Science That Changes Lives
From breakthroughs in the lab to real-world progress—accelerating research that delivers results for families today.
Grant – Winter 2013 – MG - Muthusamy Thiruppathi, Ph.D.
Muthusamy Thiruppathi, a postdoctoral research associate in microbiology and immunology in the College of Medicine at the University of Illinois at Chicago, was awarded an MDA development grant totaling $180,000 over a period of three years to pursue ways to restore normal immune system function in myasthenia gravis (MG).
MG occurs when certain cells in the body’s immune system mistakenly target specific proteins on skeletal muscle, causing weakness. The immune system is usually tightly regulated by immune cells called regulatory T cells. In other autoimmune disorders, it is now recognized that there is a defect in the number or function of these cells, and that this contributes to the development of autoimmunity (a condition in which the body's immune system mistakenly attacks its own tissues).
Thiruppathi and colleagues recently have shown that in MG, the number of regulatory T cells is normal, but they do not function properly to suppress unwanted immune responses. “We will now thoroughly examine the nature of this immune defect in MG,” he says, using blood cells collected from individuals with MG and unaffected individuals.
Thiruppathi also will be exploring a strategy to enhance the function of these cells using a natural immune system growth factor called granulocyte-macrophage colony-stimulating factor.
By developing a deeper understanding of exactly how the immune system goes awry, it may be possible to “change the approach to the treatment of myasthenia gravis from global, nonspecific immune modulation to focused, individualized, cellular therapy,” he says.
Funding for this MDA grant began Feb. 1, 2013.
Grantee: MG - Muthusamy Thiruppathi, Ph.D.
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Grant - Winter 2012 - CMT - Garth Nicholson, M.D., Ph.D.
MDA awarded a research grant totaling $420,000 over three years to professor Garth Nicholson at the ANZAC Research Institute, University of Sydney in New South Wales, Australia.
The funds will help support Nicholson's research into the biological and cellular effects caused by mutations in the copper transport gene ATP7A in Charcot-Marie-Tooth disease (CMT).
Nicholson and colleagues have discovered that mutations in the copper transport gene ATP7A cause slow but progressive degeneration of the long ends (axons) of the nerve cells called motor neurons that send signals to the limb muscles.
The ATP7A protein is essential for human copper metabolism; it is involved with the delivery of copper for physiological processes, and also in maintaining copper balance in humans.
Nicholson's team has shown that mutant ATP7A protein does not traffic copper properly in the presence of elevated copper levels. Now it plans to determine whether ATP7A mutations cause disease symptoms by a mild reduction in intracellular copper movement from motor neurons, or whether the mutations work by some other mechanism such as poor delivery of copper to the distal axon, due to the trafficking defect.
Using human cellular and research mouse models, the investigators plan to determine the biological and cellular effects of the impaired ATP7A trafficking. They will investigate the role of interacting proteins in ATP7A trafficking relevant to axonal copper delivery as a means of exploring the possible mechanistic links between motor neuron disorders and copper; and they will establish a transgenic mouse model that carries mutations in the ATP7A gene.
Funding for this MDA grant began February 1, 2012.
Grantee: CMT - Garth Nicholson, M.D., Ph.D.
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Grant - Spring 2014 - MMD/DM - Bernard Jasmin, Ph.D.
Bernard Jasmin, a professor in the Department of Cellular & Molecular Medicine at the University of Ottawa, has been awarded an MDA grant totaling $253,800 over three years to examine the role of a protein called staufen 1 in type 1 myotonic muscular dystrophy (MMD or DM) . In this disorder, staufen 1 interacts with abnormally expanded genetic material in muscle cells. Jasmin and colleagues will conduct laboratory experiments to understand the functions of staufen 1, with the goal of developing new strategies for treating type 1 MMD.
Funding for this MDA research grant began May 1, 2014.
Grantee: MMD/DM - Bernard Jasmin, Ph.D.
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Grant – Winter 2013 – MG - David Richman, M.D.
David Richman, professor of neurology at the University of California, Davis, was awarded an MDA research grant totaling $412,500 over a period of three years to study the anti-MuSK myasthenia (AMM) form of myasthenia gravis (MG).
