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.

Ellen Barrett, professor of physiology and biophysics at the University of Miami (Florida) Miller School of Medicine was awarded an MDA grant totaling $297,102 over three years. The funds will support Barrett's study of the disease process and potential therapies in familial, or inherited, ALS (amyotrophic lateral sclerosis, or Lou Gehrig's disease).

It has been observed in some cases of ALS that motor nerve terminals (the part of the motor neuron, or nerve cell that conveys signals from the brain to muscles) deteriorate prior to the death of the motor neuron cell body.

In previous studies, Barrett and colleagues have demonstrated that motor nerve terminal health relies heavily on the proper function of cellular "energy factories" called mitochondria. The team also has found that mitochondrial function in motor nerve terminals is impaired in presymptomatic mice with an ALS-like disease, and that it worsens as the mice age and begin to show symptoms.

In her new work, Barrett will test various mitochondria-protective drugs in a research mouse model of ALS and then observe whether more motor terminals remain intact and functional in mice that receive treatment versus mice that do not.

Results from this work may point the way toward a therapeutic strategy involving a combination of treatments: some designed to protect mitochondria and preserve motor nerve terminals, and others targeted toward preservation of motor neuron cell bodies.

"MDA funding has been critical to research progress in our laboratory," Barrett said. "We have especially appreciated MDA’s (1) willingness to support basic as well as clinical research with relevance to neuromuscular diseases; (2) support for pilot projects investigating new research directions; and (3) excellent reviewers, who have always read our grant applications carefully and offered valuable suggestions."

Funding for this MDA grant began February 1, 2011.

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.

Harold Bernstein, professor of pediatrics at the University of California, San Francisco, has been awarded an MDA research grant totaling $540,000 over three years. The award will help support Bernstein's study of human muscle development and potential cell-based therapies for treatment of degenerative muscle diseases such as Duchenne muscular dystrophy (DMD).

In his new work, Bernstein and colleagues will study the pathways that different types of muscle stem cells follow as they form new muscle, and identify the particular muscle stem cell types that appear most suited for therapeutic development.

The team will first observe the maturation of human stem cells into muscle cells in culture (in the laboratory), as a means of identifying the stages of normal muscle development. The investigators will then transplant the cells at various stages of development into the leg muscles of mice with a disease resembling DMD and study the process by which these cells become new muscle tissue, how this affects the animals' ability to exercise, and the strength of the treated muscles.

Bernstein's team hopes to fully elucidate the process of normal human muscle stem cell development and, in addition, identify specific stem cell types that may provide therapeutic benefit when transplanted into DMD-affected muscle.

"Funding from the Muscular Dystrophy Association will allow us to extend our research on muscle development and stem cell biology into studies specifically focused on therapy," Bernstein said. "This funding provides important support for research that will directly translate into improved treatment for patients with muscular dystrophy."

Funding for this MDA grant began February 1, 2011.

MDA has awarded a clinical research training grant totaling $180,000 to clinical research fellow James Berry at Massachusetts General Hospital (MGH) in Boston. The grant will support completion of a two-year fellowship during which Berry plans to study the effects of a drug called ISIS-333611 in familial, or inherited, ALS (amyotrophic lateral sclerosis, or Lou Gehrig’s disease).

Familial ALS accounts for 5 to 10 percent of all ALS cases. About 20 percent of those (1 to 2 percent of all ALS cases) are caused by a mutation in the SOD1 gene, which leads to production of abnormal SOD1 protein.

Berry is a member of the study team currently planning a phase 2 clinical trial of intrathecal (into the spinal canal) administration of the experimental drug ISIS-333611 (made by Isis Pharmaceuticals of Carlsbad, Calif.) in people with familial ALS. The trial will be a follow-on study to a phase 1 trial of the drug, currently under way, if results from that trial are favorable.

Previous studies of the drug in rats have shown that it is safe and tolerable, that it reduces mutant SOD1 RNA (the chemical step between DNA and protein synthesis) and protein levels, and slowed progression of the disease. It's thought that decreasing mutant SOD1 levels in humans may confer similar therapeutic benefits.

The planned phase 2 study will test ISIS-333611 over an extended period of time to assess its safety and tolerability. If the phase 2 trial is successful, a phase 3 trial may be planned to test efficacy of the drug.

"MDA funding is critical to my career development and my ability to begin my career as a clinical researcher in ALS," Berry said. "I am incredibly excited to have received this award, and I am looking forward to getting started on the project."

Funding for this MDA grant began February 1, 2011.

MDA has awarded a grant totaling $347,094 over three years to François Berthod, a professor in the department of surgery at Laval University in Quebec City, Quebec, Canada. The funds will help support Berthod's study of the underlying molecular mechanisms and disease process in ALS (amyotrophic lateral sclerosis, or Lou Gehrig's disease).

ALS is characterized by the degeneration of motor neurons (nerve cells that control muscle movement) in the spinal cord and brain.

Berthod, who has a background in tissue engineering, previously has shown that human motor neurons can differentiate (mature) from a population of stem cells obtained from human skin.

