Philadelphia - Children's Hospital of Philadelphia

David Pleasure, M.D.
(RG) Role of mitochondria in excitotoxicity in motor neurons
$ 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 engineer clonal human NT2-N neurons to closely resemble somatic motor neurons, and use them to test the hypothesis that excitotoxicity in ALS is due to mitochondrial dysfunction.

Philadelphia - Thomas Jefferson University

Edgar Davidson, Ph.D.
(RG) Analysis and genetic correction of a mitochondrial 
protein defect resulting in a mitochondrial myopathy
$ 59,616.00	7/1/99 - 6/30/00	Year 1
$ 59,810.00	7/1/00 - 6/30/01	Year 2
$ 60,574.00	7/1/01 - 6/30/02	Year 3

Summary: Researchers will use cultured cells to study a mutation which causes muscle disease. Researchers will also use this model to develop genetic therapy for the eventual treatment of patients with similar mutations.

Diane E. Merry, Ph.D.
(RG) Creation of a transgenic model for spinal 
and bulbar muscular atrophy (SBMA)
$ 73,440.00	7/1/99 - 6/30/00	Year 1
$ 72,360.00	7/1/00 - 6/30/01	Year 2
$ 71,820.00	7/1/01 - 6/30/02	Year 3

Summary: Researchers plan to study the mechanism by which mutant androgen receptor causes motor neuron degeneration by studying the effects of mutant gene expression on motor neuron function and survival in transgenic mice.

Philadelphia - University of Pennsylvania

Peter Crino, M.D., Ph.D.
(RG) Differential gene expression in affected and unaffected 
motor neurons and astrocytes in amyotrophic lateral sclerosis (ALS)
$ 35,000.00	1/1/00 - 12/31/00	Year 1
$ 35,000.00	1/1/01 - 12/31/01	Year 2

Summary: An intriguing hallmark of ALS is the lack of involvement of neurons that supply the external ocular muscles. Researchers will analyze mRNA expression profiles in affected and unaffected neurons and astrocytes to identify relative differences in expression of select mRNAs which may provide clues to the selective vulnerability of motor neurons in ALS.

Dennis Discher, Ph.D.
(RG) Biophysics of adhesion of dystrophic cell membranes
$ 50,000.00	1/1/00 - 12/31/00	Year 1
$ 50,000.00	1/1/01 - 12/31/01	Year 2
$ 50,000.00	1/1/02 - 12/31/02	Year 3

Summary: Researchers have developed a new cell manipulation method to understand how muscle cells adhere, deform, and even eradicate themselves in a benchmark culture system. This approach should allow rapid testing, for instance, of current and future dystrophin mini-constructs small enough to pack into viral vectors.

Charles Emerson, Ph.D.
(RG) Developmental signals that regulate myoblast determination
$ 68,818.00	1/1/00 - 12/31/00	Year 3

Summary: Molecular genetic studies to investigate the fundamental mechanisms of skeletal muscle and cartilage lineage determination in embryos.

David Goldhamer, Ph.D.
(RG) Regulation of the MyoD gene in injured and dystrophic muscle
$ 60,000.00	1/1/00 - 12/31/00	Year 2
$ 60,000.00	1/1/01 - 12/31/01	Year 3

Summary: The MyoD gene is essential for skeletal muscle regeneration. Researchers will determine how the expression of MyoD is regulated in regenerating muscle.

Markus Hildinger, Ph.D.
(FRS) Adeno-associated virus for gene transfer to skeletal muscle
$ 35,000.00	7/1/99 - 6/30/00	Year 1

Summary: Researchers will develop use of AAV vectors with various growth hormones on muscular dystrophies.

Roland Kallen, M.D., Ph.D.
(RG) Periodic paralysis: Pathomechanisms and treatment
$ 62,021.00	1/1/00 - 12/31/00	Year 2
$ 64,502.00	1/1/01 - 12/31/01	Year 3

Summary: Researchers will create a transgenic mouse model of the human diseases, HYPP, PC and AMC, and study excised diseased muscles in detail to understand: the precipitating factors, what determines their variable severity from patient to patient (even within the same family) and the mechanism of the beneficial role of therapeutic agents.

