Science That Changes Lives
From breakthroughs in the lab to real-world progress—accelerating research that delivers results for families today.
Grant - Summer 2011 - Muscle Physiology — Samantha Harris, Ph.D.
Samantha Harris, an associate professor in the department of neurobiology, physiology and behavior at the University of California, Davis, has been awarded an MDA grant totaling $244,024 over two years. The funding will help Harris in her quest to determine the properties of a skeletal-muscle protein called myosin binding protein C.
Mutations in the gene for myosin binding protein C affect muscle contraction and could play a role in a number of muscle diseases.
"MDA support of this work comes at a pivotal time," Harris said, "not only for the opportunity it provides for making rapid inroads into our understanding of [muscle contraction abnormalities], but also for the opportunity it provides in opening up new research directions for my lab by fostering new collaborations. I am eager to get started!"
Funding for this MDA grant began August 1, 2011.
Grantee: Muscle Physiology — Samantha Harris, Ph.D.
Grant type: Research Grant
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Grant - Summer 2011 - Muscle Physiology — Kristen Nowak, Ph.D.
MDA awarded a research grant totaling $329,091 over two years to Kristen Nowak, an associate professor at the University of Western Australia in Perth, and the Western Australian Institute for Medical Research. The funds will support Nowak's study of diseases caused by defects in the skeletal muscle actin gene, which include "essentially any genetic neuromuscular disease that tends to be severe in some patients and mild in others."
Nowak's team will concentrate on development of a therapy for people with skeletal muscle actin diseases, while also looking for genetic modifiers of disease severity.
Using a research mouse model with severely affected skeletal muscle, the researchers will search for modifying genes that activate cardiac (heart) actin, or any other gene able to rescue the mice through another mechanism.
"Identified genes will become the focus of future studies determining how to utilize them to formulate treatments," Nowak said.
Nowak acknowledged the importance of MDA funding in both previous and current work.
"Being able to continue this work with the current project is of utmost importance, not only for patients with skeletal muscle actin disease and their families, but hopefully for people with other neuromuscular diseases as well."
Funding for this MDA grant began August 1, 2011.
Grantee: Muscle Physiology — Kristen Nowak, Ph.D.
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Grant - Summer 2011 - MM - Mito. Myopathy — Pere Puigserver, Ph.D.
MDA has awarded a research grant totaling $313,551 over three years to Pere Puigserver, associate professor in the department of cancer biology at the Dana-Farber Cancer Institute, and department of cell biology at Harvard Medical School in Boston. The funds will help support Puigserver’s research into the study of two newly identified genes that may increase muscle performance in mitochondrial myopathies.
It’s known that activation of a gene called PGC1-alpha has the potential to be an effective treatment for mitochondrial myopathy in people with neuromuscular disorders, Puigserver explained. But it makes for a difficult “druggable” target.
Puigserver’s research team has identified two new genes, mTORC1 and YY1, that form new “teammates” that stimulate PGC1-alpha and increase healthy skeletal muscle performance. The two genes appear to be easily targeted by small molecules and other drugs.
The team will assess how the mTOR/YY1 complex activates PGC1-alpha, and then will perform a small-molecule chemical screen to identify compounds that activate PGC1-alpha in skeletal muscle cells modified with genetic mutations from people with myopathies.
“The importance of MDA funding for our project is crucial,” Puigserver said, providing “a unique avenue to accelerate research that can impact people with muscle diseases.”
Funding for this MDA grant began August 1, 2011.
Grantee: MM - Mito. Myopathy — Pere Puigserver, Ph.D.
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Grant - Summer 2011 - MM - Mito. Myopathy — Edward Owusu-Ansah, Ph.D.
MDA has awarded a development grant totaling $180,000 over three years to Edward Owusu-Ansah, a postdoctoral fellow in the department of genetics at Harvard Medical School in Boston. The funds will help support Owusu-Ansah's research into the molecular mechanisms underlying mitochondrial myopathies.
A system consisting of five large protein complexes, known as the functional oxidative phosphorylation system, or OXPHOS, plays a crucial role in the generation of energy (ATP) in the cellular power factories known as mitochondria. Disruption of this system results in the compromise of a range of biochemical and metabolic activities in cells, resulting in mitochondrial myopathy.
In a fruit fly research model Owusu-Ansah plans to examine the intracellular signaling that contributes to mitochondrial myopathy, particularly with regard to one of the five larger protein complexes that is part of the OXPHOS system.
