Muscular Dystrophy is a serious health problem in the United States and throughout the world. While the genetic basis underlying many forms of muscular dystrophy is known, therapies for these disorders remain elusive. The most common genetic form of muscular dystrophy is Duchenne muscular dystrophy (DMD), an X-linked disorder that afflicts roughly one in every 3500 boys. Our laboratory has identified a novel means of inhibiting the dystrophic process from developing in mdx mice, a model for DMD. This involves the overexpression of a glycosyltransferase called the CT GalNAc transferase, either using transgenic or gene therapy approaches. This proposal seeks to characterize the mechanism by which the CT GalNAc transferase (CT) inhibits muscular dystrophy.
The first aim will test whether overexpression of utrophin, a dystrophy-sparing protein, is required for inhibition of muscular dystrophy in CT transgenic mdx mice.
The second aim will determine if increased expression of utrophin and extracellular matrix proteins in CT transgenic mdx muscles occurs via changes in protein affinity for dystroglycan, the major protein glycosylated with the CT carbohydrate in skeletal muscle.
The third aim will test whether increased expression of the CT GalNAc transferase inhibits the development of muscular dystrophy in models for two forms of congenital muscular dystrophy-dy mice and myd mice.
The fourth aim will demonstrate the relationship between overexpression of the CT GalNAc transferase and myostatin signaling. Myostatin inhibition is another means of ameliorating muscular dystrophy in mdx mice, and this Aim will identify a novel means of modulating expression of myostatin and its inhibitors by altering muscle glycosylation. The long- term goal of this proposal is to validate the use of the CT GalNAc transferase as a therapeutic in models for DMD and other forms of muscular dystrophy and to develop therapies based on these findings. Another long-term goal is to develop a novel connection between glycosylation and myostatin signaling that may more broadly impact therapies for muscle aging and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR049722-05
Application #
7798563
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Nuckolls, Glen H
Project Start
2006-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2012-03-31
Support Year
5
Fiscal Year
2010
Total Cost
$294,299
Indirect Cost
Name
Nationwide Children's Hospital
Department
Type
DUNS #
147212963
City
Columbus
State
OH
Country
United States
Zip Code
43205
Cramer, Megan L; Shao, Guohong; Rodino-Klapac, Louise R et al. (2017) Induction of T-Cell Infiltration and Programmed Death Ligand 2 Expression by Adeno-Associated Virus in Rhesus Macaque Skeletal Muscle and Modulation by Prednisone. Hum Gene Ther 28:493-509
Zygmunt, Deborah A; Singhal, Neha; Kim, Mi-Lyang et al. (2017) Deletion of Pofut1 in Mouse Skeletal Myofibers Induces Muscle Aging-Related Phenotypes in cis and in trans. Mol Cell Biol 37:
Zygmunt, Deborah A; Crowe, Kelly E; Flanigan, Kevin M et al. (2017) Comparison of Serum rAAV Serotype-Specific Antibodies in Patients with Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, Inclusion Body Myositis, or GNE Myopathy. Hum Gene Ther 28:737-746
Thomas, Paul J; Xu, Rui; Martin, Paul T (2016) B4GALNT2 (GALGT2) Gene Therapy Reduces Skeletal Muscle Pathology in the FKRP P448L Mouse Model of Limb Girdle Muscular Dystrophy 2I. Am J Pathol 186:2429-48
Crowe, Kelly E; Shao, Guohong; Flanigan, Kevin M et al. (2016) N-terminal ? Dystroglycan (?DG-N): A Potential Serum Biomarker for Duchenne Muscular Dystrophy. J Neuromuscul Dis 3:247-260
Singhal, Neha; Martin, Paul T (2015) A role for Galgt1 in skeletal muscle regeneration. Skelet Muscle 5:3
Xu, Rui; Singhal, Neha; Serinagaoglu, Yelda et al. (2015) Deletion of Galgt2 (B4Galnt2) reduces muscle growth in response to acute injury and increases muscle inflammation and pathology in dystrophin-deficient mice. Am J Pathol 185:2668-84
Chicoine, Louis G; Rodino-Klapac, Louise R; Shao, Guohong et al. (2014) Vascular delivery of rAAVrh74.MCK.GALGT2 to the gastrocnemius muscle of the rhesus macaque stimulates the expression of dystrophin and laminin ?2 surrogates. Mol Ther 22:713-24
Camboni, Marybeth; Wang, Chiou-Miin; Miranda, Carlos et al. (2014) Active and passive immunization strategies based on the SDPM1 peptide demonstrate pre-clinical efficacy in the APPswePSEN1dE9 mouse model for Alzheimer's disease. Neurobiol Dis 62:31-43
Camboni, Marybeth; Hammond, Sue; Martin, Laura T et al. (2012) Induction of a regenerative microenvironment in skeletal muscle is sufficient to induce embryonal rhabdomyosarcoma in p53-deficient mice. J Pathol 226:40-9

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