Grant – Winter 2011 – FA - Joseph Sarsero, Ph.D.
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.
Grantee: FA - Joseph Sarsero, Ph.D.
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Grant – Winter 2011 – FA - Giovanni Coppola, M.D.
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.
Grantee: FA - Giovanni Coppola, M.D.
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Grant – Winter 2011 – DMD/BMD - Masahiko Hoshijima, M.D., Ph.D.
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.
Grantee: DMD/BMD - Masahiko Hoshijima, M.D., Ph.D.
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Grant – Winter 2011 – DMD/BMD - Jianming Liu, Ph.D.
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.
Grantee: DMD/BMD - Jianming Liu, Ph.D.
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Grant – Winter 2011 – DMD/BMD - Harold Bernstein, M.D., Ph.D.
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.
Grantee: DMD/BMD - Harold Bernstein, M.D., Ph.D.
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Grant – Winter 2011 – DMD/BMD - David Kass, M.D.
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.
Grantee: DMD/BMD - David Kass, M.D.
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Grant – Winter 2011 – DMD/BMD - Andrew Brack, Ph.D.
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.
Grantee: DMD/BMD - Andrew Brack, Ph.D.
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Grant – Winter 2011 – DMD - Young-Jin Son, Ph.D.
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.
Grantee: DMD - Young-Jin Son, Ph.D.
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Grant – Winter 2011 – DMD - Xander Wehrens, M.D., Ph.D.
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.
Grantee: DMD - Xander Wehrens, M.D., Ph.D.
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Grant – Winter 2011 – DMD - Pier Lorenzo Puri, M.D., Ph.D.
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.
Grantee: DMD - Pier Lorenzo Puri, M.D., Ph.D.
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Grant – Winter 2011 – DMD - Jen-Chywan Wang, Ph.D.
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.
Grantee: DMD - Jen-Chywan Wang, Ph.D.
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Grant – Winter 2011 – DMD - Hao Shi, Ph.D.
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.
Grantee: DMD - Hao Shi, Ph.D.
Grant type: Development Grant
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Grant – Winter 2011 – DMD - Grace Pavlath, Ph.D.
MDA has awarded a research grant totaling $295,269 over three years to Grace Pavlath, professor in the department of pharmacology at Emory University in Atlanta. The new funds will help support Pavlath’s study of abnormal muscle regeneration in the muscular dystrophies, particularly Duchenne muscular dystrophy (DMD).
Pavlath intends to study the abnormal "branched" muscle fibers that sometimes appear as part of the muscle regeneration process after illness or injury. Such fibers have shown characteristic functional abnormalities; they also are weaker and more prone to injury than normal, long cylindrical cells.
Although the exact contribution of branched myofibers to DMD muscle is unclear, muscles containing high levels of branched myofibers are unlikely to function normally. Thus, decreasing the number of branched myofibers likely will be beneficial for improving both muscle physiology, and the efficiency of cell and gene therapy approaches for muscular dystrophy.
Recent work out of Pavlath's lab analyzing the role of MOR23 in muscle regeneration revealed that it's a necessary factor in the proper skeletal muscle regeneration in mice; loss of MOR23 leads to increased myofiber branching.
Using both a healthy mouse and a research mouse model with a DMD-like disease, Pavlath’s team will manipulate two molecules, MOR23 and kirrel12, and examine their roles in regulating myofiber branching in muscle regeneration.
Findings from Pavlath’s work could lead to a clearer understanding of the underlying mechanisms that cause abnormal muscle-fiber branching in regeneration and, in addition, provide biological targets at which to aim future therapies.
"MDA funding has been extremely critical for this and past projects," Pavlath said. "We would not be able to study the mechanisms of myofiber branching without it."
Funding for this MDA grant began February 1, 2011.
Grantee: DMD - Grace Pavlath, Ph.D.
Grant type: Research Grant
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Grant – Winter 2011 – DMD - Dongsheng Duan, Ph.D.
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.
Grantee: DMD - Dongsheng Duan, Ph.D.