Now, Berthod plans to develop a three-dimensional model of the human spinal cord using neural (nervous system) cells obtained from the tissues of people with ALS. The human tissue-engineered spinal cord (TESC) model is expected to mimic the human disease "in vitro," or in a laboratory setting. Its design will permit testing of the interactions of various neural cell types, including motor neurons and neuroprotective cells such as astrocytes, microglia and Schwann cells, as a means of determining the conditions that induce or aid motor neuron death in ALS.

Findings from Berthod's work are expected to improve understanding of the causes and progression of sporadic ALS.

"MDA funding over the years has been the only source of support for our research on amyotrophic lateral sclerosis," Berthod said, adding that it's been "the strongest encouragement to continue developing innovative in vitro models of this disease."

Funding for this MDA grant began February 1, 2011.

Andrew Brack, an assistant professor at the Center for Regenerative Medicine at Massachusetts General Hospital in Boston, was awarded an MDA research grant totaling $353,259 over three years. The funds will help support Brack's research into the function of adult muscle stem cells called "satellite cells" in Duchenne muscular dystrophy (DMD) and possibly in other muscular dystrophies as well.

Satellite cells are responsible for tissue maintenance and repair over a lifetime. It's widely accepted among scientists that these cells are sufficient to promote muscle repair; however, it is unknown what is required of them for regeneration of diseased skeletal muscle and whether the number and function of cells in the satellite cell pool can be manipulated as a means of slowing or ameliorating disease progression.

Brack and colleagues plan to use targeted genetic approaches to manipulate the number and function of adult satellite cells in a research mouse model of DMD. From this they hope to gain an understanding of the relative importance of both number and functionality of satellite cells needed for effective muscle repair.

Results from Brack's work may shed light on new therapeutic strategies for slowing disease progression that are based on retaining a functional pool of satellite cells in people with DMD and other muscular dystrophies.

"Without funding through MDA," Brack said, "this project would not have been realized."

Funding for this MDA grant began February 1, 2011.

MDA has awarded a research grant totaling $398,541 to Giovanni Coppola, assistant professor and co-director at the University of California, Los Angeles, Informatics Center for Neurogenetics and Neurogenomics. The funds will help support Coppola's research into biological indicators, called "biomarkers," in Friedreich's ataxia (FA).

In a recent pilot study, Coppola and colleagues used microarray technology (a technique that allows researchers to check the gene "expression," or activity, level of thousands of genes at the same time) to identify a set of 77 genes that exhibited changes that correlated with disease status in 10 FA-affected individuals, 10 healthy volunteers and 10 FA "carriers," (people who carry only one defective copy of the gene responsible for FA).

In his new work, Coppola plans to validate the 77 previously identified genes by studying a 10-times larger group of subjects over a period of three years.

Coppola hopes to identify a "signature" of disease that can be used in clinical trials to monitor disease progression and the effects of experimental treatments.

"MDA funding will allow me to test an innovative approach to identifying biomarkers in Friedreich's ataxia, which can potentially be applied to a number of other neurogenetic diseases as well," Coppola said.

In parallel with its biomarker studies, Coppola's team plans to collect genetic information, including gene expression data, from study participants. The researchers will store the data in a large Web-based database, providing the scientific community with the first centralized repository of gene expression data in FA.

Funding for this MDA grant began February 1, 2011.

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.

Dongsheng Duan, professor in the department of molecular microbiology & immunology at the University of Missouri in Columbia, has received an MDA grant totaling $527,670 over three years. The funds will help support Duan's continued research into gene therapy in Duchenne muscular dystrophy DMD).

DMD is caused by a mutation in the dystrophin gene, which leads to the absence, or near absence, of dystrophin protein.

Duan has worked extensively in the past with adeno-associated virus (AAV) "vectors," the emptied shells of viruses used to encapsulate healthy genes (or modified — in this case, shortened "mini-" or "mirco-dystrophin" genes), which are then injected locally or systemically into research model test subjects undergoing gene therapy treatment.

In previous studies, AAV-mediated micro-dystrophin gene therapy has shown great promise in ameliorating the symptoms of DMD, and recent developments in systemic AAV delivery suggest the potential for whole-body correction of the flawed dystrophin gene responsible for the disease.

In his latest work, Duan and colleagues plan to test both a new AAV delivery vehicle and a new micro-dystrophin gene, first in a research mouse model of DMD and later in another animal research model of the disease. The investigators will evaluate whether the novel combination ameliorates DMD symptoms.

Findings from this study potentially could accelerate DMD gene therapy research and help advance the strategy to human clinical testing.

"We can now cure a mouse with a DMD-like disease; however, this accomplishment has not been reproduced in people with the disease," Duan said. "The support we receive from MDA is essential for us to move DMD gene therapy forward."

Funding for this MDA grant began February 1, 2011.