In most people with MG, an autoimmune disease of muscle, individuals make antibodies that react against a part of the muscle called the acetylcholine receptor. But, Richman says, in the AMM form of the disease, antibodies are made against a second protein, muscle-specific kinase (MuSK), also located on the muscle surface. Many of the usual MG treatments are not effective against the AMM form of the disease.
Richman has developed a rat model of AMM, and will use magnetic resonance imaging (MRI) to measure muscle loss in the rats. He also will conduct microscopic and biochemical tests to characterize the affected muscles, and experiments on cells in culture to test various chemical treatments that could have therapeutic potential.
Funding for this MDA grant began Feb. 1, 2013.
Grantee: MG - David Richman, M.D.
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Grant - Summer 2012 - DMD/BMD — Atsushi Asakura, Ph.D.
Atsushi Asakura, assistant professor at the University of Minnesota Medical School in Minneapolis, was awarded an MDA research grant totaling $378,531 over three years to study how the system of blood vessels known as the vasculature affects muscles in Duchenne (DMD) and Becker (BMD) muscular dystrophies.
Data from recent studies suggests that dystrophin — the protein deficient in DMD — plays a role in blood vessel health and maintenance. The absence of dystrophin in the vasculature results in vascular deficiency, making it likely that disturbed blood flow also is a cause of DMD-related muscle damage.
Therefore, Asakura says, “Definitive treatment of DMD will require both muscle fiber and blood vessel repair.”
With colleagues, Asakura is working to understand how vasculature affects muscle stem cells and regeneration in muscular dystrophies, and to develop a therapy based on growing new blood vessels. The team will examine the effects of increased blood-vessel growth on muscles in a research mouse model of DMD.
“The hope is that at least some, or combinations of, the vascular-targeted therapies will soon have clinical utility and provide current and future human beings living with DMD or other muscular dystrophies enhanced control over their own destiny,” Asakura says.
Funding for this MDA grant began Aug. 1, 2012.
Grantee: DMD/BMD — Atsushi Asakura, Ph.D.
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Grant - Winter 2012 - CMT - Charles Abrams, M.D., Ph.D.
Charles Abrams, an associate professor at SUNY Downstate Medical Center in Brooklyn, N.Y., was awarded an MDA research grant totaling $414,787 over a period of three years to study the role of connexin protein mutations in type 1X Charcot-Marie-Tooth disease (X-linked CMT, or CMT1X).
X-linked CMT differs from other types of CMT in that many people with the disease develop central nervous system signs and symptoms in addition to dysfunction of the peripheral nervous system. (In the CNS long nerve tracts convey information through the spinal cord to the brain, and from the brain down the spinal cord to the peripheral, or outer, nerves and muscles. ThePNS is comprised of nerve fibers outside the spinal cord that send signals to the muscles and relay information from the periphery of the body back to the spinal cord and brain.)
More than 300 mutations in the gene for the connexin 32 protein have been linked to CMT1X. Abrams and colleagues will study whether interactions between mutated connexin 32 protein and a related CNS protein, connexin 47, are the cause of the CNS dysfunction found in the disease.
"We are at the early stages in our understanding of the roles of mutations in connexin 32 in the CMT1X disease process," Abrams said. "We have identified some of the ways in which mutations disrupt the function of connexin 32, but we still do not fully understand why these disruptions lead to both peripheral and central nervous system dysfunction."
Funding for this MDA grant began February 1, 2012.
Grantee: CMT - Charles Abrams, M.D., Ph.D.
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Grant – Winter 2013 – DD – Laing Distal Myopathy - Leslie Leinwand, Ph.D.
Leslie Leinwand, professor of molecular, cellular and developmental biology at the University of Colorado in Boulder, was awarded an MDA research grant totaling $338,775 over a period of three years to study the causes and treatment of Laing distal myopathy (MPD1).
MPD1 is an inherited muscle disease characterized by early and selective weakness of the lower leg that affects ankle and great toe bending. With time, the disease progresses to other muscles, including those of the neck and face. MPD1 is caused by mutations in a gene called MYH7, which encodes a protein called myosin heavy chain-ß. This protein works in heart and skeletal muscle to create the pulling force that allows muscles to contract, Leinwand says, “but how these mutations lead to disease is unknown.”