"Due to the extensive similarity between fruit fly and human genomes," Owusu-Ansah said, "I anticipate that information obtained from this study should uncover novel therapeutic strategies for alleviating mitochondrial myopathy in humans."
Funding for this MDA grant began August 1, 2011.
Grantee: MM - Mito. Myopathy — Edward Owusu-Ansah, Ph.D.
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Grant - Summer 2011 - MM - Mito. Myopathy - Carlos Moraes
MDA awarded a grant totaling $363,672 to Carlos Moraes, professor of neurology at the University of Miami School of Medicine, to study the effects generated by an increase in functional mitochondria (the "energy factories" in cells) in mitochondrial myopathy.
In previous studies, Moraes and colleagues increased the production of new mitochondria (a process called "mitochondrial biogenesis") in the cells of mice with a disease resembling mitochondrial myopathy. The mice, which began receiving treatment during the embryonic stage of development, exhibited improved symptoms and prolonged life.
As part of their new work, Moraes and his team will test various methods, alone and in combination, of increasing production of mitochondria in adult mice with a disease similar to human mitochondrial myopathy. The investigators also will study whether endurance-based exercise increases production of mitochondria.
"This project may lead to improved treatment for mitochondrial myopathies," Moraes said.
Funding for this MDA grant began August 1, 2010.
Grantee: MM - Mito. Myopathy - Carlos Moraes
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Grant - Summer 2011 - MD — Kathryn Wagner, M.D., Ph.D.
MDA has awarded a research grant totaling $362,760 over three years to Kathryn Wagner, an associate professor of neurology and neuroscience at the Johns Hopkins School of Medicine and director of the Center for Genetic Muscle Disorders at the Kennedy Krieger Institute, both in Baltimore.
The grant will help support Wagner's studies of how a muscle protein called myostatin regulates the fate of muscle stem cells. The studies may have particular application to Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), congenital muscular dystrophy (CMD), facioscapulohumeral muscular dystrophy (FSHD) and limb-girdle muscular dystrophy (LGMD).
In most muscular dystrophies, muscle regeneration becomes less effective over time, and muscle is replaced by fibrosis (scar tissue).
"The factors that govern the establishment of fibrosis are not well-understood," Wagner said. "However, myostatin, a regulator of muscle growth, is one important factor in the development of fibrosis. In the absence of myostatin, muscle regenerates more quickly and with less fibrosis."
Wagner's studies will determine whether one of the cells that's important for muscle regeneration, a muscle stem cell called a satellite cell, can become misdirected and contribute to fibrosis. "The studies will specifically evaluate whether myostatin is a cue that directs satellite cells away from forming new muscle and toward fibrosis," Wagner said.
She noted that, if this hypothesis is correct, then anti-myostatin therapies could have an important role to play in stimulating muscle regeneration and reducing muscle fibrosis in a variety of diseases.
Funding for this MDA grant began August 1, 2011.
Grantee: MD — Kathryn Wagner, M.D., Ph.D.
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Grant - Summer 2011 - LGMD/IBM — Alfred Goldberg, Ph.D.
Alfred Goldberg, professor or cell biology at Harvard Medical School in Boston, has received an MDA research grant totaling $410,777 over three years to continue research into the mechanisms underlying muscle atrophy, with particular relevance for limb-girdle muscular dystrophy (LGMD) and possibly inclusion-body myositis (IBM).
In his previous work, Goldberg has helped clarify the general mechanisms of muscle atrophy resulting from motor neuron disease, inactivity, various systemic diseases and myopathies.
Goldberg and his research team will focus now on mechanisms that normally inhibit a protein called FoxO, which has been implicated in stimulating muscle protein breakdown.
Of particular interest to the team are two proteins, PGC1-alpha and SIRT1, both of which previously have been shown to inhibit FoxO function.
Further studies of these and other proteins' protective mechanisms could suggest new ways of combating muscle degeneration and atrophy.
"Over the years, my laboratory has received generous support from the Muscular Dystrophy Association, which has made possible a number of important findings about protein metabolism in muscle, and specifically about the mechanisms of muscle atrophy," Goldberg said. "My colleagues and I are very grateful for the support."
Funding for this MDA grant began August 1, 2011.
Grantee: LGMD/IBM — Alfred Goldberg, Ph.D.
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Grant - Summer 2011 - LGMD/DD — Jennifer Levy, Ph.D.