MDA has awarded a research grant totaling $442,023 over three years to Madeleine Durbeej-Hjalt, a professor in muscle biology at Lund University (Sweden), Department of Experimental Medical Science. The grant will help support Durbeej-Hjalt's study of muscle-protein degradation processes in type 1A congenital muscular dystrophy (CMD1A).

CMD1A is caused by mutations in the gene for laminin alpha 2, a protein strand in a larger protein called merosin that connects muscle fibers to their surrounding tissue. Without the laminin alpha 2 strand, the normally three-stranded merosin protein can't perform this connective function and severe neuromuscular dysfunction results.

Although evidence indicates that loss of laminin alpha 2 leads to CMD1A, the underlying molecular mechanisms that cause muscle damage and loss in the disease remain unclear. Durbeej-Hjalt and colleagues hypothesize that muscle degeneration may be caused, at least in part, by increased destruction of muscle proteins through one or both of two major cellular protein degradation systems: the cellular "garbage can" known as the proteasome, or via the autophagic-lysosomal pathway, in which cell components are degraded and recycled through the cellular "recycle bin," or lysosome.

Durbeej-Hjalt's team has data indicating that activity in both protein degradation systems is increased when laminin alpha 2 is missing, and the investigators plan to test whether treatment with proteasome or autophagy inhibitors can block protein degradation and lead to improvement in muscle health.

Findings from Durbeej-Hjalt’s new study may generate important preclinical data that could lead to the development of therapies for people with CMD1A.

"I am extremely grateful for the MDA funding I have received since 2005," Durbeej-Hjalt said. "Without the MDA grants, my research group would not exist today."

Funding for this MDA grant began February 1, 2011.

MDA has awarded a research grant totaling $375,000 over three years to David Goldhamer, associate professor, director of the Center for Regenerative Biology, and associate director of the UConn Stem Cell Institute at the University of Connecticut in Storrs. The new funds will help support Goldhamer’s study of muscle stem cells and the repair of damaged muscle in Duchenne muscular dystrophy (DMD).

"Satellite" cells are adult muscle stem cells that are responsible for postnatal muscle growth and the repair of damaged muscle in injury and disease. In DMD, accumulation of intramuscular fat and connective tissue represent hallmarks of advanced disease, and the presence of these non-muscle tissues significantly affects muscle structure and function.

Satellite cells have been implicated as a possible cell of origin for increased fat and fibrotic (scarred) tissue in DMD muscle, but their involvement remains uncertain and controversial.

Using a research mouse model with a DMD-like disease, Goldhamer and colleagues will examine whether satellite cells promote increased fat and fibrosis in diseased muscle. In addition, the team will study regulators of muscle regeneration that may interact with or regulate satellite cell functions.

Results from Goldhamer’s work may help determine the potential benefits of modulating satellite cell behavior as a therapeutic strategy in DMD.

Funding for this MDA grant began February 1, 2011.

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.

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.

MDA awarded a grant totaling $367,386 over three years to Masahiko Hoshijima, professor of medicine at the University of California, San Diego in La Jolla, Calif. The funds will help support Hoshijima's research into connections between cardiac and respiratory failure in muscle diseases such as Duchenne (DMD), Becker (BMD) and other muscular dystrophies (MDs).

Hoshijima plans to study how heart failure and respiratory failure are interlinked in MD. Weakness of the respiratory muscles, including the diaphragm and intercostal (part of the rib cage) muscles, leads to inadequate breathing called "hypoventilation" in many MDs. In contrast, these diseases affect the heart muscle directly.

Using the BIO14.6 hamster research model, Hoshijima and colleagues will administer gene therapy selective for muscle type at two different time points: early-stage treatment meant to prevent disease onset and progression, and later treatment meant to "rescue" animals after heart and respiratory system damage is well-developed.

One group of animals will receive heart treatment only; a second group will be treated with a therapy that targets skeletal and respiratory muscles and excludes heart treatment. The study team hopes data from these studies can clarify how heart failure and respiratory failure are independently as well as collaboratively contributing to the ultimate disability and death of the animal model of muscular dystrophy.

In further studies, the investigators plan to administer muscle-specific gene therapy to the rodent model in order to determine whether heart treatment can improve respiratory function and whether skeletal muscle-specific gene therapy can benefit systemic circulation.

Findings from Hoshijima's work may provide a better understanding of how better to treat human muscular dystrophies that affect more than one muscle type.

MDA funding, Hoshijima noted, is "vital to select rare-disease patient groups who can find hope in the potential for development of therapies tailored to their diseases."

Funding for this MDA grant began February 1, 2011.

Update (April 1, 2015): Adrian Israelson is now at Ben-Gurion University of the Negev in Beer Sheva, Israel.

MDA has awarded a research development grant totaling $180,000 over three years to Adrian Israelson, a postdoctoral researcher at the University of California, San Diego in La Jolla, Calif. The funds will help support Israelson’s study of the underlying mechanisms governing motor neuron (nerve cell) death in SOD1-related familial ALS (amyotrophic lateral sclerosis, or Lou Gehrig's disease).