Her goal is to learn more about how mutations in MYH7 cause the cellular defects that are at the root of MPD1. Specifically, she is interested in determining the effects of mutations on the ability of multiple myosin proteins to link together, which they must do to function properly. She thinks it’s likely that a defect in that linking ability may reduce the stability of sarcomeres, the basic unit of muscle that exerts the pulling force.
She also will create a mouse model of MPD1 in order to better study the effects of mutation and to test potential therapies. “We hope that our experiments will expose the pathogenesis of the disease and will lead to a successful molecular treatment for MPD1, for which there is currently no treatment,” says Leinwand.
Funding for this MDA grant began Feb. 1, 2013.
Grantee: DD – Laing Distal Myopathy - Leslie Leinwand, Ph.D.
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Grant - Spring 2014 - MMD/DM - Andrew Berglund, Ph.D.
Andrew Berglund, a professor of biochemistry, biophysics and molecular biology at the University of Oregon in Eugene, has been awarded an MDA research grant totaling $253,800 over three years to pursue changing the shape of the abnormal genetic material underlying type 1 and type 2 myotonic muscular dystrophy (MMD or DM). Berglund and colleagues will conduct laboratory experiments to see whether changing the shape of abnormally expanded genetic material (RNA) in these two forms of MMD can reduce or eliminate their harmful effects.
Funding for this MDA research grant began May 1, 2014.
Grantee: MMD/DM - Andrew Berglund, Ph.D.
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Grant - Winter 2012 - CMD/LGMD - Jeffrey Miller, Ph.D.
MDA awarded a research grant totaling $343,860 over a period of three years to Jeffrey Boone Miller, senior scientist at Boston Biomedical Research Institute in Watertown, Mass., and associate professor of neurology at Harvard Medical School in Boston. The funds will help support Miller’s study of the underlying causes of, and potential therapeutic strategies for, three muscular dystrophies: type 1A congenital muscular dystrophy (MDC1A/CMD), and types 2C and 2D limb-girdle muscular dystrophy (LGMD2C, LGMD2D).
During normal skeletal muscle development, immature muscle cells calledmyoblasts fuse together to form large, tube-shaped cells called myotubes. Myotubes ultimately mature into muscle fibers.
“We find that myotubes formed in culture from human MDC1A, LGMD2C and LGMD2D patient myoblasts, but not normal myoblasts, spontaneously undergo cell death,” Miller said.
Miller and colleagues have found that the abnormal activation of the cell death, caused by the Bax protein and its binding partner Ku70, may underlie the cell-death changes in each of the three diseases under investigation.
In his new work, Miller plans to examine the role dysregulation of the Ku70/Bax pathway plays in muscle development. He first plans to determine whether the abnormal function of proteins that modify Ku70 function cause abnormalities in muscle. In a second set of experiments, he will test the hypothesis that restoring Ku70 function to a normal level will inhibit cell death and decrease the abnormalities in human myogenic cells.
“From our results, we hope to identify potential therapeutic strategies that could be effective for multiple diseases.”
Funding for this MDA grant began February 1, 2012.
Grantee: CMD/LGMD - Jeffrey Miller, Ph.D.
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Grant - Winter 2012 - CMD - Mahasweta Girgenrath, Ph.D.
MDA awarded a research grant totaling $357,465 over a period of three years to Mahasweta Girgenrath, an assistant professor in the Health Sciences Department at Boston University in Boston. The funds will help support Girgenrath’s work to find a combination therapy to treat type 1A congenital muscular dystrophy (MDC1A).
Girgenrath and colleagues plan to explore strategies designed to inhibit the inflammation and fibrosis (muscle scarring) associated with MDC1A, either alone or in combination with improved muscle regeneration.
The team will conduct their studies in the DyW mouse model, which develops a muscular dystrophy that closely matches the disease process seen in humans with MDC1A.