Jennifer Levy, a postdoctoral research fellow in the department of molecular physiology & biophysics at the University of Iowa Carver College of Medicine, has been awarded an MDA development grant totaling $180,000 over three years. (This type of grant reflects MDA's commitment to the career development of promising young researchers.) The funds will support Levy's research on repair of the muscle-fiber membrane.
Each muscle fiber is surrounded by a membrane that undergoes frequent rounds of damage and repair, assisted by a protein called dysferlin.
Dysferlin is deficient in the type 2B form of limb-girdle muscular dystrophy (LGMD) and the Miyoshi form of distal muscular dystrophy (DD). In these forms of MD, muscle-fiber membrane repair is ineffective and is accompanied by inflammation. However, the relationship between dysferlin deficiency and inflammation is not fully understood.
"I aim to identify the aberrant membrane repair mechanisms that compensate for the loss of dysferlin," Levy said, "and to determine if dysferlin-independent membrane repair signals immune cells to augment inflammation at sites of muscle injury."
She said identifying new factors that contribute to muscle inflammation in dysferlin-deficient patients may also lead to the discovery of new therapeutic strategies for other muscular dystrophies also associated with inflammation.
"MDA is critical to the funding of my research," Levy said. "As I am currently a postdoctoral research fellow, this funding will be beneficial in my development into an independent investigator."
Funding for this MDA grant began August 1, 2011.
Grantee: LGMD/DD — Jennifer Levy, Ph.D.
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Grant - Summer 2011 - FSHD — Michael Kyba, Ph.D.
MDA awarded a research grant totaling $375,000 over three years to Michael Kyba, assistant professor in the Lillehei Heart Institute and department of pediatrics at the University of Minnesota in Minneapolis. The funds will help support Kyba's efforts to identify and test experimental therapies in facioscapulohumeral muscular dystrophy (FSH, or FSHD).
The mutation associated with FSHD is a contracted (deleted) segment of DNA in a region of chromosome 4 called D4Z4. The D4Z4 region consists of a series of repeated DNA sequences. It is not yet fully understood how the contraction causes the disease, but scientists have found that it appears to modify the packaging of this part of chromosome 4 so that a gene named DUX4, which is encoded within each D4Z4 repeat, becomes active.
Kyba and colleagues are developing mice that carry the DUX4 gene. The team aims to identify and test drug- and genetic-based inhibitors of DUX4 in the mice, the most promising of which potentially may lead to experimental therapies for FSHD.
"This research project is directed at developing a treatment for FSHD," Kyba said. "As MDA is dedicated to curing muscular dystrophy, this is a natural partnership. Support from MDA is critical to our success."
Funding for this MDA grant began August 1, 2011.
Grantee: FSHD — Michael Kyba, Ph.D.
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Grant – Winter 2011 – SM - Claudio Sette, Ph.D.
MDA has awarded a research grant totaling $219,000 over three years to Claudio Sette, associate professor for the department of public health and cell biology at the University of Rome Tor Vergata in Rome, Italy. The new funds will help support Sette’s study of the molecular mechanisms underlying spinal muscular atrophy (SMA).
SMA is caused by mutations in the SMN1 gene, which leads to a deficiency of the protein SMN (for "survival of motor neuron") and subsequent degeneration and death of the motor neurons in the spinal cord. Although SMN2, a gene almost identical to SMN1, is present in humans, it's unable to compensate for SMN1's loss due to differences in the two genes' protein-building instructions. With the exception of the case in which an occasional error may result in a functional or partially functional protein, SMN2-derived proteins are short, highly unstable, and for the most part nonfunctional.
Sette and colleagues intend to test a variety of ways to modulate the SMN2 gene, forcing it to mimic the SMN1 gene and process its protein-building instructions in such a way as to lead to the production of functional SMN protein and prevention of motor neuron degeneration and death. Results from Sette’s work should increase understanding of the molecular mechanisms responsible for SMA — in particular, the molecular defects responsible for motor neuron degeneration. In addition, the group’s studies may lead to new therapeutic approaches for treatment of the disease.
Funding for this MDA grant began February 1, 2011.
Grantee: SM - Claudio Sette, Ph.D.
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Grant – Winter 2011 – SBMA - J. Paul Taylor, M.D., Ph.D.
J. Paul Taylor, associate member of St. Jude Children’s Research Hospital in Memphis, Tenn., has received an MDA research grant totaling $330,000 over three years. The funds will help support Taylor’s continued research into a number of possible therapeutic targets in spinal-bulbar muscular atrophy (SBMA).
