The broad objective of this project is to define the functional roles for glycosylation in neuromuscular development and disease. This work will focus on the roles of a glycosyltransferase, Galgt2, which creates the cytotoxic T cell (CT) carbohydrate antigen. Both Galgt2 and the CT antigen are normally confined to the neuromuscular junction in mammalian skeletal muscle. The ectopic expression of the CT antigen in extrasynaptic regions of the myofiber membrane alters the expression of other normally synaptic proteins, including Synaptic laminins, utrophin, and neural cell adhesion molecule (NCAM), in transgenic mice. In addition, Galgt2 overexpression alters important aspects of muscle and neuromuscular development, and inhibits the formation of muscular dystrophy in mdx mice, a model for Duchenne muscular dystrophy. The principal protein that is glycosylated by Galgt2 in transgenic muscles is alpha dystroglycan, a major binding protein for the extracellular matrix (ECM). This grant will test a model wherein modification of dystroglycan by Galgt2 alters its properties and function. In addition, it will test mechanisms for altered laminin expression using muscle cells, transgenic mice, and gene knockout mice. These experiments will decipher mechanisms responsible for the functional roles of Galgt2 in muscle and neuromuscular development, as well as for its therapeutic role in muscular dystrophy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR050202-04
Application #
7190590
Study Section
Pathobiochemistry Study Section (PBC)
Program Officer
Nuckolls, Glen H
Project Start
2004-11-01
Project End
2009-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
4
Fiscal Year
2007
Total Cost
$266,591
Indirect Cost
Name
Nationwide Children's Hospital
Department
Type
DUNS #
147212963
City
Columbus
State
OH
Country
United States
Zip Code
43205
Chandrasekharan, Kumaran; Yoon, Jung Hae; Xu, Ying et al. (2010) A human-specific deletion in mouse Cmah increases disease severity in the mdx model of Duchenne muscular dystrophy. Sci Transl Med 2:42ra54
Fernandez, Karen; Serinagaoglu, Yelda; Hammond, Sue et al. (2010) Mice lacking dystrophin or alpha sarcoglycan spontaneously develop embryonal rhabdomyosarcoma with cancer-associated p53 mutations and alternatively spliced or mutant Mdm2 transcripts. Am J Pathol 176:416-34
Wang, Chiou-Miin; Devries, Sarah; Camboni, Marybeth et al. (2010) Immunization with the SDPM1 peptide lowers amyloid plaque burden and improves cognitive function in the APPswePSEN1(A246E) transgenic mouse model of Alzheimer's disease. Neurobiol Dis 39:409-22
Chandrasekharan, Kumaran; Martin, Paul T (2010) Genetic defects in muscular dystrophy. Methods Enzymol 479:291-322
Martin, Paul T; Xu, Rui; Rodino-Klapac, Louise R et al. (2009) Overexpression of Galgt2 in skeletal muscle prevents injury resulting from eccentric contractions in both mdx and wild-type mice. Am J Physiol Cell Physiol 296:C476-88
Yoon, Jung Hae; Chandrasekharan, Kumaran; Xu, Rui et al. (2009) The synaptic CT carbohydrate modulates binding and expression of extracellular matrix proteins in skeletal muscle: Partial dependence on utrophin. Mol Cell Neurosci 41:448-63
Xu, Rui; DeVries, Sarah; Camboni, Marybeth et al. (2009) Overexpression of Galgt2 reduces dystrophic pathology in the skeletal muscles of alpha sarcoglycan-deficient mice. Am J Pathol 175:235-47
Martin, Paul T; Shelton, G Diane; Dickinson, Peter J et al. (2008) Muscular dystrophy associated with alpha-dystroglycan deficiency in Sphynx and Devon Rex cats. Neuromuscul Disord 18:942-52
Kim, Mi-Lyang; Chandrasekharan, Kumaran; Glass, Matthew et al. (2008) O-fucosylation of muscle agrin determines its ability to cluster acetylcholine receptors. Mol Cell Neurosci 39:452-64
Martin, Laura T; Glass, Matthew; Dosunmu, Eniolami et al. (2007) Altered expression of natively glycosylated alpha dystroglycan in pediatric solid tumors. Hum Pathol 38:1657-68

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