Israelson noted that mutant SOD1 has been shown to inappropriately associate with the cellular "energy factories," called mitochondria that are responsible for generating the power to run all cellular processes — but only in nervous system cells.

He previously has demonstrated in cell culture and in an ALS rat research model that mutant SOD1 binds directly to a key protein channel called VDAC1, which controls the import and export of chemicals required by mitochondria for power production. He also has shown that the misfolded portion of mutant SOD1 that is present in spinal cord mitochondria binds to the VDAC1 channel, inhibiting its conductance and compromising the energy supply for motor neurons.

Israelson's new work will focus on the ways in which mutant SOD1 protein associates with mitochondria, and whether and how that interaction affects the energy factories' function, possibly leading to motor neuron death. In addition the data may shed light on how modification of mutant SOD1 misfolding and the protein's association with mitochondria might affect mutant SOD1 toxicity.

Findings from these studies may provide valuable insight needed for development of therapies that either slow or prevent the degenerative process in ALS.

"Generous funding from MDA is very important," because of the Association's commitment to stopping rare diseases, Israelson said. "Thanks to the support of MDA, we’re able to keep investigating neuromuscular diseases that otherwise might go underfunded and unstudied."

Funding for this MDA grant began February 1, 2011.

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.

MDA has awarded a research grant totaling $210,618 over two years to David Kass, professor of cardiology, medicine and biomedical engineering at Johns Hopkins University in Baltimore. The new funds will help support Kass’ study of the disease process and potential therapeutic strategies in Duchenne (DMD), Becker (BMD) and other muscular dystrophies.

One particular problem in DMD is hyperactive "TRPC" channels in the muscle cell membrane that leak calcium and sodium. These channels can increase calcium levels inside the cell, stimulating oxidative stress, which can lead to cell damage and/or death.

Kass and colleagues recently discovered that a protein called PKG (for protein kinase G) can directly suppress TRPC channels.

Kass plans to test the importance of PKG activation to block stimulated TRPC channels in both heart muscle and skeletal muscle cells in research models of muscular dystrophy, and determine if such modification can inhibit muscle damage associated with excess calcium and oxidative stress.

Findings from Kass’ work may inform development of a treatment based on the pathways relevant to TRPC channel regulation. A number of drugs already approved for treatment of other conditions by the U.S. Food and Drug Administration (including sildenafil, or Viagra) hold potential for this type of treatment.

"It's great to become part of the MDA family, and I am very excited about pursuing the work we are undertaking," Kass said.

Funding for this MDA grant began February 1, 2011.

MDA has awarded a research grant totaling $251,596 over two years to Shireen Lamande, senior research fellow and group leader for muscular dystrophy research and musculoskeletal disorders at Murdoch Childrens Research Institute in Parkville, Victoria, Australia. The new funds will help support Lamande’s research into the identification of new genes responsible for two types of congenital muscular dystrophy (CMD), Bethlem myopathy and Ullrich congenital muscular dystrophy.

Lamande and colleagues plan to identify new genes responsible for collagen 6-related congenital muscular dystrophies, and determine how and why mutations associated with the genes cause muscle disease.

To date, the study team has screened 100 people with Bethlem myopathy and Ullrich CMD, and has found collagen 6 mutations in 62. The remaining 38 do not have collagen 6 mutations, an indication that other, as yet unidentified, genes also underlie these disorders.

Of the 38 individuals whose mutations were unknown, the investigators have identified new mutations in 11. They now plan to use a variety of methods to examine the newly uncovered genes, and identify those that are new muscular dystrophy candidate genes.

Results from Lamande’s work should improve the diagnostic process for individuals and families, and increase scientists’ understanding of muscle biology and disease.

Funding for this MDA grant began February 1, 2011.

MDA has awarded a research grant totaling $341,250 over three years to Jocelyn Laporte at the University of Strasbourg, France. The new funds will help support Laporte’s efforts to identify genes responsible for centronuclear/myotubular myopathies (CNM)/(MTM).

Laporte noted that his lab identified some of the first genes associated with these types of diseases in 1996, but that a number of other CNM-causing genes remain to be identified. Using a sophisticated technology called "high-throughput sequencing," also known as "massively parallel sequencing," Laporte and colleagues plan to uncover new genes associated with CNM.

The main challenge of this novel approach is the identification of the causative mutation among the many DNA variants that are not connected to the myopathy. It will require special effort to analyze the data.

Findings from Laporte’s work likely will facilitate diagnosis of CNM in individuals, improve genetic counseling services, and lend insight to better care and follow-up after diagnosis. In addition, the identification of causative genes will help inform scientists of the underlying disease mechanisms, help researchers determine eligibility for human clinical testing, and provide new targets at which to aim potential new therapies.

"MDA funding is a key factor for successful research on rare muscle diseases," Laporte said.

Funding for this MDA grant began February 1, 2011.

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.

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.