In prior research funded by MDA, Taylor and colleagues developed a fruit fly model of SBMA and used it to determine how mutations in the androgen receptor (AR) gene lead to the death of motor neurons (nerve cells) and deterioration of muscle in this disease.
Specifically, the study team determined that toxicity occurs only when mutant AR enters the cell nucleus and binds to DNA. The team determined that toxicity is mediated by a small interaction surface on AR called "AF2." The team also has determined that toxicity is strongly enhanced by a chemical modification called "sumoylation."
Now, Taylor intends to continue along the same line of study, testing the validity of two therapeutic targets, AF2 and sumoylation, identified in his previous work.
The team will engineer new mouse models of SBMA, some carrying normal forms of AR and others carrying mutant forms of the protein that are defective in DNA binding, incapable of undergoing sumoylation, or have a disrupted or nonfunctional AF2 surface. In parallel, the team will work to identify small molecule inhibitors of these targets in their fruit fly model.
Findings derived from Taylor’s studies could lead to the identification of compounds that can be developed for human clinical testing.
"Funding from MDA has been essential to my research program," Taylor said. "Our previous findings were made possible by MDA, and this new grant from MDA is essential to translating those findings into meaningful therapies."
Funding for this MDA grant began February 1, 2011.
Grantee: SBMA - J. Paul Taylor, M.D., Ph.D.
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Grant – Winter 2011 – Mito. Myopathy - Antoni Barrientos, Ph.D.
MDA has awarded a research grant totaling $346,500 over three years to Antoni Barrientos, an associate professor in the departments of neurology and biochemistry and molecular biology at the University of Miami (Florida) Miller School of Medicine. The grant will help support Barrientos' study of the underlying molecular mechanisms in some forms of mitochondrial myopathy.
In the mitochondrial myopathies, commonly caused by the deficiency of an enzyme called cytochrome c oxidase (COX), cellular energy production is severely compromised, affecting brain, muscle and other organs with high energy demands. A complete understanding of COX synthesis is essential for uncovering the molecular basis underlying these diseases.
Barrientos and colleagues recently identified in a yeast research model two "chaperone" proteins responsible for helping assemble the COX enzyme.
Now, Barrientos plans to study the human equivalents of the two yeast proteins to determine whether their functions in humans are comparable. To do this, his team will use a gene silencing technique to "turn off" the genes that carry instructions for production of the chaperones, essentially inhibiting the proteins' production and enabling the investigators to identify what happens (or what doesn't happen) in their absence.
Barrientos' previous MDA-funded work has resulted in significant contributions to scientists' understanding of factors involved in COX assembly and regulation of the COX biogenetic process. Now, findings from his new work potentially may lead to therapeutics based on targeting the genes that carry instructions for the two COX assembly chaperones.
"MDA support is extremely important to our laboratory," Barrientos said, adding, "I have been working on cytochrome c oxidase assembly for the last 12 years, beginning with my postdoctoral studies at Columbia University, always with the support of MDA."
Funding for this MDA grant began February 1, 2011.
Grantee: Mito. Myopathy - Antoni Barrientos, Ph.D.
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Grant – Winter 2011 – MTM - James Dowling, M.D., Ph.D.
MDA has awarded a research grant totaling $353,679 to James Dowling, assistant professor in the departments of pediatrics and neurology at the University of Michigan Medical Center in Ann Arbor. The funds will help support Dowling's research into potential therapies for myotubular myopathy (MTM).
For his latest line of research, Dowling has partnered with Christopher Pierson, an assistant professor in the department of neuropathology at Nationwide Children's Hospital in Columbus, Ohio.
Recently the two identified abnormalities in a part of the muscle called the neuromuscular junction (NMJ), the meeting point of nerve cells and muscle fibers, in a model of MTM. They also found that treatment targeted to the NMJ greatly improved function in the model.
Now, using a research mouse model of MTM, the study team will examine the relationship between the NMJ and the disease. In addition, the investigators will test a commonly used NMJ-modifying drug in the model to determine whether it affects disease progression.
Findings from this work are expected to significantly advance understanding of the MTM disease process, and may lead directly to treatment for people with the disease.
"MDA has been and continues to be a critical funding source for my research," Dowling said. "My work in this area of study started with support from the MDA in the form of an MDA development grant. Using the funding from that grant, I was able to make major inroads in terms of our understanding of MTM. This work also provided the relevant data from which the hypothesis for our new study evolved.