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Grant - Summer 2010 - SMA — John Manfredi
MDA awarded a grant totaling $79,277 to John Manfredi, chief scientific officer at Sfida BioLogic Inc., in Salt Lake City, Utah, for continued research into new drug compounds that promote the growth and function of motor neurons (nerve cells), and that may have potential as therapeutics for treatment of spinal muscular atrophy (SMA).
Manfredi's research team aims to determine the therapeutic potential of their compounds using a zebra fish research model that has been genetically engineered to simulate aspects of SMA. Results will determine whether the drugs merit future testing in more sophisticated and expensive models of the disease.
The compounds identified by Manfredi and colleagues "exhibit attractive pharmaceutical properties," Manfredi said. "They are not toxic; they penetrate the central nervous system; they exhibit appropriate half-lives in tissues; they can be administered orally; their permeability and solubility characteristics are drug-like; and they can be economically synthesized."
The group also will test a sample of their compounds alongside a collection of biochemically similar, commercially available drugs. If the commercial drugs show effects in the zebra fish model of SMA, the results will support the hypothesis that their SMA-relevant effects are due to shared biochemical activity with the investigators' novel drugs. Positive results also could lead to development of the commercial compounds as SMA therapeutics.
"The funding provided by MDA is absolutely critical for evaluating the potential of our company’s proprietary compounds to treat spinal muscular atrophy," Manfredi said. "Indeed, if these or derivative compounds prove to be efficacious for the treatment of SMA, MDA can legitimately claim responsibility for their success."
Funding for this MDA grant began August 1, 2010.
Grantee: SMA — John Manfredi
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Grant - Summer 2010 - SBMA — Albert La Spada
MDA awarded Albert La Spada, chief of the division of genetics in the department of pediatrics at the University of California, San Diego, $330,000 to study what causes nerve cells called motor neurons to die in spinal-bulbar muscular atrophy (SBMA) and other neurodegenerative diseases such as ALS (amyotrophic lateral sclerosis, or Lou Gehrig's disease) and spinal muscular atrophy (SMA).
La Spada and colleagues have created mouse and motor neuron cell-culture models of SBMA, which results from a genetic flaw in the androgen receptor (AR) gene. Completed studies have led to the identification of candidate pathways that may spur motor neuron degeneration.
Now, La Spada's team will focus on the androgen receptor (AR) protein, which is biochemically modified and made toxic in SBMA. An understanding of the particular proteins, or "enzymes," that catalyze such chemical modifications will set the stage for identification of drug compounds designed to inhibit them.
The team also will work to identify other cell types involved in driving the SBMA disease process. Using a specialized mouse model, the investigators will "turn off" activity of the mutant, or flawed, AR protein in different cell types, starting with motor neurons and muscle cells, in order to determine whether those cells contribute to making motor neurons sick.
"MDA funding has been critical in allowing us to aggressively pursue cutting-edge research approaches in my lab," La Spada said. "Without MDA, there is no way that we could have made all the progress that we did over the last decade."
Findings from the new work may identify targets for the development of therapies to treat SBMA, ALS and SMA.
Funding for this MDA grant began August 1, 2010.
Grantee: SBMA — Albert La Spada
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Grant - Summer 2010 - PP — Kurt Beam
MDA awarded a grant totaling $303,438 to Kurt Beam, professor in the department of physiology and biophysics at the University of Colorado School of Medicine in Denver, for research into a process called excitation-contraction coupling responsible for the contraction of muscle cells necessary for voluntary movement and breathing.
"Excitation-contraction coupling is a fundamental process in skeletal muscle that is not yet well-understood," Beam said. "Additionally, mutations of the key proteins involved in excitation-contraction coupling cause serious human muscle diseases, including periodic paralyses, malignant hyperthermia and central core disease."
The process is initiated by electrical impulses which move along the membrane that separates the inside and outside of each muscle cell, and depends, at least in part, on two proteins called DHPR and RyR1.
In completed studies, Beam and his group have shown that mutations of either DHPR or RyR1 affect the behavior of both proteins. In their new work, the investigators will study cultured mouse muscle cells as they attempt to uncover the molecular mechanism for communication between DHPR and RYR1.