Jon Lindstrom, Ph.D.
(RG) Nicotinic acetylcholine receptors and myasthenia gravis (MG)
$ 58,406.00	7/1/99 - 6/30/00	Year 3

Summary: Researchers will test whether experimental autoimmune MG in rats can be treated by suppressing their autoimmune response to acetylcholine receptors through feeding them acetylcholine receptors produced in bacteria from cloned human DNA.

Yongliang Liu, Ph.D.
(DG) Molecular cloning of MyoD regulatory proteins
$ 35,000.00	1/1/00 - 12/31/00	Year 1
$ 35,000.00	1/1/01 - 12/31/01	Year 2
$ 35,000.00	1/1/02 - 12/31/02	Year 3

Summary: MyoD is a master gene that controls myoblast formation in the embryo and skeletal muscle regeneration in adults. Researchers will clone proteins that regulate MyoD in embryonic and regenerating muscle.

Joseph W. Sanger, Ph.D.
(RG) Myosins in myofibril assembly: Insights into diseases
$ 64,081.00	7/1/99 - 6/30/00	Year 1
$ 60,000.00	7/1/00 - 6/30/01	Year 2
$ 60,000.00	7/1/01 - 6/30/02	Year 3

Summary: The focus of the proposal is on determining the role of a non-muscle form of the myosin protein in the formation of muscle in developing skeletal myotubes.

Hansell Stedman, M.D.
(PPG) Systemic gene therapy for Duchenne (DMD) 
and limb-girdle muscular dystrophy (LGMD)
$ 200,000.00	1/1/00 - 12/31/00	Year 2

Summary: Newly developed vectors are used in conjunction with a unique strategy to permeabilize capillaries to achieve widespread transfer of the genes to treat DMD and LGMD.

H. Lee Sweeney, Ph.D.
(PPG) Viral modulation of muscular dystrophy
$ 150,000.00	1/1/00 - 12/31/00	Year 3

Summary: This project will evaluate recombinant viruses that may prove useful for gene therapy for human muscular dystrophies. The project will use a mouse model of Duchenne muscular dystrophy for much of the evaluation.

James Wilson, M.D., Ph.D.
(PPG) Gene therapy for neuromuscular disorders
$ 1,080,000.00	11/1/99 - 10/31/00	Year 3

Summary: Researchers propose to develop a center for gene therapy of neuromuscular diseases at the University of Pennsylvania, whose goal is focused on both discovery and rapid evaluation of promising gene therapies in people with inherited muscular dystrophies.

Pittsburgh - University of Pittsburgh

Paula R. Clemens, M.D.
(RG) Adenoviral vector targeting of GLUT4 for muscle gene transfer
$ 50,000.00	7/1/99 - 6/30/00	Year 1
$ 50,000.00	7/1/00 - 6/30/01	Year 2

Summary: In this project, researchers propose to improve targeting of an adenoviral vector to muscle thereby improving efficiency in delivering a therapeutic gene to muscle.

Joseph Glorioso, Ph.D.
(PPG) Design of HSV vectors for long-term transduction of stem cells
$ 125‚000.00	7/1/00 - 6/30/01	Year 1

Summary: The goal of this project is to determine whether these vectors can transfer genes to stem cells derived from both mature muscle tissue and from bone marrow. Ultimately, researchers will deliver the dystrophin gene, which is defective in Duchenne muscular dystrophy patients, to these stem cells prior to transplantation into dystrophin deficient mice and ascertain whether the animals exhibit improved muscle strength.