“We previously have shown that improving regeneration by increased activity of a growth factor called IGF1 improves muscle mass, but does not affect inflammation,” Girgenrath said. The group will now try a therapy designed to prevent inflammation in the muscles of the DyW mice, both alone and in combination with IGF1-based regeneration therapy.
“If successful,” Girgenrath said, “our results may lead to a combination therapy to fight the devastating prognosis of MDC1A.”
Funding for this MDA grant began February 1, 2012.
Grantee: CMD - Mahasweta Girgenrath, Ph.D.
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Grant - Summer 2012 - DMD/BMD — Adam Engler, Ph.D.
Adam Engler, assistant professor at the University of California, San Diego, in La Jolla, was awarded an MDA research grant totaling $390,000 over three years to study cell-based therapies designed for Duchenne (DMD) and Becker (BMD) muscular dystrophies and other muscle diseases.
Engler and colleagues are working with adipose-derived stem cells, orASCs (stem cells derived from fat). These cells, Engler says, are readily available, can develop into muscle, and — once they become muscle — can integrate into damaged skeletal muscle tissue. But the ASCs so far have been unable to repair DMD-related damage and restore muscle function.
Now Engler’s team, which has demonstrated the function of ASC-derived muscle in the lab, plans to translate those findings into animal models of muscular dystrophy.
The investigators are using a new method to coax ASCs into turning into mature muscle cells that they say should “better mimic” the conditions in which muscle cells in the body mature. This should make the cells more likely not only to integrate into damaged muscle tissue, but also help repair it.
”Stem-cell-based regenerative applications for muscle diseases, including muscular dystrophy, are showing increasing signs of feasibility in our lab," Engler says. "But our research and others' address critical stumbling blocks that currently prevent successful translation of these therapies in animal models of the disease and in humans."
Funding for this MDA grant began Aug. 1, 2012.
Grantee: DMD/BMD — Adam Engler, Ph.D.
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Grant - Winter 2012 - Cell Therapy - Ilona Skerjanc, Ph.D.
MDA awarded a research grant totaling $280,487 over a period of two years to Ilona Skerjanc, a professor in the department of biochemistry, microbiology & immunology at the University of Ottawa in Ontario, Canada.
The funds will help support Skerjanc’s investigation into using cell therapies to enhance muscle repair in any of a number of muscle diseases, including congenital muscular dystrophy (CMD); Duchenne (DMD) and Becker (BMD) muscular dystrophies; and Emery-Dreifuss muscular dystrophy (EDMD).
Several cell sources, including satellite cells (a type of immature muscle cell) and mesenchymal stem cells (derived from bone marrow), are currently under study for potential use in therapies to reverse muscle degeneration and strengthen existing muscle. However, Skerjanc noted, difficulties with these approaches include the requirement for invasive procedures, the availability of suitable donors and a limited potential for long-term benefit.
Skerjanc and colleagues recently showed that human embryonic stem (hES) cells can mature into skeletal muscle via progenitor and myoblast (both immature muscle cell types) stages.
In her new work, Skerjanc will isolate skeletal muscle progenitors from hES cells and examine their ability to engraft into skeletal muscle in a mouse model of DMD.
“The overall goal is to provide a method of hES cell differentiation(maturation) and enrichment that will generate human myoblasts and progenitors for long-term engraftment and future therapeutic applications,” Skerjanc said.
Funding for this MDA grant began February 1, 2012.
Grantee: Cell Therapy - Ilona Skerjanc, Ph.D.
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Grant - Summer 2012 - DMD — Tathagata Chaudhuri, Ph.D.
Postdoctoral research fellow Tathagata Chaudhuri, at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, was awarded an MDA development grant (DG) totaling $180,000 over three years to develop a stem cell therapy for muscular dystrophies, including Duchenne muscular dystrophy (DMD), that will lead to muscle regeneration.
MDA development grants are awarded to exceptional postdoctoral candidates who have the best chance of becoming independent researchers and future leaders of neuromuscular disease research.
Some experimental cell therapies for muscular dystrophies are designed to use cells from healthy human donors, but the successful transplantation of cells from one person to another requires the use of immunosuppressants in order to keep the body from rejecting the new cells.