"We believe the results of this study, funded by the MDA, will lead to the first therapy for MTM."
Funding for this MDA grant began February 1, 2011.
Grantee: MTM - James Dowling, M.D., Ph.D.
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Grant – Winter 2011 – MMD - Mani Mahadevan, M.D.
MDA has awarded a research grant totaling $435,000 over three years to Mani Mahadevan, professor in the department of pathology, medical director of the molecular diagnostics lab and associate director of the cytogenics lab at the University of Virginia in Charlottesville. The new funds will help support Mahadevan’s study of the underlying molecular mechanisms in type 1 myotonic muscular dystrophy (MMD1, or DM1).
MMD1 is caused by an expanded section of DNA in the DMPK gene that results in the accumulation of mutated DMPK RNA (the chemical step between DNA instructions and protein production) in the cell’s nucleus. These "RNA foci" are thought to lead to RNA toxicity by affecting the function of RNA binding proteins that interact with the toxic RNA, disrupting normal RNA processing.
Using muscle cells taken from research mouse models and MMD1-affected individuals, Mahadevan and colleagues plan to examine the interactions in MMD1 between a number of particular proteins and DMPK RNA.
Mahadevan’s work potentially may lead to a greater understanding of the molecular mechanisms that drive MMD1, which will further inform researchers’ efforts to design therapeutics to combat the disease.
"MDA has funded research in my lab since 1998, and often has been the first agency to fund our research at its earliest stages," Mahadevan said. "I am sincerely grateful for the trust and confidence the Association has placed in us and our research."
Funding for this MDA grant began February 1, 2011.
Grantee: MMD - Mani Mahadevan, M.D.
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Grant – Winter 2011 – MMD - John Lueck, Ph.D.
MDA has awarded a research development grant totaling $180,000 over three years to John Lueck, a postdoctoral fellow at the University of Iowa Carver College of Medicine in Iowa City. The new funds will help support Lueck’s research into the mechanisms responsible for muscle weakness and degeneration in type 1 myotonic muscular dystrophy (MMD1, or DM1).
Although a number of bodily systems are affected in MMD1, likely due to flaws in a number of molecular pathways, and while some progress has been made in understanding certain of these areas, the particular mechanism that underlies muscle weakness and degeneration in the disease has yet to be elucidated.
Lueck and colleagues plan to use a multifaceted approach, using research mouse models of MMD1 and tissue taken from individuals with MMD1 to zero in on the specific molecular flaws responsible for muscle weakness and degeneration, as well as the mechanisms through which those flaws work. Such understanding is crucial for both understanding the MMD1 disease process and for pinpointing targets at which potential therapeutics may be aimed.
"As I am in the early career stages of becoming an independent investigator, the process of obtaining MDA funding has been crucial for gaining experience in grantsmanship, and securing funding for my work," Lueck said. "Importantly, MDA is promoting basic and applied research to not only better understand normal function but also mechanisms of muscle disease and therapy development."
Funding for this MDA grant began February 1, 2011.
Grantee: MMD - John Lueck, Ph.D.
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Grant – Winter 2011 – MMD - Araya Puwanant, M.D.
MDA has awarded a clinical research training grant totaling $173,400 to Araya Puwanant at the University of Rochester (New York) Medical Center. The new funds will support completion of a two-year fellowship during which Puwanant will study the disease process in myotonic muscular dystrophy (MMD, or DM).
"In recent years there has been progress in understanding why people with MMD develop muscle weakness and stiffness," Puwanant said. "As more is being learned about the disease, scientists are making progress in developing experimental treatments."
Some therapies currently under development likely will move from laboratory testing to testing in human clinical trials.
"In preparation for clinical trials, we need to have detailed information about how the condition changes over time," said Puwanant. "We also need to find good ways to measure whether new treatments are having a beneficial effect."
Puwanant will be taking part in research studies to carefully chart the progression of MMD over time in a large group of individuals with the disease. Analysis of these observations is expected to help to determine the best way to measure the severity of MMD. Additionally, information gained from Puwanant’s study may help determine the effectiveness of future experimental treatments for the disease.
Funding for this MDA grant began February 1, 2011.
Grantee: MMD - Araya Puwanant, M.D.