Leaf Huang, Ph.D.
(RG) Systemic delivery of DNA to muscle cells
$ 54,000.00	7/1/99 - 6/30/00	Year 1
$ 54,000.00	7/1/00 - 6/30/01	Year 2

Summary: This project will investigate and develop method by which DNA encoding therapeutic genes can be delivered to muscles by systemic delivery routes. Success of the project will enable gene therapy for dystrophic diseases such as Duchenne muscular dystrophy.

Johnny Huard, Ph.D.
(RG) Myoblast mediated ex vivo viral gene transfer 
to Duchenne muscular dystrophy (DMD) muscle
$ 65,000.00	1/1/00 - 12/31/00	Year 2
$ 65,000.00	1/1/01 - 12/31/01	Year 3

Summary: Myoblast mediated ex vivo viral gene transfer to DMD muscle

(SG) Pittsburgh Orthopaedic Tissue Engineering Symposium
$ 10,000.00	4/1/00 - 4/30/00	Year 1

(RG) The identification and characterization of muscle derived stem cells
$ 125,000.00	7/1/00 - 6/30/01	Year 1

Summary: The long-term goal of this proposal is the development of muscle derived stem cell transplantation to further improve muscle regeneration, structure and function of dystrophic muscle.

Anthony J. Kanai, Ph.D.
(RG) Cardiac nitric oxide synthase inhibition improves dystrophic hearts
$ 63,000.00	7/1/99 - 6/30/00	Year 1
$ 63,000.00	7/1/00 - 6/30/01	Year 2

Summary: In Becker muscular dystrophy, heart failure may be caused by excessive nitric oxide (NO) production. Researchers will determine "if selective inhibition of cNOS with NG-monomethyl-L-arginine improves cardiac function." These studies may provide a new treatment for the cardiovascular complications of muscular dystrophy.

Marcia Ontell, Ph.D.
(RG) Muscle regeneration and myogenic regulatory factors
$ 65,000.00	1/1/00 - 12/31/00	Year 1
$ 65,000.00	1/1/01 - 12/31/01	Year 2
$ 65,000.00	1/1/02 - 12/31/02	Year 3

Summary: Muscular dystrophy is characterized by regeneration that fails to keep pace with degeneration. Proposed studies focus on the role of Myf-5 and MyoD, myogenic regulatory factors, in muscle maturation and regeneration.

Paul Robbins, Ph.D.
(PPG) Development of approaches to facilitate expansion 
and transplantation of muscle and bone marrow-derived stem cells
$ 125‚000.00	7/1/00 - 6/30/01	Year 1

Summary: Approaches for improving methods for expanding, differentiating and transplanting muscle stem cells for long term persistence as a treatment of Duchenne muscular dystrophy will be developed.

Simon Watkins, Ph.D.
(RG) The dystrophin cytoskeleton in muscle development and disease
$ 53,159.00	7/1/99 - 6/30/00	Year 3

Summary: Abnormalities of interconnected molecules at the surface of the muscle fiber are responsible for several muscular dystrophies. Researchers will study the process of development, assembly and integration of these molecules and their role(s) in establishing and maintaining normal muscle function. Understanding these processes will allow the therapeutic regimens being developed to be optimized.

Xiao Xiao, Ph.D.
(PPG) Ex vivo and in vivo muscle gene therapy with adeno-associated viral vectors
$ 125‚000.00	7/1/00 - 6/31/01	Year 1

Summary: Researchers will use the adeno-associated virus to carry the therapeutic genes into the muscle ancestor cells or directly into muscle tissues to treat Duchenne muscular dystrophy (DMD).

University Park - Pennsylvania State University

Lars Larsson, M.D., Ph.D.
(RG) Thyroid hormone regulation of myosin synthesis
$ 51,364.00	1/1/00 - 12/31/00	Year 1
$ 52,526.00	1/1/01 - 12/31/01	Year 2
$ 53,857.00	1/1/02 - 12/31/02	Year 3

Summary: An animal experimental model will be used to improve our understanding of the impaired muscle function associated with low circulating levels of thyroid hormone, i.e., hypothyroid myopathy.

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