The overall objectives of this proposal are to improve our basic understanding of how dystroglycan binds laminin, and to explore the effectiveness of expressing LARGE and applying drugs of several classes in treating dystroglycan-related muscular dystrophies. In particular, the role of a novel post-translational phosphate modification?an O-linked mannose that is part of the laminin-binding glycan structure of alpha-dystroglycan?in laminin binding will be investigated. Also, new antibodies that recognize only immature alpha-DG with a terminal phosphate modification will be developed and used to evaluate the post-translational modification status of alpha-DG in tissues or cells collected from individuals with various types of dystroglycanopathies (by immunofluorescence, immunoblotting, and radioisotope-labeling). These studies will improve our understanding of the modifications required for dystroglycan to serve as a laminin receptor, and advance patient diagnosis by improving biomarker correlations with clinical severity. In vitro experiments with patient cells have suggested that overexpression of the glycosyltransferase LARGE can bypass alpha-dystroglycan glycosylation defects in a broad range of dystroglycanopathies. This hypothesis will be corroborated In vivo by assessing the ability to prevent disease in different dystroglycanopathy mouse models through either systemic or muscle-specific expression of the Large transgene. This will provide a better understanding of the feasibility and likelihood of success of broadly applying a LARGE-based therapy to the genetically diverse group of dystroglycanopathies. Furthermore, existing clinical drugs will be tested for their potential to ameliorate disease in dystroglycanopathy mouse models. The group of drugs to be tested includes a premature stop-codon readthrough drug (PTC124), as well as steroids (Prednisone) and PDES inhibitors (Sildenafil);the latter two compounds have already shown promise in the treatment of non-dystroglycan related muscular dystrophies. The effectiveness of these treatments will be explored using a combination of cell culture and in vivo mouse studies and measuring dystroglycan function, muscle physiology and pathology. The proposed research will provide a platform for new therapeutic avenues, some of which it will be possible to implement directly in the care of dystroglycanopathy patients

Public Health Relevance

This project outline represents an opportunity to maximize the basic science expertise that contributes to the University of lowa MDCRC to achieve our goal of translating our research discoveries into clinical applications for the diagnosis and treatment of dystroglycan-related muscular dystrophy. Our basic science and translational approach on dystroglycanopathy mouse models will provide the groundwork for future clinical trials in dystroglycanopathy patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54NS053672-08
Application #
8377944
Study Section
Special Emphasis Panel (ZNS1-SRB-S)
Project Start
Project End
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
8
Fiscal Year
2012
Total Cost
$532,061
Indirect Cost
$169,287
Name
University of Iowa
Department
Type
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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Brun, Brianna N; Mockler, Shelley R H; Laubscher, Katie M et al. (2017) Comparison of brain MRI findings with language and motor function in the dystroglycanopathies. Neurology 88:623-629
Brun, Brianna N; Mockler, Shelley R H; Laubscher, Katie M et al. (2017) Childhood Activity on Progression in Limb Girdle Muscular Dystrophy 2I. J Child Neurol 32:204-209
Shaw, Natalie D; Brand, Harrison; Kupchinsky, Zachary A et al. (2017) SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome. Nat Genet 49:238-248
Rader, Erik P; Turk, Rolf; Willer, Tobias et al. (2016) Role of dystroglycan in limiting contraction-induced injury to the sarcomeric cytoskeleton of mature skeletal muscle. Proc Natl Acad Sci U S A 113:10992-7
Praissman, Jeremy L; Willer, Tobias; Sheikh, M Osman et al. (2016) The functional O-mannose glycan on ?-dystroglycan contains a phospho-ribitol primed for matriglycan addition. Elife 5:
Turk, Rolf; Hsiao, Jordy J; Smits, Melinda M et al. (2016) Molecular Signatures of Membrane Protein Complexes Underlying Muscular Dystrophy. Mol Cell Proteomics 15:2169-85
de Greef, Jessica C; Hamlyn, Rebecca; Jensen, Braden S et al. (2016) Collagen VI deficiency reduces muscle pathology, but does not improve muscle function, in the ?-sarcoglycan-null mouse. Hum Mol Genet 25:1357-69
Inamori, Kei-Ichiro; Beedle, Aaron M; de Bernabé, Daniel Beltrán-Valero et al. (2016) LARGE2-dependent glycosylation confers laminin-binding ability on proteoglycans. Glycobiology 26:1284-1296
Jerber, Julie; Zaki, Maha S; Al-Aama, Jumana Y et al. (2016) Biallelic Mutations in TMTC3, Encoding a Transmembrane and TPR-Containing Protein, Lead to Cobblestone Lissencephaly. Am J Hum Genet 99:1181-1189

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