Chaudhuri and colleagues are working on the development of a cell-based therapy that uses a person's own stem cells — adult mesenchymal stem cells (MSCs), which are taken from bone marrow and coaxed into becoming muscle cells.
The team first plans to demonstrate that MSCs can reliably be differentiated(grown) into muscle cells. They'll then use the cells they produce to study muscle regeneration in animal models of muscular dystrophy.
Next, Chaudhuri and his team will determine the optimum time for transplanting the maturing cells into a recipient. They'll monitor the development of the human MSCs in animal models to determine how well the MSCs integrate with existing muscle fibers and whether they have any effect on muscle repair and regeneration over time.
Treatment with adult stem cells that develop into muscle cells may provide a means to correct skeletal muscle function in muscular dystrophy, Chaudhuri says, noting that this type of therapy for DMD and other dystrophies "is currently becoming an increasingly attractive area of research in the muscular dystrophy community."
Funding for this MDA grant began Aug. 1, 2012.
Grantee: DMD — Tathagata Chaudhuri, Ph.D.
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Grant – Winter 2013 – LGMD - Noah Weisleder, Ph.D.
Noah Weisleder, associate professor of physiology and cell biology at Ohio State University in Columbus, was awarded an MDA research grant totaling $405,000 over a period of three years to study muscle repair for development of treatment for limb-girdle muscular dystrophies (LGMD).
In all muscular dystrophies, muscles are damaged during normal use. Part of that damage occurs when the outer membrane of the muscle cell tears under the force of normal muscle contraction. The cell has mechanisms to repair torn membranes, allowing the survival of these damaged cells, but these mechanisms are insufficient in LGMD and other muscular dystrophies.
“These findings suggest that a therapeutic approach that increases membrane repair capacity could have broad efficacy across a number of different muscular dystrophies in human patients,” Weisleder says.
His group has previously shown the importance of a protein called Mitsugumin 53 (MG53) in the repair process, and has demonstrated that it can be directly applied to cells and tissues to increase the repair capacity, including in a rodent model of Duchenne muscular dystrophy (DMD). He will now test this strategy in various rodent models of LGMD, to determine if this protein could be used as a therapeutic approach in humans.
“If MG53 can improve pathology in a number of different muscular dystrophies,” Weisleder says, “it is more likely that this protein therapy could be effectively moved towards clinical trials, as it would be able to treat a relatively large patient population spread across various types of muscular dystrophy.”
While such therapy would not be a definitive cure for any of the muscular dystrophies, it could provide meaningful therapy for patients until definitive treatments for the underlying causes of these diseases are available.
Funding for this MDA grant began Feb. 1, 2013.
Grantee: LGMD - Noah Weisleder, Ph.D.
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Grant - Summer 2012 - CMT/FA — Jeffrey Milbrandt, M.D., Ph.D.
MDA awarded a research grant totaling $357,366 over three years to Jeffrey Milbrandt, professor and head of the department of genetics, and professor of pathology & immunology, medicine and neurology at Washington University School of Medicine in St. Louis.
The funds will help support Milbrandt's work in determining how Schwann cells contribute to nerve damage (neuropathy) in neuromuscular diseases such as Charcot-Marie-Tooth disease (CMT) and Friedreich's ataxia (FA).
Neuropathies and neuromuscular diseases like CMT and FA are associated with poor function of mitochondria, the energy producer in cells.
In previous work, Milbrandt and colleagues found that mice with mitochondrial deficits in Schwann cells develop a progressive neuropathy. (Schwann cells are a type of support — or glial — cell in the nervous system outside the brain and spinal cord; they support the function and maintenance of nerve fibers, or axons.)
Milbrandt's new project focuses on determining how Schwann cells obtain their energy when their mitochondria are damaged, and the mechanisms by which Schwann cell metabolism causes damage to the peripheral nerves (bundles of nerve fibers that run between the spinal cord and the muscles). He also plans to test whether pharmacological interventions to manipulate Schwann cell metabolism will help restore normal peripheral nerve function.