MDA has awarded a research development grant totaling $179,912 over three years to Jianming Liu in the department of cell and tissue biology at the University of California, San Francisco. The new funds will help support Liu’s study of the disease process in Duchenne (DMD) and  Becker (BMD) muscular dystrophies. Using research mouse models for DMD and BMD, Liu and colleagues plan to investigate a potential stem-cell-based therapy for the two diseases using engineered stem cells designed to help regenerate healthy skeletal muscle tissues.

One of the hallmarks of muscular dystrophy is the rapid depletion of immature muscle cells due to repeated cycles of muscle degeneration and regeneration, Liu noted. Therefore, using normal, healthy stem cells to promote muscle regeneration represents a possible therapeutic approach.

Liu and colleagues will investigate the potential of cell-based therapy for muscular dystrophy using engineered stem cells with modified cell signaling capabilities designed to prompt regeneration of healthy skeletal muscle tissues. Findings from Liu’s work are expected to help increase understanding of the potential for muscle regeneration in the muscular dystrophies as well as provide testing data for potential therapeutics.

"I'm currently a postdoc but am in the process of transitioning into an independent researcher able to lead my own research team and tackle the challenges of finding cures for devastating muscle diseases; for that reason, MDA support at this time is essential and pivotal for my career development and for making fast progress in my research," Liu said. "I am greatly appreciative of the opportunity and the support MDA has provided me.

Funding for this MDA grant began February 1, 2011.

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.

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.

MDA has awarded a research grant totaling $350,133 over three years to Michael Miller, associate professor in the department of biology at the University of Alabama, Birmingham. The grant will help support Miller's research into the fundamental molecular mechanisms responsible for the death of nerve cells called motor neurons in ALS (amyotrophic lateral sclerosis, or Lou Gehrig's disease) and spinal muscular atrophy (SMA).

Using nematode (worm) and fly research models, Miller and colleagues have generated preliminary data suggesting that mutations in genes associated with familial (inherited) ALS and SMA disrupt a signaling mechanism that controls function of the cellular "energy factories" called mitochondria, which are necessary for motor neuron health.

Now, using a nematode model, the study team plans to combine biochemical and genetic manipulation with the ability to directly monitor changes in the worm’s cellular mitochondria as a means of uncovering the fundamental molecular mechanisms responsible for motor neuron death in ALS and SMA — mechanisms the team hypothesizes may influence mitochondrial function.

Miller expects the major impacts of his work will be the identification of mitochondria as the linchpin in neurodegenerative disorders including ALS and SMA, and the long list of drug targets his team expects to identify through its screening process.

"Funding by the MDA for this project is critically important," Miller said, "as without this support, the momentum gained over the past few years would come to a halt."

Funding for this MDA grant began February 1, 2011.

MDA has awarded a research grant totaling $362,466 over three years to Alysson Muotri, assistant professor at the University of California, San Diego in La Jolla. The new funds will help support Muotri’s generation of a new research model of ALS (amyotrophic lateral sclerosis, or Lou Gehrig’s disease).

Muotri and co-principal investigator Mayana Zatz, Ph.D., professor of genetics and director of the Human Genome Research Center in São Paulo, Brazil, plan to generate a human cellular model of ALS using cells taken from individuals with a particular form of the disease called ALS8.

ALS8 was first mapped in a Brazilian family, and is an autosomal dominant form of the disease, meaning an individual only has to receive one defective copy of the gene, from either parent, to get the disease. An individual with ALS8 has a 50 percent chance of transmitting the condition to each of their offspring. 

Muotri noted that a critical need exists for new human cellular ALS models in which to study ALS, and suggested that recent advances in stem cell biology, including the availability of induced pluripotent stem cells (adult cells that are reprogrammed back to an immature stem-cell-like state) could help unravel the disease mechanisms underpinning ALS. These advances allow the DNA of people with ALS to be captured in an induced pluripotent stem cell line, from which cells can then be matured, isolated and evaluated for specific ALS-causing gene defects.

The new model will be made available to other research groups, and is expected to help determine biological indicators that can help scientists predict the disease course in individuals. It’s hoped the new model also will help make diagnosis easier with early-diagnostic tools and inspire new therapeutic strategies.

"The support of the MDA is crucial to moving the idea of modeling ALS disease using human motor neurons to real outcomes that can benefit patients," Muotri said.

Funding for this MDA grant began February 1, 2011.

MDA has awarded a research grant totaling $420,000 over three years to Thien Nguyen, assistant professor in the department of neurology at Johns Hopkins University School of Medicine in Baltimore. The new funds will help support Nguyen’s research into the breakdown of peripheral nerves (nervous tissue that connects the spinal cord with muscles and sensory organs) in Charcot-Marie-Tooth disease (CMT).

Degeneration of the axons (the long fibers that carry signals from nerve cell bodies to muscle) is a hallmark of type 1 CMT and is the primary determinant of the severity of symptoms in people with the disease. It follows that prevention of axonal degeneration should improve clinical outcomes for people with CMT1.

The same principle also should be applied to other types of CMT, Nguyen noted.

