Boston - Beth Israel Deaconess Medical Center

Ernest Terwilliger, Ph.D.
(RG)  A genetic treatment to prevent motor neuron degeneration
$ 50,000.00	1/1/00 - 12/31/00	Year 3

Summary: The delivery of genes encoding products known to protect neurons to the spine, where they could direct the sustained manufacture of these proteins, has the potential to be an effective treatment for diseases such as amyotrophic lateral sclerosis. Researchers will test this novel therapeutic strategy directly, using a new viral vector system and a mouse model for motor neuron degenerative diseases.

Boston - Brigham and Women's Hospital

Paul Allen, M.D., Ph.D.
(RG)  The relationship of E-C coupling protein 
interactions to myopathy
$ 59,143.00	1/1/00 - 12/31/00	Year 2
$ 61,420.00	1/1/01 - 12/31/01	Year 3

Summary: Researchers will study the effects of elimination of skeletal calsequestrin on skeletal muscle E-C coupling and using their RyR1 (calcium channel) knockout mouse to test a mutation in RyR1 as the basis of central core disease (CCD).

(RG)  Duchenne muscular dystrophy (DMD) gene therapy 
by using HSV/AAV hybrid vector system
$ 60,000.00	7/1/99 - 6/30/00	Year 1
$ 60,000.00	7/1/00 - 6/30/01	Year 2

Summary: Researchers will develop a new hybrid virus (HSV/AAV) vector for greater efficiency in gene therapy for DMD.

Robert Friedlander, M.D., M.A.
(RG)  Mediation of neuronal cell death in amyotrophic 
lateral sclerosis (ALS) by the ICE cell death cascade
$ 50,000.00	7/1/99 - 6/30/00	Year 3

Summary: Activation of the ICE cell death gene appears to play an important role in causing cell death in ALS. Researchers will attempt to inhibit the ICE cell death action that will provide a novel therapeutic approach for the treatment of ALS.

(PPG)  Inhibition of neuronal cell death in amyotrophic lateral 
sclerosis (ALS) by modulating the ICE and Bcl-2 apoptotic families
$ 60,000.00	7/1/99 - 6/30/00	Year 2

Summary: The ICE and Bcl-2 cell death families play an important role mediating ALS in mice. Researchers will study methods to manipulate both ICE and Bcl-2 hoping to provide a novel approach for the treatment of ALS.

Boston - Children's Hospital of Boston

Alan H. Beggs, Ph.D.
(RG)  Genetics of nemaline myopathy
$ 66,000.00	7/1/99 - 6/30/00	Year 1
$ 64,000.00	7/1/00 - 6/30/01	Year 2
$ 60,000.00	7/1/01 - 6/30/02	Year 3

Summary: Researchers will identify and characterize the genes which, when mutated, cause nemaline myopathy, and to use this information to develop improved diagnostic and prognostic tests for patients and their family members.

Emanuela Gussoni, Ph.D.
(NIDA)  Isolation and characterization of human muscle stem cells
$ 96‚207.00	7/1/00 - 6/30/01	Year 1
$ 93‚309.00	7/1/01 - 6/30/02	Year 2
$ 94‚286.00	7/1/02 - 6/30/03	Year 3

Summary: Identify and characterize immature (stem) cells from human skeletal muscle. Evaluate the potential of these stem cells as a therapy for muscular dystrophy.

Louis M. Kunkel, Ph.D.
(RG)  Analysis of muscle stem cells for myoblast 
transfer therapy of Duchenne muscular dystrophy (DMD)
$ 70,701.00	7/1/99 - 6/30/00	Year 2
$ 72,823.00	7/1/00 - 6/30/01	Year 3

Summary: This project is designed to characterize stem cells and test their potential to improve the efficacy of myoblast transplantation.

(EMG)  Restricted funds for DMD research
$ 206,646.91	4/1/99 - 3/30/00	Year 1

(EMG)  Restricted funds for limb-girdle muscular dystrophy research
$ 520,000.00	4/1/99 - 3/30/00	Year 1

l Rosenberg, M.D., Ph.D.
(RG)  Molecular basis of the glutamate transport 
defect in amyotrophic lateral sclerosis (ALS)
$ 60,000.00	1/1/00 - 12/31/00	Year 3

Summary: A decrease in glutamate transport in nerve endings occurs in ALS. The aim of this project is to identify the transporter molecules in nerve endings and to find out how they are affected by the disease.