"For these studies, we will use a mouse model in which mitochondria are dysfunctional specifically and exclusively in Schwann cells," Milbrandt explains. "These mice, called Tfam-SCKO mice, are a good model for these studies because they develop many critical features of human neuromuscular disease and peripheral neuropathy."
Millbrandt notes: "Peripheral neuropathy research is entering a new era as we learn more about how axons are dismantled and the role of glia in maintaining axon health. There are unparalleled opportunities now to develop new treatments for this debilitating condition that is reaching epidemic proportions worldwide."
Funding for this MDA grant began Aug. 1, 2012.
Grantee: CMT/FA — Jeffrey Milbrandt, M.D., Ph.D.
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Grant – Winter 2013 – FSHD - Rabi Tawil, M.D.
Rabi Tawil, professor of neurology at the University of Rochester Medical Center in Rochester, N.Y., was awarded a one-year MDA research grant totaling $92,222 to develop a biomarker for facioscapulohumeral muscular dystrophy (FSHD).
FSHD is caused by aberrant expression (activity) of a gene called DUX4, which is usually silenced in adult muscle tissue. DUX4 turns on other genes, and activity of these genes is believed to cause disease by multiple mechanisms, including direct toxicity, interference with normal cell function and provoking the immune system.
“Having identified potential therapeutic targets in FSHD,” says Tawil, “it becomes crucial to identify sensitive, disease-related biological markers [biomarkers] that can be easily measured in blood or muscle tissue to assess the effectiveness of future disease-modifying drugs.” FSHD researchers recently came to consensus that development of biomarkers was a top priority for progress in the disease.
Tawil will be investigating whether a small group of these abnormally expressed genes may serve as biomarkers. He will examine muscle biopsies and blood serum from individuals with FSHD and unaffected individuals, and compare the level of proteins made from these genes. Any differences will then be correlated with the overall disease severity and the severity of changes in the muscle.
“At the end of this study we hope to have promising biomarkers for future clinical trials,” he says. “Research is now focused on treatment of FSHD, and consequently having all the tools ready for future clinical trials is essential.”
Funding for this MDA grant began Feb. 1, 2013.
Grantee: FSHD - Rabi Tawil, M.D.
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Grant – Winter 2013 – FSHD - Michael Kyba, Ph.D.
Michael Kyba, associate professor of pediatrics at the University of Minnesota in Minneapolis, was awarded an MDA research grant totaling $358,227 over a period of three years to study muscle developmental deficits in facioscapulohumeral muscular dystrophy (FSHD). The new grant complements previous MDA-funded work by Kyba to identify and test experimental therapies in FSHD.
FSHD is caused by aberrant expression (activity) of a gene called DUX4, which is usually silenced in adult muscle tissue. DUX4 turns on other genes, and activity of these genes is believed to cause disease by multiple mechanisms, including direct toxicity, interference with normal cell function and provoking the immune system.
“The mechanism of muscle degeneration in FSHD is enigmatic,” Kyba says, since unlike other muscular dystrophies, there is apparently neither ongoing muscle fiber damage, nor ongoing regeneration. “The mechanism of how genetic changes actually lead to deteriorated muscle is still very unclear.”
To answer some of those questions, he has generated muscle cells from patient skin cells in order to study the effects of the mutation that causes FSHD. He will now use newly developed “gene-editing” technology to correct the FSHD mutation, and to compare muscle development between uncorrected and corrected cells.
“This project will shed light on the molecular mechanism underlying FSHD, and will provide tools for genetic correction of the FSHD mutation in cells in culture,” says Kyba. “Understanding the genetic mechanism is essential to developing rational pharmaceutical therapies for FSHD. In addition, with a view toward future cell therapies, having methods to correct the genetic mutation that causes FSHD will facilitate autologous (self) transplantation of genetically corrected cells.”
Funding for this MDA grant began Feb. 1, 2013.
Grantee: FSHD - Michael Kyba, Ph.D.
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Grant - Spring 2014 - MM - David Chan, M.D., Ph.D.