In previous studies, Nguyen and colleagues have determined that mutations in genes for myelin-making cells called "Schwann cells" can lead to mutant Schwann cells that may instruct axons to degenerate through certain specific signaling molecules that normally promote stability and survival, including one called myelin-associated glycoprotein (MAG). Study results out of Nguyen's lab have suggested that another signaling molecule, called netrin-1, may play an important role in axonal survival in CMT, making it a potential therapeutic target.

The investigators will determine whether increasing netrin-1 activity might prevent axonal degeneration in cell culture and in a research mouse model.

Findings from Nguyen’s work could reveal the potential therapeutic benefit of netrin-1 and lead to its development as a neuroprotective therapeutic for CMT.

"In theory, results from the project also could be expanded to axonal degeneration even without demyelination," Nguyen said. "Thus, there could be applicability to many of the neurodegenerative disorders covered by MDA."

Funding for this MDA grant began February 1, 2011.

MDA has awarded a research grant totaling $369,165 over three years to Bradley Olwin, professor of molecular, cellular & developmental biology at the University of Colorado in Boulder. The new funds will help support Olwin’s study of muscle regeneration in injured and diseased skeletal muscle — particularly in the muscular dystrophies, including Duchenne muscular dystrophy (DMD).

Olwin is a longtime MDA grantee, having received funding from the Association almost continuously since the early 1980s.

Diseases such as the muscular dystrophies that result in progressive loss of skeletal muscle tissue reflect disruption of the normal muscle regenerative processes. If the cells responsible for normal repair could be augmented by drug therapies or cell replacement therapies, regeneration might be enhanced, slowing or halting the loss of skeletal muscle function.

In previous studies, Olwin and colleagues identified a rare stem cell that they hypothesize is a primary source of skeletal muscle stem cells (also called "satellite" cells). The team plans to study the newly identified cells and uncover any contributions they may make to the regeneration process in injured and diseased skeletal muscle. Next, the team will transplant the cells into the muscles of a research mouse with a DMD-like disease in order to determine how well they restore muscle function, slow muscle scarring (called fibrosis), and produce the protein missing in DMD, dystrophin.

Findings from Olwin’s studies may result in new drug-based or cell-based strategies to enhance new muscle growth in progressive muscle diseases.

"I have been funded by the MDA for the majority of my career as a research scientist, beginning in the early 1980s," Olwin said. "Without MDA funding, I may not have continued in skeletal muscle research."

Funding for this MDA grant began February 1, 2011.

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.

MDA has awarded a research grant totaling $309,336 over three years to Pier Lorenzo Puri, professor of pediatrics at the University of California, San Diego, and associate professor of muscle development and regeneration at the Sanford-Burnham Medical Research Institute, both in La Jolla, Calif. The funds will help support Puri's study of the molecular underpinnings of, and the identification of treatments for, Duchenne muscular dystrophy (DMD).

Puri and colleagues plan to examine the regulation of skeletal muscle regeneration at the molecular level, with a particular focus on various regeneration signals and the ways in which different cellular populations in the regenerative environment activate distinct programs of gene expression (activity).

This knowledge is instrumental, Puri said, to gaining an understanding of the molecular and functional interactions between the cellular components of the muscle stem cell population (satellite cells), and identification of targets at which to aim selective interventions that will promote muscle regeneration and stave off the invasion of fibrosis (scarring) and fatty tissue.

To do this, the investigators first will isolate and manipulate muscle-derived cell populations from mouse models of muscular dystrophies; then they'll determine those cells' molecular, epigenetic (gene regulation) and functional characteristics.

Data obtained from Puri's studies is expected to inspire and drive new pharmacological strategies suitable for speedy translation into treatments for muscular dystrophies and other neuromuscular diseases. The study team will prioritize potential interventions based on strategies or compounds that can be translated most quickly into clinical trial testing.

"I have been supported by MDA since my early career stages with a development grant, through my current position as an established investigator with a primary research grant," Puri said. "This support helped me maintain the focus of my interest and efforts on the disease process and treatment of muscular dystrophies."

Funding for this MDA grant began February 1, 2011.

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.

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.

MDA has awarded a research grant totaling $416,250 over three years to Joseph Sarsero, head of the Friedreich Ataxia Laboratory Research Program at the Murdoch Childrens Research Institute in Parkville, Victoria, Australia. The new funds will help support Sarsero’s development of a new mouse model of Friedreich’s ataxia (FA).

Prior to evaluating new therapies in people with FA, it is important that they be tested in appropriate biological models of the disease, Sarsero noted.

"Animal models that are generated by the 'knocking out' of specific genes often manifest the main symptoms of the corresponding human disorder; however, such models rarely recapitulate the precise molecular cause that underlies the human disease."

Accurate "humanized" mouse models of disease are designed to contain an entire human gene of interest and harbor the specific disease-causing mutations found in people with the disease. Such mice should not only manifest the main symptoms of a disorder, but also provide the correct underlying molecular cause of the disease.