"The importance of MDA to neuromuscular research cannot be measured in dollars alone. In particular, MDA has been at the forefront in promoting basic and applied research directed toward understanding normal muscle function, mechanisms of muscle disease and development of therapies for these diseases," Beam said. "An especially important role that MDA plays is to provide funding during early career stages and at times when funding from other sources becomes scarce. I do not believe that I would have been able to establish and maintain my neuromuscular research had it not been for funding from MDA at crucial points in my career."
Funding for this MDA grant began August 1, 2010.
Grantee: PP — Kurt Beam
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Grant - Summer 2010 - MM - Mito. Myopathy — Leo Pallanck
MDA awarded $312,699 to Leo Pallanck, associate professor of genome sciences at the University of Washington, Seattle, for research into elimination of flawed cell machinery that is the underlying cause of mitochondrial myopathy.
Mitochondria, the tiny "power plants" responsible for producing nearly all of the energy needed for a human cell to function properly, have their own genes — stretches of DNA that carry the genetic instructions used in protein production. There can be hundreds of mitochondria in a single cell, and large cells with particularly high energy demands, such as skeletal and cardiac (heart) muscle cells, may harbor more than 10,000.
Mutated, or flawed, mitochondrial genes lead to flawed mitochondrial proteins that impair the ability of the mitochondria to produce energy and, by extension, the ability of the cell to function.
Recent studies have shown that have a pair of proteins known as PINK1 and Parkin can recognize damaged mitochondria and promote their destruction.
Pallanck and his research team aim to test the hypothesis that PINK1 and Parkin, in conjunction with other cellular factors, can detect and selectively destroy flawed mitochondria, thus alleviating the symptoms associated with mitochondrial mutations by keeping numbers of the defective mitochondria low.
In experiments on a fruit fly model, the investigators will vary the amounts of PINK1 and Parkin, and study the effects on the frequency of mitochondrial mutations and their associated symptoms, including degeneration of muscles and nerves. The work could lead to the development of strategies that can be used to reduce the overall amount of mutation-bearing mitochondria in humans.
"This is my first grant from the Muscular Dystrophy Association, and I cannot overstate the importance of this funding to our work," Pallanck said. "We couldn't perform these studies without support from the MDA."
Funding for this MDA grant began August 1, 2010.
Grantee: MM - Mito. Myopathy — Leo Pallanck
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Grant - Summer 2010 - MM - Mito. Myopathy — Lee-Jun Wong
MDA awarded $411,000 to Lee-Jun Wong, professor in the department of molecular and human genetics at Baylor College of Medicine, Houston, for research designed to produce a one-step diagnosis procedure for complex mitochondrial myopathies.
Diagnosis of mitochondrial disorders often is difficult because the disease can present with any of a number of different symptoms including muscle weakness, exercise intolerance, paralysis or weakness of the eye muscles, deafness, seizures, lack of coordination, movement disorder, and strokelike episodes.
Current diagnostic methods are based on the genetic testing of individual genes, one by one. Such a process can be tedious, expensive and time-consuming, and isn't able to uncover all the different types of mutations that may be responsible for mitochondrial disorders.
"The availability of a one-step diagnostic approach is particularly important since mitochondrial myopathy accounts for a large proportion of patients, from children to adults, with muscular dystrophy," Wong said. "Prompt, definitive diagnosis is essential for proper patient management, treatment and genetic counseling."
Wong's group plans to establish a one-step technology that will allow for the detection of all of the various types of mutations that can result in mitochondrial myopathy. The team will validate its technique using archived DNA samples from people with mitochondrial neuromuscular disorders.
"My first research grant was from MDA, and it helped me develop a comprehensive method to screen mutations in mitochondrial DNA," Wong said. "Now, as an established and experienced principal investigator focusing on the molecular diagnosis of mitochondrial disorders, new MDA funding allows me to bring in an innovative one-step approach to comprehensive diagnosis of the complex dual genome mitochondrial disorders."
Funding for this MDA grant began August 1, 2010.