Terri Thompson, Ph.D.
(RF)  Characterization of the sarcoglycan complex 
in normal and dystrophic muscle
$ 35,000.00	7/1/99 - 6/30/00	Year 2

Summary: Researchers will study the sarcoglycan group of proteins affecting limb-girdle muscular dystrophy (LGMD).

Boston - Dana-Farber Cancer Institute

Michael Eck, Ph.D.
(RG)  Crystal structures of dystrophin/b-dystroglycan complexes
$ 75,000.00	1/1/00 - 12/31/00	Year 1
$ 75,000.00	1/1/01 - 12/31/01	Year 2
$ 75,000.00	1/1/02 - 12/31/02	Year 3

Summary: Researchers studies will provide the first high resolution 3-D pictures of a large fragment of human dystrophin, showing how it forms a complex with beta-dystroglycan.

Boston - Harvard Medical School

Alfred Goldberg, Ph.D.
(RG)  Protein breakdown in muscle in normal and disease states
$ 60,000.00	1/1/00 - 12/31/00	Year 3

Summary: Researchers hope to elucidate the biochemical basis for the excessive protein breakdown in muscle seen in many disease states and to identify agents that reduce this deleterious process.

Deirdre A. Sullivan, Ph.D.
(DG)  Structural studies of acetylcholine receptor 
extracellular regions
$ 35,000.00	1/1/00 - 12/31/00	Year 2

Summary: The goal of this study is to gain structural information on regions of the acetylcholine receptor for the design of therapeutic agents for neuromuscular diseases such as myasthenia gravis.

Boston - Massachusetts General Hospital

Merit Cudkowicz, M.D., M.Sc.
(RG)  Safety and efficacy trial of topiramate in 
amyotrophic lateral sclerosis (ALS)
$ 52,656.00	1/1/00 - 12/31/00	Year 1
$ 54,027.00	1/1/01 - 12/31/01	Year 2

Summary: Researchers will test the safety and clinical efficacy of topiramate, a glutamate receptor antagonist, in 288 subjects with ALS.

Lana Tsao, M.D.
(NIDA)  Enhancement of stem-cell mediated 
muscle regeneration by IGF-1
$ 100‚000.00	7/1/00 - 6/30/01	Year 1
$ 100‚000.00	7/1/01 - 6/30/02	Year 2
$ 100‚000.00	7/1/02 - 6/30/03	Year 3

Summary Insulin-like growth factor-I (IGF-1) is normally produced by damaged skeletal and cardiac muscles to promote cell growth and tissue repair. Genetic engineering strategies to provide supplemental IGF-1 may enhance the capacity of muscle precursor cells to repopulate dystrophic muscle, restoring function.

Boston - New England Medical Center

Elliot Androphy, M.D.
(RG)  Characterization of the spinal muscular atrophy (SMA) SMN protein
$ 60,000.00	7/1/99 - 6/30/00	Year 2
$ 60,000.00	7/1/00 - 6/30/01	Year 3

Summary: Spinal muscular atrophy is a motor neuron disease caused by mutations of the SMN gene. Cellular expression and functions of the SMN protein will be investigated.

Christian Lorson, Ph.D.
(NIDA)  Prevention of spinal muscular atrophy 
(SMA) by stimulating full-length expression from SMN2
$ 74,540.00	1/1/00 - 12/31/00	Year 1
$ 74,540.00	1/1/01 - 12/31/01	Year 2
$ 74,540.00	1/1/02 - 12/31/02	Year 3

Summary: SMA is caused by mutation of the SMN1 gene. This proposal is designed to identify factors that increase expression of full-length SMN protein from a nearly identical copy of SMN1 called SMN2.

Boston - Northeastern University

Volkmar Weissig, Ph.D., Sc.D.
(DG)  Non-viral vector for gene therapy of mitochondrial myopathy
$ 30,000.00	1/1/00 - 12/31/00	Year 1
$ 30,000.00	1/1/01 - 12/31/01	Year 2
$ 30,000.00	1/1/02 - 12/31/02	Year 3

Summary: The goal of this project is the development of a method making gene therapy of neuromuscular diseases caused by defects in the mitochondrial genome for the first time feasible.