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Grant – Winter 2011 – MG - Pragna Patel
MDA has awarded a research grant totaling $121,139 to Pragna Patel, professor at the Institute for Genetic Medicine, Keck School of Medicine, at the University of Southern California in Los Angeles. The new funds will help support Patel’s research aimed at determining the faulty gene responsible for myasthenia gravis (MG) in a particular family with the disease.
Although MG tends to be sporadic, Patel and colleagues have identified a family in which 10 individuals in two consecutive generations are affected with the disease. The study team has narrowed down the region of DNA in which the gene responsible for these familial, or inherited, cases is likely located; using state-of-the-art technology the team plans to identify not only the gene, but genetic factors that operate in the same cellular pathway or through similar means.
"The typical person with MG has no family history of the disease, thus making it very challenging to identify genes responsible for causing the disease," Patel said. "The knowledge gained from studying the rare family with MG could potentially be used to identify genetic factors that act in the same cellular pathway, or by a similar mechanism, in all or most cases of MG.
Findings from Patel’s study could uncover biological targets at which scientists could aim future therapies.
"MDA funding is vital to our ability to accomplish our goal of finding MG-associated genes," Patel said, noting previous support from the Association has allowed her to conduct a number of studies and add to the collective knowledge pool surrounding MG and also type 1 Charcot-Marie-Tooth disease (CMT1A).
Funding for this MDA grant began February 1, 2011.
Grantee: MG - Pragna Patel
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Grant – Winter 2011 – MG - Jon Lindstrom
MDA has awarded a research grant totaling $450,000 over three years to Jon Lindstrom, professor of neuroscience and pharmacology at the Medical School of the University of Pennsylvania in Philadelphia. The new funds will help support Lindstrom’s continued efforts to develop an immunosuppressive therapy for myasthenia gravis (MG).
MG is caused by an immune system attack, via antibodies, on acetylcholine receptors in muscle. The attack leads to the degradation and loss of the acetylcholine receptors, disrupting communication between nerves and muscles. The cause of the disease is unknown.
Lindstrom and colleagues are working on the continued development of a specific immunosuppressive therapy for MG, which they developed using a rat research model of the disease. The team will continue testing the therapy while working in parallel to determine the mechanisms by which it works.
Current therapies for MG compensate for the loss of acetylcholine receptors by using inhibitors to block the enzyme that destroys acetylcholine, along with drugs that cause massive suppression of all, or nearly all, immune responses.
In contrast, the therapy under development by Lindstrom's team is designed to target only the immune system attack on acetylcholine receptors. Such a therapy is expected to be more effective than those in use now and likely would preclude some of their known side effects.
Results of Lindstrom’s work may lead to further insight into the MG disease process and inform researchers’ efforts at therapy development.
"Support from the MDA has been important to my career from its very beginning when we first discovered EAMG and made progress in understanding its nature," Lindstrom said. "Hopefully, this new support from the MDA will help us go full circle, from helping to discover the autoimmune nature of the disease to helping to discover how to specifically suppress the autoimmune response in MG."
Funding for this MDA grant began February 1, 2011.
Grantee: MG - Jon Lindstrom
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Grant – Winter 2011 – MG - Chi Wai Lee
MDA has awarded a research development grant totaling $180,000 over three years to Chi Wai Lee, postdoctoral fellow in the department of cell biology at Emory University School of Medicine in Atlanta. The grant will help support Lee’s research into therapeutic strategies to ameliorate the symptoms in myasthenia gravis (MG).
In MG, the immune system attacks the acetylcholine receptors responsible for nerve-to-muscle communication, leading to muscle weakness due to the loss of nerve signals. Lee’s team plans to uncover the mechanisms underlying the attack and subsequent loss of acetylcholine receptors.
Using frog and mouse MG research models, Lee and colleagues plan to examine the molecular and cellular mechanisms underlying proper functioning of the neuromuscular junction (NMJ), the place where nerve meets muscle and where acetylcholine receptors do their job.
Results from Lee's work are expected to provide increased understanding of the molecular and cellular mechanisms underlying degradation and loss of acetylcholine receptors in the NMJ. In addition, data analysis may point the way to new therapies designed to ameliorate MG symptoms by targeting the mechanisms underlying acetylcholine receptor loss.
"I am very grateful to receive this MDA development grant at the early stage of my scientific career," Lee said. "The support from MDA will allow me to extend my current research and training to become an independent researcher focusing on the study of neuromuscular diseases."
Funding for this MDA grant began February 1, 2011.
Grantee: MG - Chi Wai Lee
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Grant – Winter 2011 – MD - Xiaohua Wu, M.D., Ph.D.