Grantee: MM - Mito. Myopathy — Lee-Jun Wong
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Grant - Summer 2010 - MMD — Ju Chen
MDA awarded $330,000 to professor of medicine Ju Chen at the University of California, San Diego, for research into the role of a protein called Cypher in skeletal muscle function and disease.
Mutations in Cypher result in myofibrillar myopathy (MFM) and late-onset distal myopathy, and results from completed studies in people with myotonic muscular dystrophy (MMD, or DM) indentified flawed Cypher isoforms (different forms of the same protein) in skeletal muscle tissues. Cypher activity also has been shown to be significantly decreased in mice exhibiting skeletal muscle atrophy.
"These observations suggest that Cypher plays essential roles in skeletal muscle function and disease," Chen said. "A better understanding of the function of Cypher in its various forms is key to developing therapies for Cypher-based MFM and potentially other myopathies."
In its work to understand the role of Cypher in skeletal muscle function and gain insight into the mechanisms by which mutations in Cypher cause skeletal muscle myopathy, the Chen research team will conduct experiments using three different genetically manipulated mouse models: an adult mouse lacking Cypher in skeletal muscle; mice lacking a short form of Cypher; and mice lacking a long form of the protein. Analysis will include comprehensive biochemical and functional evaluation, as well as evaluation of the microscopic structure of cells in skeletal mouse muscle tissue.
"Without funding from MDA, it would not be possible to perform these important studies," Chen said.
Funding for this MDA grant began August 1, 2010.
Grantee: MMD — Ju Chen
Grant type: Research Grant
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Grant - Summer 2011 - FSHD — Fedik Rahimov, Ph.D.
MDA has awarded a development grant totaling $180,000 over a period of three years to Fedik Rahimov, a postdoctoral research fellow at the program in genomics at Harvard Medical School and Children's Hospital Boston. The funds will help further elucidate the molecular mechanisms underlyingfacioscapulohumeral 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. Although it's not yet fully understood how the contraction causes the disease, it appears to be one of two factors necessary to cause abnormal activation of a gene called DUX4.
The protein produced from the DUX4 gene instructions is toxic to muscle cells, and causes muscle degeneration and weakness.
Fedik and colleagues plan to assess DUX4 activity in FSHD-affected muscles in an attempt to uncover the mechanisms underlying FSHD. It's hoped that understanding and defining these mechanisms may lead to the discovery of disease biomarkers.
"Funding from MDA will help us enormously as we continue our work on biomarker discovery using advanced technologies," Rahimov said. "Data generated from this study will be deposited into public repositories, and the discovery nature of our study will allow the generation of new hypotheses to test for new therapeutic targets."
Funding for this MDA grant began August 1, 2011.
Grantee: FSHD — Fedik Rahimov, Ph.D.
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Grant - Summer 2010 - MMD — Fernando Morales
Fernando Morales, head of the genetic section at the Health Research Institute of the University of Costa Rica, has received an MDA grant totaling $366,210 over three years. The funding will help support Morales’ research to define the molecular underpinnings of type 1 myotonic dystrophy (MMD1, or DM1) and factors that modify the course of this highly variable, multisystem disease.
The MMD1-causing mutation, an expansion in the DNA of a gene on chromosome 19, changes over time, usually becoming larger during a person's lifetime and when being passed between generations. In general, the larger the DNA expansion, the more profound the effects of it are likely to be. However, the correlation between disease severity and age of onset and size of the mutation isn't perfect.
In this project, Morales and colleagues aim to analyze how the MMD1 mutation changes over time and how the changes relate to the clinical course of the disease. They also plan to identify genetic and other modifiers of the MMD1 mutation.
"Importantly," said Morales, "these modifiers of the MMD1 mutation could also be modifiers of the disease, and if so, they could be used as therapeutic targets to delay disease onset and progression."
Morales said he hopes the project will generate more reliable genetic data that can provide more accurate information about prognosis to families and improve disease management and quality of life.
"Funding by MDA is of great importance to our project," Morales said. "Thanks to it, we can investigate in more detail several biological and clinical aspects related to MMD1 in which there is still controversy."
Funding for this MDA grant began August 1, 2010.