David Chan, a professor of biology at the California Institute of Technology in Pasadena, has been awarded an MDA research grant totaling $253,800 over three years, to study mitochondria in mice. Mitochondria are the energy-producing parts of cells, and an aspect of their normal functioning involves fusing together and dividing. Chan and colleagues will study mice with defects in the fusion or division of mitochondria to improve the understanding of mitochondrial myopathies.
Funding for this MDA research grant began May 1, 2014.
Grantee: MM - David Chan, M.D., Ph.D.
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Grant - Summer 2012 - CMT — Stephan Züchner, M.D.
Stephen Züchner, associate professor of human genetics and neurology at the University of Miami Miller School of Medicine in Florida, was awarded an MDA research grant totaling $390,000 over three years to identify genes responsible for Charcot-Marie-Tooth disease (CMT).
"Genetic research over the past 25 years has identified more than 50 different CMT genes,” Züchner explains. “While the subtype CMT1 is largely explained by these genes, CMT2 and a number of other subtypes of CMT are less well-understood.”
It’s thought that many more genes need to be found to explain the majority of CMT found in people with the disease, but a new generation of DNA sequencing machines — called next-generation sequencers — is making that endeavor much easier and cheaper
“We have been pioneering the application of these new instruments for neuromuscular and other diseases,” Züchner says, “and have already identified and published multiple novel genes using this approach in a number of diseases.”
In his new work, Züchner and colleagues are focused on identifying additional genes that cause CMT.
“We believe that the more genes we know, the better will be our understanding of gene networks that work together in a process that leads to disease,” Züchner says. “Instead of focusing on a single gene, there will be benefits in understanding the entire disease process.”
Such understanding may lead to development of therapies that, instead of targeting a specific gene, influence gene networks or pathways — meaning a single treatment could help people with mutations in different genes.
Funding for this MDA grant began Aug. 1, 2012.
Grantee: CMT — Stephan Züchner, M.D.
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Grant – Winter 2013 – FA - Mark Payne, M.D.
Mark Payne, professor of pediatrics and medical and molecular genetics at the Indiana University School of Medicine in Indianapolis, was awarded an MDA research grant totaling $298,048 over a period of two years to study ways to overcome the vulnerability of heart muscle in Friedreich’s ataxia (FA).
Heart muscle is especially vulnerable in FA, leading to the possibility of severe heart failure and early death. The reason, Payne says, appears to relate to how mitochondria, the cell’s energy producers, obtain their own cellular fuel. “It appears that the mitochondria in the heart, which normally produce energy for the heart to beat, are not capable of using certain fuels (fats and sugars) to make energy. The result is that the heart does not have enough energy to withstand stressful situations.”
Payne will study this phenomenon further in a mouse model of FA, to understand altered mitochondrial function in the heart that may contribute to the development of heart failure. “In particular, we will determine if the mitochondria are capable of using fats and sugars from the diet in an appropriate manner to make energy,” he says, using a variety of advanced molecular biology and imaging techniques. He also will study whether supplying a good copy of the mutated gene responsible for the disease can reverse the faulty metabolism of the heart.
“The goal of this project is to understand the basic mechanisms of heart failure in this disease, and then develop approaches to improve heart function and save lives,” Payne says.
Funding for this MDA grant began Feb. 1, 2013.
Grantee: FA - Mark Payne, M.D.
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Grant - Spring 2014 - MM - Catarina Quinzii, M.D
Catarina Quinzii, an assistant professor at Columbia University Medical Center in New York, has been awarded an MDA research grant totaling $253,800 over three years to investigate how flaws in the gene for a protein called RMND1 lead to abnormalities in mitochondria, the energy-producing parts of cells. Quinzii will conduct experiments in human cells, mouse cells and mice with abnormal or deficient RMND1 protein, with an eye to developing a treatment for a human mitochondrial myopathy that results from an RMND1 gene mutation.
Funding for this MDA research grant began May 1, 2014.
Grantee: MM - Catarina Quinzii, M.D
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Grant - Summer 2012 - CMT — Bogdan Beirowski, M.D., Ph.D.
Postdoctoral research scholar Bogdan Beirowski, in the department of genetics at the Washington University School of Medicine in St. Louis, was awarded an MDA development grant totaling $180,000 over three years to study how defective Schwann cells lead to nerve-cell damage in Charcot-Marie-Tooth disease (CMT).