MDA has awarded a research grant totaling $224,863 over three years to Xiaohua Wu, research faculty for the drug discovery group at the McColl-Lockwood Laboratory for Muscular Dystrophy Research at Carolinas Medical Center in Charlotte, N.C. The new funds will help support Wu’s research into effective therapies for various types of muscular dystrophy (MD).
The majority of muscular dystrophies are associated with compromised linkages between key structures due to various genetic defects, Wu said. The linkages play crucial roles in muscle function, and strengthening them by increasing the activity of certain genes has proven useful in MD mouse models.
In his new work, Wu and colleagues plan to screen more than 100,000 small compounds and identify those that might help enhance muscle function in various MDs.
The team will then test the therapeutic potential of the identified compounds in cell culture and MD mouse models.
Findings from Wu's work are expected to speed development of drugs for treatment of a number of muscular dystrophies.
"The new MDA grant is essential for our project," Wu said, "allowing us to gather enough resources to conduct the research necessary for developing drugs for MDs."
Funding for this MDA grant began February 1, 2011.
Grantee: MD - Xiaohua Wu, M.D., Ph.D.
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Grant – Winter 2011 – MC - Mark Rich, M.D., Ph.D.
MDA has awarded a research grant totaling $53,358 to Mark Rich, an associate professor at Wright State University in Dayton, Ohio. The new funds will help support Rich’s study of the disease process in myotonia congenita (MC).
MC is an inherited muscle disease in which muscle is stiff because it contracts too much. The cause of stiffness is a mutation in a protein that is involved in electrical signaling in muscle.
Rich and colleagues plan to study a particular clinical feature of MC: While patients exercise, their muscle stiffness lessens. The effect is temporary and reverses after exertion. The team will work with a mouse model of MC that, like humans with the disease, experiences muscle stiffness that decreases with exercise.
Rich’s goal is to determine the molecular mechanisms underlying the exercise effect in MC. His team hypothesizes that a single protein may be responsible for "turning on" during exercise and causing the reduction in stiffness. If findings from the work identify such a protein, then it potentially could be targeted and manipulated into turning on all the time, providing symptomatic relief to individuals with the disease.
The investigators will test the drug in the mouse and observe whether it reduces their stiffness.
"MDA funding is critical to the success of this project," Rich said.
Funding for this MDA grant began February 1, 2011.
Grantee: MC - Mark Rich, M.D., Ph.D.
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Grant – Winter 2011 – LGMD - Peter Kang, M.D.
MDA has awarded a research grant totaling $299,722 over three years to Peter Kang, assistant professor of neurology at Harvard Medical School and director of the electromyography laboratory at Children’s Hospital Boston. The funds will help support Kang’s research into identification of gene mutations that can cause limb-girdle muscular dystrophy (LGMD).
"More than 18 different genes have been linked to various forms of LGMD," Kang said. "Each subtype is rare, but in combination the LGMDs comprise a major class of inherited muscle diseases."
Kang and colleagues have gathered and analyzed DNA samples from a number of families affected by LGMD. The investigators will use both the traditional technique called "linkage analysis," and the newer "whole-genome sequencing" to find the new genes, after which they plan to determine which of those identified are likely to be causative mutations.
Whole-genome sequencing is expected to become widely available, probably on a clinical or even direct-to-consumer basis, within a few years, Kang noted. The major question that will surround the enormous volume of data will be clinical interpretation. This project will illustrate how whole-genome sequencing results can be meaningful for individual patients, and may serve as an example of how they can be applied in non-research settings.
The identification of additional LGMD-related genes is expected to expand scientists’ knowledge of muscle disease processes, and potentially lead to new therapeutic strategies for a number of LGMDs and other muscular dystrophies.
"The importance of MDA funding for a project such as this is enormous," Kang said. "MDA is one of the most significant funding agencies for research in this field, and has had a major impact on advancing our knowledge of neuromuscular diseases."
Funding for this MDA grant began February 1, 2011.
Grantee: LGMD - Peter Kang, M.D.
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Grant – Winter 2011 – LGMD - Michael Hauser, Ph.D.
Michael Hauser, an associate professor in the Section of Medical Genetics, Department of Medicine at Duke University Medical Center in Durham, N.C., has been awarded an MDA grant totaling $383,856 over a period of three years. The funds will help support Hauser's efforts to identify mutations responsible for dominantly inherited (type 1) limb-girdle muscular dystrophy (LGMD). (Dominant inheritance means only one gene mutation, inherited from one parent, is sufficient to cause the disease. As a result, offspring of affected individuals have a 50 percent probability of inheriting the condition from their parents.)