Grantee: MMD — Fernando Morales
Grant type: Research Grant
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Grant - Summer 2011 - FSHD — Eric Wagner, Ph.D.
MDA awarded a research grant totaling $284,778 over a period of three years to Eric Wagner, an assistant professor in the department of biochemistry and molecular biology at the University of Texas Health Science Center in Houston. The funds will help support Wagner’s investigations into the role of the DUX4 gene in facioscapulohumeral muscular dystrophy (FSH, or FSHD).
Recent findings implicate the DUX4 gene as a likely causative factor in FSHD and a potential target for molecular therapies. It was found that in people with the disease the normally silent DUX4 gene is inappropriately activated, causing major problems in the muscles.
Wagner and colleagues have developed a reporter system that will monitor their ability to inhibit and study DUX4 expression in normal and FSHD-affected cells.
“The system allows us to design and test inhibitory agents that can antagonize Dux4 expression, which is thought to be the causative agent in FSHD,” Wagner said.
“The value of MDA research funding cannot be underestimated in bringing this research together,” Wagner said. “The recent and critical findings that demonstrated the importance of DUX4’s role in FSHD was funded by MDA, and is what encouraged my lab team to work on this problem.”
Funding for this MDA grant began August 1, 2011.
Grantee: FSHD — Eric Wagner, Ph.D.
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Grant - Summer 2010 - LGMD — Richard Cripps
MDA awarded a grant totaling $339,561 to Richard Cripps, professor and chair of biology at the University of New Mexico in Albuquerque, for research into the role of the Trim32 gene in type 2H limb-girdle muscular dystrophy (LGMD).
The Trim32 gene carries instructions for the important Trim32 protein, required by muscle cells at the right times and in the necessary amounts for muscles to remain healthy and stable.
Cripps and colleagues currently are working to establish a model system in which to study the fruit fly version of Trim32.
"Our research will address fundamental questions about how this gene and its protein specifically behave in both the healthy and muscular dystrophy disease states of muscle," Cripps said. "Finding the answers to these questions will help researchers find critical points of intersection for the future treatment of this form of limb-girdle muscular dystrophy."
In experiments involving the fruit fly model, the team aims to identify the roles and behavior of Trim32 in muscles, including the structures it forms, the role these structures play in tissue stability, and interaction between the Trim32 protein and any other proteins.
"Having been funded by MDA off and on since I was a postdoctoral fellow in 1991-1992, I can deeply appreciate the support that MDA provides to scientists and fellows," Cripps said. "There is a greater willingness in MDA to take a chance on research that is of a higher risk, and the value of this approach has been borne out by the many achievements that MDA funding brings."
Funding for this MDA grant began August 1, 2010.
Grantee: LGMD — Richard Cripps
Grant type: Research Grant
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Grant - Summer 2010 - LGMD — Renzhi Han
Renzhi Han, assistant professor of physiology at Loyola University Medical Center in Maywood, Ill., received an MDA grant totaling $405,000 to study mutations in the dysferlin gene that lead to development of several types of muscle diseases known as "dysferlinopathies," including type 2B limb-girdle muscular dystrophy (LGMD).
Previous studies have shown that inflammation, a component of the "innate immune system," is prominent in muscle samples deficient in dysferlin protein. (The innate immune system specializes in providing immediate defense against infection in the body. By contrast, the adaptive immune system specializes in building up protective immunity.)
Han speculates that an attack carried out by the innate immune system might play a role in the onset and progression of muscle diseases that result from dysferlin mutations, and that disabling this immunological response may ameliorate the symptoms of muscular dystrophies caused by dysferlin deficiency.
The investigators will use research mouse models deficient in both dysferlin and the innate immune system to test their hypothesis. The team also will study whether increasing the activity of a biochemical inhibitor of the immune system has any effect on disease progression in dysferlin-deficient mice.
"This research will enable us to accomplish the critical step in our goal to design a therapy for dysferlin-deficient muscular dystrophy," Han said. "This work could not go further without the support of MDA."
Funding for this MDA grant began August 1, 2010.
Grantee: LGMD — Renzhi Han
Grant type: Research Grant
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