Utilizing information and resources generated as part of the Human Genome Project, coupled with their expertise in handling the FA gene and their preliminary mouse models of the disease, Sarsero and colleagues plan to generate an improved humanized FA mouse model that will contain the entire human FA gene.

Funding for this MDA grant began February 1, 2011.

"The mouse model will more accurately reflect the underlying molecular cause of FA and exhibit the key molecular, biochemical, epigenetic and behavioral traits of the disorder," Sarsero said.

This new research tool is expected to enable scientists to better understand the molecular underpinnings of FA as well as provide a better subject in which to test potential FA therapeutics.

"MDA support has been pivotal in allowing us to pursue major projects aimed at identifying new pharmacological therapies for Friedreich's ataxia and the generation of accurate mouse models of the disorder," Sarsero said.

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.

MDA has awarded a research development grant totaling $180,000 over three years to Hao Shi, associate research scientist at Yale University in New Haven, Conn. The new funds will help support Shi’s study of muscle repair and regeneration in Duchenne muscular dystrophy (DMD).

Shi plans to study the functional role of a protein called mitogen-activated protein kinase (MAPK) phosphatase-5, or MKP-5, in DMD. It is known that muscle repair and regeneration are dependent on the MAPKs. However, little is known about how the regulatory pathways that inactivate the MAPKs control muscle repair or whether they are involved in the disease process in skeletal muscle disorders.

Using a mouse model of DMD, Shi and colleagues plan to elucidate the role of MPK-5 in skeletal muscle. They will study the protein's role in muscular dystrophy; define its role in skeletal muscle regeneration; and identify the molecular mechanisms of MKP-5 in muscle stem cell function.

Additionally, the team will use a mouse model engineered to be deficient in MKP-5 to study the process of post-development muscle regeneration.Results from Shi’s studies potentially may reveal one or more biological pathways involved in muscle regeneration at which scientists might target new therapeutics in the disease.

"MDA funding not only provides an alternative avenue of financial support to basic science in an exciting and promising field, but it also facilitates the translation of academic research into potentially meaningful clinical outcomes," Shi said. "We believe that these studies will set the foundation from which validation of MKP-5 as a new therapeutic target for the treatment of muscular dystrophy can be established."

Funding for this MDA grant began February 1, 2011.

MDA has awarded a research grant totaling $396,000 over three years to Shanthini Sockanathan, associate professor of neuroscience at Johns Hopkins School of Medicine in Baltimore. The new funds will help support Sockanathan’s study of motor neuron (nerve cell) development in neurodegenerative diseases such as ALS (amyotrophic lateral sclerosis, or Lou Gehrig’s disease).

In previous work, Sockanathan and colleagues showed that a protein called GDE2 controls the production of spinal motor neurons through extracellular glycerophosphodiester phosphodiesterase (GDPD) activity.

More recently, the team discovered that GDE2 activity is itself regulated by a second protein, Prdx1. Prdx1 activates GDE2 by breaking a particular coupling called a "disulfide bond" inside GDE2 that normally inhibits GDE2 function. Thus, the disulfide bond within GDE2 acts a molecular switch that turns motor neuron production "on" or "off." By extension, the pathways that modify disulfide bond formation play pivotal roles in the control of motor neuron differentiation (maturation).

One question that emerges from this work is: How are active forms of Prdx1 generated to ensure efficient initiation of GDE2-dependent motor neuron differentiation?

Sockanathan's study team will test the hypothesis that inactive forms of Prdx1 are reactivated through separate pathways.

In addition, building off their recent finding of another Prdx molecule that is expressed with GDE2 and inhibits its activity, the team suggests the possibility that this mechanism regulates the initiation, extent and rate of motor neuron differentiation. The team will test this theory using a combination of different approaches.

Taken together, these studies are expected to provide insight into how the pathways that modify disulfide-bond formation intersect to control the onset and progression of motor neuron differentiation.

Funding for this MDA grant began February 1, 2011.

MDA has awarded a research grant totaling $375,000 over three years to Young-Jin Son, associate professor of developmental neurobiology at Temple University in Philadelphia. The new funds will help support Son’s study of nerve and muscle interaction in muscle diseases such as Duchenne muscular dystrophy (DMD).

Stable maintenance of muscle size and also the connections between nerves and muscles are critical for normal neuromuscular function in adulthood, Son said, noting disruption of the balance plays a central role in the initiation and progression of numerous neuromuscular disorders.

Son and colleagues plan to study whether cellular structures called "muscarinic acetylcholine receptors" (mAChRs) comprise a novel receptor system that is used by nerve cells and muscles to monitor nervous system activity, and to maintain stable nerve-muscle connections and solid muscle mass.

The investigators also will explore the possibility that muscle atrophy can be prevented via treatments that directly target muscarinic receptors. Our studies will provide insights that may prevent synaptic loss and muscle atrophy, and has the potential to develop new strategies for treating a broad range of neuromuscular disorders.

Results from Son’s work may provide leads on the development of new strategies for treating a broad range of neuromuscular disorders.