Charlestown - Massachusetts General Hospital

Robert H. Brown, D.Phil., M.D.
(RG)  Analysis of dysferlin in the pathogenesis of limb-
girdle muscular dystrophy (LGMD) 2B and Miyoshi myopathy
$ 64,994.00	7/1/99 - 6/30/00	Year 1
$ 74,800.00	7/1/00 - 6/30/01	Year 2
$ 76,799.00	7/1/01 - 6/30/02	Year 3

Summary: This is a proposal to study a new muscle protein "dysferlin" to determine how its defects cause two types of muscular dystrophy (LGMD2B and Miyoshi myopathy) and to use it to develop a new animal model of muscular dystrophy.

Lawrence Hayward, M.D., Ph.D.
(RG)  Transgenic mouse model of hyperkalemic 
periodic paralysis (HYPP)
$ 53,991.00	1/1/99 - 6/30/00	Extended

Summary: The proposed experiments will investigate abnormal sodium channels in mouse models of two inherited muscle diseases: HYPP and sodium channel myotonia.

Jeffrey B. Miller, Ph.D.
(RG)  Cell death genes in developing and dystrophic muscle
$ 56,445.00	7/1/99 - 6/30/00	Year 1
$ 58,702.00	7/1/00 - 6/30/01	Year 2
$ 61,050.00	7/1/01 - 6/30/02	Year 3

Summary: The work proposed is designed to increase the understanding of how skeletal muscles are formed in early life and how skeletal muscle cells die during muscle disease.

Craig Neville, Ph.D.
(DG)  The E protein transcription factors and 
muscle cell diversity
$ 35,000.00	7/1/99 - 6/30/00	Year 2
$ 35,000.00	7/1/00 - 6/30/01	Year 3

Summary: This research investigates the mechanisms responsible for the establishment and maintenance of the myofibers responsible for conferring strength, but in Duchenne muscular dystrophy are selectively lost.

Waltham - Brandeis University

Carolyn Cohen, Ph.D.
(RG)  Atomic structures of the muscle motor and its regulator
$ 47,963.00	1/1/00 - 12/31/00	Year 1
$ 48,771.00	1/1/01 - 12/31/01	Year 2

Summary: Myosin is the fundamental protein involved in muscle contraction. Researchers will study how this motor works by obtaining "snapshots" of the molecule at different stages of contraction. Many critical muscle diseases are due to defects in the motor itself or in its control machinery.

Worcester - University of Massachusetts

Jeanne Lawrence, Ph.D.
(RG)  RNA processing, transport and nuclear compartments 
in myotonic dystrophy (MMD) and spinal muscular atrophy (SMA)
$ 25,000.00	1/1/00 - 12/31/00	Year 2
$ 25,000.00	1/1/01 - 12/31/01	Year 3

Summary: This work will examine how defects in the genes which cause MMD or SMA impact gene expression or function within the context of nuclear structure. Genes, RNAs and proteins will be examined in single cell nuclei using fluorescence microscopy for abnormal effects.

Atsushi Mikami, M.D., Ph.D.
(DG)  Functional expression of the retrograde transport motor
$ 35,000.00	7/1/99 - 6/30/00	Year 1
$ 35,000.00	7/1/00 - 6/30/01	Year 2
$ 35,000.00	7/1/01 - 6/30/02	Year 3

Summary: Gene expression technology will be used to determine fundamental properties of the retrograde axonal transport motor protein.

Kelly P. Smith, Ph.D.
(DG)  The role of nuclear structure in spinal muscular 
atrophy (SMA) and myotonic dystrophy (MMD)
$ 35,000.00	1/1/00 - 12/31/00	Year 2
$ 35,000.00	1/1/01 - 12/31/01	Year 3

Summary: This project investigates the role of nuclear "gem" structures in the cause of SMA and the involvement of nuclear domains in defective gene expression in MMD. Genes and their RNAs are visualized directly within each cell nucleus.

Rossella Tupler, M.D., Ph.D.
(RG)  Analysis of gene expression in facioscapulohumeral 
muscular dystrophy (FSHD) affected muscle
$ 60,000.00	7/1/99 - 6/30/00	Year 1
$ 60,000.00	7/1/00 - 6/30/01	Year 2

Summary: Researchers will analyze genes that are differentially expressed in FSHD muscle which will lead to understand what causes the disease and to develop new therapeutic tools.

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