Although a number of genes have been associated with various types of LGMD, others remain as yet unidentified. Hauser and colleagues plan to uncover additional mutations responsible for type 1 LGMD.
To do this, the investigators will examine DNA samples collected from 18 families affected by dominantly inherited LGMD. They plan to use a sophisticated technique called whole exome sequencing to probe the genetic blueprints of the affected individuals and compile a list of possible LGMD-causing mutations. Finally, the team will test the mutations in a zebra fish research model of LGMD in order to determine which of them interfere with muscle function.
"Zebra fish are perfect for this approach, because they incorporate the mutated proteins into their own muscles and can be analyzed in just a few days," Hauser said. "The combination of whole exome sequencing and functional testing in the zebra fish is extremely powerful, and we hope to identify several new causes of muscular dystrophy in this way."
MDA funding, Hauser said, has played an "extremely important" role in his career.
Funding for this MDA grant began February 1, 2011.
Grantee: LGMD - Michael Hauser, Ph.D.
Grant type: Research Grant
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Grant – Winter 2011 – LEMS - William Atchison, Ph.D.
MDA awarded a research grant totaling $336,503 to William Atchison, professor of pharmacology/toxicology and acting dean for research at Michigan State University College of Veterinary Medicine in East Lansing. The funds will support Atchison's research into the biological mechanisms underlying Lambert-Eaton myasthenic syndrome (LEMS).
In LEMS, the immune system mistakenly mounts an attack, targeting proteins called "types P and Q calcium channels" located at the neuromuscular junction, the place where motor neurons (nerve cells) and muscles meet. These proteins regulate the release of acetylcholine, the chemical messenger that carries signals between the motor neuron and the muscle.
In previous MDA-supported work, Atchison found that mice treated with plasma taken from people with LEMS reacted to an attack on the P/Q calcium channels by recruiting members of other classes of calcium channels (types L and R) in an effort to compensate for loss of the P/Q types.
In his new work, Atchison plans to study the compensation strategy and determine how muscle-controlling nerve cells try to maintain their function via recruitment of the L and R types of calcium channels.
Atchison's work could pave the way to a gene therapy strategy based on increasing the availability of compensating proteins as a means of preventing disruption of the chemical messenger.
"MDA funding has been crucial in that it has allowed us to study a relatively rare neuromuscular disease, but one that has very severe consequences, and that affects the quality of life and its length in patients with LEMS," Atchison said. "It has also allowed us to focus on aspects of this disease that might help increase general understanding of how the neuromuscular system tries to compensate for damage in other forms of autoimmune disease."
Funding for this MDA grant began February 1, 2011.
Grantee: LEMS - William Atchison, Ph.D.
Grant type: Research Grant
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Grant – Winter 2011 – IBM - Steven Greenberg, M.D.
MDA has awarded a grant totaling $444,314 over a period of three years to Steven Greenberg at Brigham and Women's Hospital and Harvard Medical School in Boston. The funds will help support Greenberg's study of the role of a protein called TDP43 in sporadic and hereditary inclusion-body myositis (IBM).
In recent studies conducted on muscle fibers taken from people with IBM, researchers have found that a significant amount of TDP43 protein moves from its normal position inside the cell nucleus to the main part of the muscle fiber called the sarcoplasm. It's also known that TDP43 binds to RNA (the chemical step between DNA and protein synthesis), making it possible that the protein's redistribution in IBM disrupts the function of important RNA molecules in muscle sarcoplasm.
Greenberg and co-principal investigator J. Paul Taylor, M.D., Ph.D., at St. Jude Children's Research Hospital in Memphis, Tenn., plan to examine the effects of TDP43 redistribution to the sarcoplasm, with a particular focus on whether it causes damage to muscle fibers. (Taylor previously has demonstrated that similar mislocation of TDP43 is toxic in the eye of a fruit fly research model.) The researchers also plan to identify the specific RNA molecules affected by the mislocated TDP43.
MDA funding is critical, Greenberg said, because, "The Association funds translational discovery research, placing a priority on relevance to people with disease."
Funding for this MDA grant began February 1, 2011.
Grantee: IBM - Steven Greenberg, M.D.
Grant type: Research Grant
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