The long-term goal of this project is to design a therapy for autosomal recessive limb-girdle muscular dystrophy type 2D (LGMD-2D), which is due to aberrations in the (-sarcoglycan gene (Sgca), and affects mainly limb and girdle muscles to lead to progressive muscle fiber necrosis and weakness, Alpha-Sarcoglycan interacts with beta-, gamma-, and delta-sarcoglycan to form a subcomplex that increases the overall stability of the dystrophin-glycoprotein complex (DGC). Epsilon-Sarcoglycan is a ubiquitously expressed homologue of the muscle-specific alpha- sarcoglycan, sharing 43% identity and a similar protein structure. Epsilon-Sarcoglycan expression is detected as early as day E8.5 in mouse embryos before the detection of alpha-sarcoglycan at E15, and preliminary data shows increased detection during muscle regeneration suggesting that epsilon-sarcoglycan is embryonic or developmental form of alpha-sarcoglycan. This project focuses on exploring the therapeutic potential of upregulating epsilon-sarcoglycan levels for the treatment of LGMD-2D.
The First Aim hypothesizes that increased expression of epsilon-sarcoglycan will replace alpha-sarcoglycan within the DGC. Characterization of transgenic mice with targeted overexpression of epsilon-sarcoglycan to muscle will test this hypothesis.
The Second Aim hypothesizes that increased expression of epsilon-sarcoglycan will compensate for an aberrant alpha-sarcoglycan to prevent the onset of muscular dystrophy. Analysis of Sgca-null mice overexpressing epsilon-sarcoglycan will test this hypothesis.
The Final Aim hypothesizes that increased and sustained epsilon-sarcoglycan expression in alpha-sarcoglycan deficiency will prevent further muscle pathology and repair the primary membrane defect to allow for normal muscle function. Adult Sgca-null mice will be intramuscularly injected with rAAVl epsilon-sarcoglycan and analyzed. This project will investigate the functional and physiological consequences of increased levels of epsilon-sarcoglycan to prevent and treat muscular dystrophy in alpha-sarcoglycan deficiency. The overall results of these experiments will develop the possibility of increased epsilon-sarcoglycan expression to compensate for (-sarcoglycan in LGMD-2D patients. Focusing on an endogenous protein like epsilon-sarcoglycan will bypass any acquired therapeutic immune response, and provides a platform for new targets for therapy and drug treatments aimed at up-regulating epsilon-sarcoglycan

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR051199-05
Application #
7390824
Study Section
Special Emphasis Panel (ZRG1-SSS-5 (07))
Program Officer
Nuckolls, Glen H
Project Start
2004-04-01
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2010-03-31
Support Year
5
Fiscal Year
2008
Total Cost
$322,090
Indirect Cost
Name
University of Iowa
Department
Physiology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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Lancioni, Alessio; Rotundo, Ida Luisa; Kobayashi, Yvonne Monique et al. (2011) Combined deficiency of alpha and epsilon sarcoglycan disrupts the cardiac dystrophin complex. Hum Mol Genet 20:4644-54
Hara, Yuji; Kanagawa, Motoi; Kunz, Stefan et al. (2011) Like-acetylglucosaminyltransferase (LARGE)-dependent modification of dystroglycan at Thr-317/319 is required for laminin binding and arenavirus infection. Proc Natl Acad Sci U S A 108:17426-31
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