Current Grants


E-Rare 2013
Neuromuscular Research Partnership

 

 

Results of the 2013 E-Rare competition

After a competitive scientific evaluation by peers, the E-Rare funding bodies recommended for funding 12 excellent scientific projects, 6 of which have a Canadian component. The funded projects cover a wide range of rare diseases including neuromuscular disorders.
Read about all the projects.

Muscular Dystrophy Canada is pleased to be contributing over $380,000 towards the 2 Canadian teams that are focused on neuromuscular research.

An international effort to understand FSHD muscular dystrophy epigenetics

Project Coordinator

Davide Gabellini

Ospedale San Raffaele

Milan, Italy

Partners

F. Jeffrey Dilworth

Ottawa Hospital Research Institute

Ottawa, Canada

Evi Soutoglou

Centre Européen de Recherche en Biologie et en Médecine (CERBM-IGBMC)

Illkrich, France

Project Description

Despite the fact they constitute two thirds of the human genome, repetitive sequences are largely ignored. FSHD is an autosomal dominant disorder with a strong epigenetic component. Unlike the majority of genetic diseases, FSHD is not caused by mutation in a protein-coding gene. Instead, the disease is associated with a reduced copy number of the D4Z4 macrosatellite repeat mapping to 4q35. Despite years of intensive research, the molecular pathogenesis of FSHD remains largely unknown. We recently identified DBE-T, a chromatin-associated lncRNA produced preferentially in FSHD patients. DBE-T mediates a Polycomb to Trithorax epigenetic switch at the FSHD locus, driving chromatin remodeling and de-repression of 4q35 protein-coding genes in FSHD patients. In FSHD, up-regulation of multiple 4q35 candidate genes has been reported. Based on this, it has been suggested that FSHD could be considered a continuous gene disease in which the epigenetic alteration of multiple genes contributes to the final outcome. Since DBE-T behaves as a master regulator of the FSHD locus being required to activate all FSHD candidate genes, it is a very intriguing candidate to develop therapeutic approaches aimed at normalizing 4q35 gene expression in FSHD patients. Nevertheless, DBE-T mechanism of action is poorly understood. Here we propose to tackle these issues by addressing the following questions: – Is DBE-T responsible for the enhanced disease penetrance of FSHD in muscle? – How is DBE-T tethered to chromatin? – How does DBE-T activate FSHD candidate genes?


Stimulating Intrinsic Repair for DMD

Project Coordinator

Michael Rudnicki

Ottawa Hospital Research Institute

Ottawa, Canada

Partners

Pura Muñoz-Cánoves

UPF (Universitat Pompeu Fabra), Ciències Experimentals i de la Salut (CEXS)

Barcelona, Spain

Gillian Butler-Browne

Institut de Myologie, INSERM U974

Paris, France

Project description

Duchenne Muscular Dystrophy (DMD) is a rare and devastating genetic disease of childhood manifested by progressive debilitating skeletal muscle weakness and wasting, and ultimately death. The Rudnicki group recently identified a role for Wnt7a/Fzd7 signaling in stimulating the regeneration of muscle by acting at two levels. Wnt7a acts on satellite stem cells to drive their symmetric expansion, and also acts on myofibers to stimulate hypertrophy. Delivery of Wnt7a significantly ameliorated dystrophic changes in the mdx mouse model of DMD. The research team represents an outstanding multidisciplinary group of investigators, who are uniquely positioned to conduct the proposed basic and preclinical studies. The overall goal of the project is to assess the utility of Wnt7a and its variants as protein therapeutics for the stimulation of intrinsic regeneration for the treatment of DMD. We propose to characterize the effects of whole body treatment in mdx mice using transgenesis as well as systemic delivery of Wnt7a. We will characterize the Wnt7a/Fzd7 signaling pathway at the molecular level and identify downstream target genes to elucidate mode of action. We will investigate the basis for the suppression of the inflammatory response by Wnt7a. Finally, we will assess the activity of Wnt7a on human satellite cells and myofibers in mice carrying humanized DMD muscle. These experiments will advance our knowledge of Wnt7a signaling in muscle and illuminate the therapeutic potential of Wnt7a as a protein biologic to stimulate intrinsic repair in a muscle-wasting disease like DMD.

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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

(2010-2015)

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

(2012-2015)

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

(2010-2015)

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

(2012-2015)

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

(2012-2015)

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

(2012-2017)

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.

 


 

Role of Xin, an actin-binding protein, in satellite cells and muscular dystrophies

(2011-2014)

Thomas Hawke, PhD
McMaster University

Dr. Thomas Hawke

Mutations to many of the proteins that compose the structure of muscle cells lead to the development of diseases such as the muscular dystrophies. These proteins, however, are part of a larger network containing other proteins whose roles are less understood. Dr. Hawke’s lab has already demonstrated that one of these poorly-understood proteins, Xin, plays a vital role in maintaining muscle stem cell function during the regenerative process that repairs muscles. Now they want not only to uncover the roles of Xin within skeletal muscle and how it is regulated, but to determine how Xin appears in human dystrophic muscles. By doing so, they hope to link Xin to the variability in the onset, progression, and severity of dystrophic conditions in order to discover new information about how muscle stem cells are regulated, and perhaps even identify a new form of muscular dystrophy.

