toxic substances that are produced in chronic disease. This research could lead to the development of new strategies to help repair the injured brain and, ultimately, to find cures for brain diseases such as ALS.



Genetic Regulation of Myogenesis


Michael Rudnicki, PhD
Ottawa Hospital Research Institute

Dr. Michael Rudnicki

Appearing in early childhood, Duchenne muscular dystrophy (DMD) is a devastating inherited muscular disorder that leads to progressive and debilitating muscle weakness and wasting, ultimately resulting in death. Dr. Rudnicki proposes to investigate the basis for the altered function of muscle stem cells in DMD. He is investigating whether muscle stem cells have undergone epigenetic changes, alterations in chromosomal structure caused by the disease environment that change the expression of genes involved in regulating stem cell function.

Dr. Rudnicki believes that such insight into the factors that contribute to the cause of DMD will lead to new modes of therapeutic intervention.



Satellite stem cells from skeletal muscle for the treatment of neuromuscular disease


Michael Rudnicki, PhD
Ottawa Hospital Research Institute

Dr. Michael Rudnicki

The growth and repair of skeletal muscle in adults is linked to a group of cells called “satellite cells” that associate with muscle fibres. Dr. Rudnicki and his team have not only discovered another group within that satellite cell grouping that they have named “satellite stem cells,” but they have also identified Wnt7a, a protein that stimulates activity in those stem cells. By investigating these satellite stem cells and their interaction with Wnt7a, Dr. Rudnicki hopes to gain information about how muscle stem cell function is controlled and how those cells contribute to the regeneration of skeletal muscle. Ultimately, this knowledge could open new avenues for the treatment of diseases such as muscular dystrophy.



Regeneration of motor neurons controlling movement and respiration from embryonic stem cells


Stephano Stifani, PhD
McGill University

Dr. Stephano Stifani

Recent progress in the field of regenerative medicine has highlighted the therapeutic potential of undifferentiated stem or progenitor cells in the replacement of neurons (nerve cells that are the core components of the nervous system) that have been lost as a result of injury or disease.

While this possibility is hindered by our lack of understanding of how specialized motor neurons are formed and become integrated into functional circuits—particularly those affected by motor neuron diseases like ALS—Dr. Stifani and his team want to study the mechanisms that control the development of these specific types of motor neurons. By arriving at a precise understanding of how particular motor neurons are generated and connected during development, Dr. Stifani hopes to facilitate the development of new strategies that promote motor neuron regeneration, replacing neurons that are lost or damaged by disorders such as ALS.



Regulation of motor neuron identity and circuit development


Stephano Stifani, PhD
McGill University

Dr. Stephano Stifani

Motor neurons are particularly vulnerable to degeneration in diseases such as ALS, but how are they generated and formed into functional motor circuits? Despite significant advances in stem cell-based regenerative therapies, we simply don’t know, and Dr. Stifani and his team want to change that. By studying a group of hindbrain motor neurons (part of the central nervous system) known as the hypoglossal nucleus, they want to characterize how these neurons control vital functions like chewing, swallowing, and breathing. Understanding how these motor neurons are generated and form connections will facilitate strategies that promote the regeneration of motor neurons in the affected area.



Correction of the dystrophin gene with Zinc Finger Proteins and TAL effector nuclease


Jacques Tremblay, PhD
Université Laval

Dr. Jacques Tremblay

Dr. Tremblay intends to develop a completely new therapeutic avenue for Duchenne muscular dystrophy (DMD) by targeting specific sequences in the dystrophin gene with engineered endonuclease proteins (enzymes that cleave the DNA chain). By using these specifically engineered endonucleases, Dr. Tremblay believes that the reading frame (i.e., groups of 3 nucleotides that code for one amino acid) of the dystrophin gene can be corrected, thus restoring dystrophin expression, which is lacking in patients with DMD. The objective of the project is to inject these meganucleases—fused with a cell-penetrating peptide—into the blood of DMD patients so that the proteins can enter in the muscle fibers and potentially correct the dystrophin gene. In time, genetic corrections like this may also be eventually used to treat other neuromuscular diseases.

“My research program aims to develop a cell therapy for recessive muscular dystrophies. The cell therapy that we are trying to develop will not only permit to introduce the normal gene in the muscle fibers of patients with various recessive muscular dystrophies but will also introduce in the muscles new muscle precursor cells that will increase its regenerative capacity.”



Studies on the molecular pathogenesis of amyotrophic lateral sclerosis (ALS)


Hiroshi Tsuda, PhD
Montreal Neurological Institute

Dr. Hiroshi Tsuda

ALS is a neurodegenerative disorder caused by the progressive loss of motor neuron function in the brain and spinal cord. As a result, patients with ALS will lose the ability to stand, walk, or use their hands and arms, and will eventually suffer respiratory failure. While there is no primary therapy for ALS, Dr. Tsuda will study Drosophila, or fruit flies, in order to better understand what events at the molecular level lead to the onset of ALS. By doing so, Dr. Tsuda hopes to gain insight into ALS that could lead to a more effective treatment of the disease.



Molecular mechanisms regulating myotubularin-related 2 lipid phosphatases mutated in neuromuscular disorder Charcot-Marie-Tooth disease


Panayiotis Vacratsis, PhD
University of Windsor

Dr. Panayiotis Vacratsis

Charcot-Marie-Tooth (CMT) disease is a common group of disorders of the peripheral nervous system that is characterized by demyelination (where the myelin sheath of neurons is disrupted), resulting in the progressive decrease of muscle tissue and touch sensation across parts of the body. The gene encoding MTMR2 (part of the MTM family of enzymes) is mutated in a certain aggressive form of Charcot-Marie-Tooth disease (CMT4B). Dr. Vacratsis’ research group wants to ultimately understand why the loss of a functional MTMR2 enzyme causes CMT. Moreover, a detailed understanding of MTMR2 biology will provide the necessary framework to identify and subsequently develop novel therapeutic strategies for CMT disease.



Cell biological mechanisms of TDP-43 in ALS


Christine Vande Velde, PhD
University of Montréal

Dr. Christine Vande Velde

Nearly 3,000 Canadians live with amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease that attacks motor neurons, and there is no treatment that will appreciably slow or treat the disease. Efforts to design therapies are hampered by our lack of understanding of the pathogenesis of the disease (the mechanism by which it is caused), but a DNA binding protein known as TDP-43, has emerged as a player in the mutations that cause some forms of ALS. TDP-43 regulates stress response in cells through stress granules (aggregations of protein and RNA that appear when a cell is under stress), a process that is affected by disease-causing mutations, making motor neurons vulnerable. Dr. Vande Velde and her team intend to further our understanding of TDP-43 by examining how it interacts with stress granules in the hope of identifying new targets for future therapeutic development.

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