Funding for this MDA grant began February 1, 2011.

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.

MDA has awarded a research grant totaling $330,000 over three years to Jiou Wang, assistant professor of biochemistry & molecular biology and neuroscience at Johns Hopkins University in Baltimore. The new funds will help support Wang’s study of the molecular mechanisms underlying ALS (amyotrophic lateral sclerosis, or Lou Gehrig’s disease).

"Genetic and protein discoveries in humans have opened the door to studying the disease in genetically-engineered animal models," Wang said. "The nematode, with its short lifespan and well-conserved nervous system, along with the availability of powerful genetic tools, provides a unique opportunity for dissecting the disease mechanisms of ALS."

With colleagues, Wang previously has established a nematode model of ALS that carries a mutation in the SOD1 gene (associated with the familial form of human ALS). In his new work, Wang and his study team plan to use the nematode model to compare the molecular mechanisms of toxicity in both the SOD1 protein and in another protein associated with ALS, TDP43. They aim to uncover the mechanisms by which the TDP43 and SOD1 disease genes trigger neurotoxicity, and then determine whether the same holds true in other mammals. It’s hoped in-depth analysis of these mechanisms will reveal pathways at which researchers can target effective therapeutics.

"Support from MDA is very special to us, as it allows us to continue our research into ALS," Wang said. "Since my graduate studies, I have focused my research on understanding the basic mechanisms of this devastating disease. Now, as an early-stage independent investigator, MDA support is critical in allowing me to continue to work on ALS."

Funding for this MDA grant began February 1, 2011.

MDA has awarded a research grant totaling $220,000 over two years to Jen-Chywan Wang, assistant professor at the University of California, Berkeley. The new funds will help support Wang’s study of the effects of chronic glucocorticoid (steroid) treatment in Duchenne muscular dystrophy (DMD).

Glucocorticoids are potent anti-inflammatory agents that frequently are used to delay and relieve DMD symptoms, including rapid progression of muscle degeneration, loss of ambulation, paralysis and shortened lifespan. Although the drugs are beneficial, they cause unwanted side effects, one of which is loss of muscle mass.

In their new work, Wang and colleagues plan to first investigate the means by which glucocorticoids cause muscles to degenerate. The investigators previously identified two genes that have been linked to reduced muscle mass; now they plan to examine how glucocorticoids increase those genes' activity ("expression").

The team also plans to identify chemical compounds that specifically suppress the ability of glucocorticoids to activate the two suspect genes without affecting the drugs' anti-inflammatory activity. In research models of the disease, Wang's team will test whether such chemical compounds can reduce inflammation without causing muscle loss.

Additionally, the investigators have identified another eight genes that exert control over the total amount of protein in cells. The group will test whether increasing the expression of these genes leads to muscle loss, and whether the genes are responsible for glucocorticoid-induced muscle loss. Such genes could potentially be targeted in an effort to improve the effectiveness of glucocorticoid treatment in DMD.Wang’s work could lead to improved glucocorticoid-based therapies for individuals with DMD.

"Private agencies such as MDA play a vital role in sustaining specific interest in particular diseases," Wang said. "This support from MDA will provide a tremendous boost to our research in the understanding of how steroid hormones affect skeletal muscle biology."

Funding for this MDA grant began February 1, 2011.

MDA has awarded a research grant totaling $313,500 to Xander Wehrens, associate professor in the departments of molecular physiology & biophysics and medicine at Baylor College of Medicine in Houston, Texas. The new funds will help support Wehrens’ research into abnormal heart function in Duchenne muscular dystrophy (DMD).

In DMD, profound muscle weakness can affect the heart, manifesting as abnormal heart rhythm or heart failure that can lead to sudden cardiac death. Up to 90 percent of individuals affected by DMD experience some type of cardiac involvement and no effective therapy exists to prevent or treat it.

In previous studies, Wehrens and colleagues have demonstrated that deficiency of dystrophin (the protein missing in DMD) leads to abnormal calcium handling in heart muscle cells. More recent studies have revealed a connection between abnormal calcium fluxes and the activation of an otherwise inactive protein within the muscle cells called calmodulin-dependent kinase (or CaMKII).

Now, Wehrens' study team will explore biological factors affecting calcium-handling in heart muscle proteins and their connection to heart failure and abnormal heart rhythms in individuals with DMD. The group will focus on determining whether increased oxidative stress and/or enhanced activation of calmodulin-dependent kinase leads to abnormal calcium release channel function, arrhythmias and heart failure.

Findings from Wehrens' work are expected to set the stage for development of drugs specifically targeting the calcium-handling proteins in DMD and, potentially, in other forms of muscle disease associated with heart failure and abnormal heart rhythms.

"MDA funding over the past three years has allowed us to explore the role of various enzymes that activate calcium release channels in animal models of DMD," Wehrens said. "This has provided us deeper insight into the causes and processes of heart failure and abnormal heart rhythms in animal models the disease."

Funding for this MDA grant began February 1, 2011.

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.