 


 

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

(2012-2017)

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.

 


 

Promoting protection of functionally intact motor units in amyotrophic lateral sclerosis (ALS)

(2010-2013)

Kelvin Jones, PhD
University of Alberta

Dr. Kelvin Jones

Amyotrophic lateral sclerosis attacks the motor neurons essential for movement. Dr. Jones and his team have discovered that motor neurons connected to fast twitch muscle are especially vulnerable to the disease, while those connected to slow twitch muscle have some resistance.

They have developed three promising interventions to change fast twitch muscle into its slow twitch counterpart in order to enhance the survival of motor neurons. The team is now examining molecular mechanisms that are involved in all three interventions to find out what genes and proteins are ultimately responsible for this protective effect. The research could result in exercise recommendations and new treatments for people with ALS.

 


 

Pathogenic mechanisms associated with neurofilament disorganization

(2010-2013)

Jean-Pierre Julien, PhD
Université Laval

Dr. Jean-Pierre Julien

Abnormal accumulations of a family of proteins called intermediate filaments are a hallmark of many neurodegenerative disorders, including peripheral neuropathies and ALS. Dr. Julien and his team are studying the exact molecular mechanisms that underlie the toxicity of disorganized neuronal intermediate filaments. Their research could lead to a better understanding of the development and progression of ALS.

 


 

Magnetic resonance imaging biomarkers in ALS

(2012-2017)

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.

 


 

Bone marrow-derived cells as gene therapy vehicles in amyotrophic lateral sclerosis (ALS)

(2009-2014)

Charles Krieger, PhD
Simon Fraser University

Dr. Charles Krieger

Dr. Krieger and his team will explore the use of bone marrow-derived cells as a delivery mechanism in ALS. Previous work has shown that bone marrow cells enter the brain and spinal cord in an animal model of ALS, and cells can be engineered to enter the central nervous system to produce substances that can prevent neuron death and slow the progression of the disease. It is anticipated that these bone marrow cells can be used as delivery vehicles that could aid in the survival of sick or dying cells in the nervous system of patients with ALS.

 


 

Glia-neuron crosstalk in early amyotrophic lateral sclerosis pathogenesis

(2011-2014)

Jasna Kriz, PhD
Université Laval

Dr. Jasna Kriz

While we understand some of the advanced stages of ALS, little is known about how the immune system and central nervous system interact in the early stages of the disease. Dr. Kriz, however, believes that incorrect responses from glial cells (cells that support and protect the brain’s neurons, which are responsible for sending electrical and chemical signals throughout the body) may lead to ALS. By studying this “crosstalk” and developing a model for analyzing the effectiveness of drugs that attempt to treat glial cells in the immune system, Dr. Kriz hopes that new therapeutic strategies for ALS will be developed.

 


 

Determination of muscle properties that alter ALS onset and disease progression using the G93A mouse model of ALS

(2009-2014)

Blair Leavitt, PhD
University of British Columbia

Dr. Blair Leavitt

Much progress has been made in understanding the disease mechanisms underlying the inherited form of ALS. Mounting evidence from numerous studies suggests that ALS is actually a multisystemic disorder, and disease progression is influenced by cells other than motor neurons. This study aims to determine the skeletal muscle properties important for modulating ALS disease progression and may lead to the development of effective muscle-based therapies for ALS.

 


 

Preclinical assessment of clinic-ready agents for the treatment of muscular dystrophy and spinal muscular atrophy

(2011-2014)

Alexander E. Mackenize, PhD
Children’s Hospital of Eastern Ontario — Ottawa

Dr. Alexander Mackenzie

Although the identification of genetic causes for inherited diseases like neuromuscular disorders has greatly improved our ability to identify and understand them, treatment options remain slim or non-existent. Dr. Mackenzie and his team propose to address this issue by screening a library of FDA-approved drugs in order to identify compounds that have the potential to treat spinal muscular atrophy (SMA) and myotonic dystrophy Type 1 (DM1). Since these drugs are already approved for clinical use in the treatment of other diseases, they hope that the most promising drugs can be quickly approved for use in the treatment of SMA and DM1.

*Generously funded by the Ilsa Mae Research Fund

 


 

Motor, multisystemic and social participation assessment in myotonic dystrophy type 1, a 9-year longitudinal study

(2010-2013)

Jean Mathieu, PhD (Université de Sherbrooke)
Cynthia Gagnon, PhD (Université de Sherbrooke)

Myotonic dystrophy is the most common adult form of muscular dystrophy, but little is known about its natural progression. Drs. Mathieu and Gagnon are taking a holistic approach to understanding the disease, looking not only at impairment and disability, but at their impact on social participation and quality of life. Their work will lead to a better understanding of the natural history of myotonic dystrophy and highlight major determinants of social participation, well-being, and quality of life for patients and their families. It also will help identify comprehensive disease management strategies and improve physicians’ prognostic abilities.