MDA development grants are awarded to exceptional postdoctoral candidates who have the best chance of becoming independent researchers and future leaders of neuromuscular disease research.
Degeneration of axons — fibers that carry electrical signals between the brain and spinal cord and the rest of the body — is a hallmark of CMT and some forms of Dejerine-Sottas disease, and is thought to be responsible for muscle weakness associated with these diseases.
In some forms of CMT, the primary molecular defect localizes to Schwann cells, which normally help nourish and protect axons by wrapping them in a multilayered membrane called myelin. But it's poorly understood how Schwann cell dysfunction causes axon damage.
Data from previous work suggests that removal of defective myelin (demyelination) causes inflammation that results in axon damage, but Beirowski hypothesizes that "defective Schwann cells deprive long axons of metabolic support, thus contributing to axon degeneration."
Beirowski has developed mouse models in which key metabolic regulators are blocked exclusively in Schwann cells, which he now will use to test whether failure of the cells to deliver nutrients to axons could explain axon loss.
The identification of specific metabolic defects in Schwann cells could lead to the development of CMT therapeutic strategies based on supporting the stability of axons.
Funding for this MDA grant began Aug. 1, 2012.
Grantee: CMT — Bogdan Beirowski, M.D., Ph.D.
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Grant - Spring 2014 -MM - Carlos Moraes, Ph.D.
Carlos Moraes, a professor of neurology, cell biology and anatomy at the University of Miami (Fla.), has been awarded an MDA research grant totaling $253,800 over three years to study a potential treatment for mitochondrial myopathies, conducting experiments in human cells and in mice. Mitochondria, the energy-producing parts of cells, contain their own DNA, which can develop mutations (flaws) and cause disease. Moraes and colleagues will study DNA-cutting enzymes targeted to mitochondria, hoping to develop this technology to correct disease-causing defects in mitochondrial DNA in patients.
Funding for this MDA research grant began May 1, 2014.
Grantee: MM - Carlos Moraes, Ph.D.
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Grant - Summer 2012 - CMS — Paul Brehm, Ph.D.
Paul Brehm, senior scientist at Oregon Health Science University in Portland, was awarded an MDA research grant totaling $351,648 over three years to study the underlying mechanisms of movement disorders in some forms of congenital myasthenic syndromes (CMS).
Brehm’s research team has identified zebrafish research models that carry mutations in the same proteins that are known to cause some forms of CMS in humans. In both fish and humans, these proteins are localized to the neuromuscular junction (the space where signals are transferred between nerve and muscle). Their deficiency results in movement disorders such as use-dependent fatigue (the inability to perform repetitive tasks).
In one model, known as the rapsyn-deficient line (in which the fish have mutations in the gene for the rapsyn protein), Brehm and his team have been exploring the basis of use-dependent fatigue.
Rapsyn deficiency has been associated with problems on the muscle side of the neuromuscular junction. Brehm’s team has found that the absence of an as-yet unidentified signal produced by muscle regulates the motor neuron and that, ultimately, the absence of this signal appears to be accountable for use-dependent fatigue.
Brehm’s team is working to uncover the mechanism underlying the reduced motor neuron activity that precedes use-dependent fatigue, as well as ways in which to rescue the nerve defect.
“The means to study neuromuscular function using the zebrafish system has been unparalleled among the vertebrates,” Brehm says. “The discovery of zebrafish models that carry these mutant proteins now opens the way to addressing directly the consequences in humans.”
Funding for this MDA grant began Aug. 1, 2012.
Grantee: CMS — Paul Brehm, Ph.D.
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Grant - Spring 2014 - LEMS - Stephen Meriney, Ph.D.
Stephen Meriney, a professor of neuroscience and psychiatry at the University of Pittsburgh, will conduct experiments in cells and mice to test a drug that may be beneficial in Lambert-Eaton myasthenic syndrome (LEMS).
Funding for this MDA research grant began May 1, 2014.
Grantee: LEMS - Stephen Meriney, Ph.D.
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