Dr. Jean Mathieu

Dr. Cynthia Gagnon

 


 

Folding and aggregation of ALS-associated mutant superoxide dismutases

(2010-2015)

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

(2012-2015)

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.

 


 

Role of calcineurin and its signalling modulators in dystrophic phenotype

(2011-2014)

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

The signature feature of muscular dystrophy is the absence of dystrophin, a key muscle fibre membrane protein, and one of the most promising strategies for countering muscular dystrophy is to replace that missing dystrophin with a similar protein called utrophin. Drs. Michel and Jasmin have found that utrophin is under the control of calcineurin, an enzyme that orchestrates muscle growth. In fact, when calcineurin is “turned on” within a muscle fibre, utrophin appears in abundance, offering the potential of rescuing fibres that are damaged by muscular dystrophy. Drs. Michel and Jasmin hope to further define the role of this enzyme in order to develop better strategies and interventions for reversing the damage caused by muscular dystrophy.

Dr. Robin Michael

Dr. Bernard Jasmin

 


 

Mouse models of Kennedy disease/spinobulbar muscular atrophy

(2011-2014)

Ashley Monks, PhD
University of Toronto

Dr. Ashley Monks

Kennedy disease, also known as spinobulbar muscular atrophy, is a neurodegenerative disease that leads to progressive muscular atrophy and weakness in affected men. While there is currently no cure, some progress has been made in tracking the cause of the disease, including the identification of mutations in the androgen receptor (AR) gene (which is crucial to the development and maintenance of the male sexual phenotype). This mutation causes abnormally long polyglutamine (polyQ) tracts that can both reduce AR function and cause it to gain harmful features. Using mice that have been developed to express this mutation, Dr. Monks will perform biochemical, anatomical, histological (the study of anatomy of cells and tissue), and behavioural tests in order to better understand which cells are affected by Kennedy disease and how that occurs, an invaluable step towards developing strategies for treating the disease.

 


 

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

(2010-2015)

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

(2011-2016)

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.

 


 

Developing specific motoneuron subtypes from embryonic stem cells, and induced pluripotent stem cells, to treat neuromuscular disorders and paralysis due to injury

(2010-2013)

Victor Rafuse, PhD
Dalhousie University

Dr. Victor Rafuse

Due to the loss of motor neurons (or motoneurons), nerve cells that control muscle movement, people with ALS gradually lose movement until they become paralyzed or are unable to control rhythmic movements such as breathing. While these motor neurons cannot regenerate themselves, Dr. Rafuse is working to develop a treatment that will transplant healthy motor neurons derived from embryonic stem cells into patients with ALS in order to restore muscle function. He is also examining whether specific classes of motoneurons can be generated from stem cells, and if motoneurons from adult tissue functions in the same way as those generated from embryonic stem cells. His work could lead to a possible treatment for ALS.

 


 

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

(2011-2016)

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

(2010-2015)

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.

 


 

Peripherin abnormalities in amyotrophic lateral sclerosis

(2009-2014)

Janice Robertson, PhD
University of Toronto

Dr. Janice Robertson

Peripherin is a protein that is associated with many of the pathological abnormalities found in the diseased motor neurons of people with ALS. Peripherin may be an important factor contributing to motor neuron degeneration in ALS. This study is aimed at further categorizing peripherin abnormalities in ALS as a means to understanding the underlying pathogenic process, which will aid in the development of effective therapeutics and eventual cure.

 


 

The TAR DNA-binding protein (TDP-43) and amyotrophic lateral sclerosis

(2011-2014)

Janice Robertson, PhD
University of Toronto

Dr. Janice Robertson

TAR DNA-binding protein (TDP-43) is a cellular protein that has been identified as one of the core components of the neuropathological abnormalities that characterize ALS. In instances of ALS that are caused by mutations of TDP-43, the protein is completely depleted from the nuclei, or control centre, of the motor neurons in the central nervous system that directly or indirectly control muscles. Instead, TDP-43 relocates to the cytoplasm, and Dr. Robertson hypothesizes that this shift in the location of TDP-43 could cause or contribute to ALS. As a result, she and her team intend to study the effect of this movement of TDP-43 in order to learn more about the part played by the protein in the development of ALS.

 


 

Mutation of KCC3: understanding a sensory motor neuropathy

(2009-2014)

Guy Rouleau, PhD
Centre Hospitalier de l’Université de Montréal

Dr. Guy Rouleau

Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) is a genetic disease. Dr. Rouleau and his team have identified the gene responsible for this disease and will now determine how the malfunctioning of this gene leads to the disorder. This knowledge will support the development of needed treatments and management strategies, which will improve the quality of life and life expectancy of people with HMSN/ACC.

 


 

Genetic Regulation of Myogenesis

(2012-2017)

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

(2011-2016)

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

(2012-2017)

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

(2012-2017)

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

(2012-2015)

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)

(2011-2016)

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

(2012-2016)

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

(2012-2015)

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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