The broad, long-term objectives of this proposal are to understand the structure and function of a novel tetraspanin called SARCOSPAN. Sarcospan is an integral component of the dystrophin-glycoprotein complex and is highly expressed in skeletal and cardiac muscles, as well as many non-muscle tissues (Crosbie et al., 1997; Crosbie et al., 1998; Crosbie et al., 1999). The dystrophin-glycoprotein complex (DGC) is a structural complex that spans the muscle plasma membrane and links the extracellular matrix with the intracellular cytoskeleton. This structural linkage is critical for normal muscle function as clearly demonstrated by the many forms of muscular dystrophy that result from mutations in the dystrophin-glycoprotein complex. Association of several signaling molecules with the DGC also suggests that this complex may play a role in mediating extracellular-intracellular communications. Furthermore, lateral associations amongst membrane components of the DGC are critical for function of this complex. It is hypothesized that sarcospan facilitates protein-protein interactions within the dystrophin-glycoprotein complex. These protein interactions are clearly important for the physical linkage between the extracellular matrix and the intracellular actin network and for the prevention of muscular dystrophy. Human mutations within the sarcospan gene have not been identified in known cases of autosomal recessive muscular dystrophy (Crosbie et al., 2000). However, these mutation searches have only examined the ubiquitous form of SSPN, which has a broad expression pattern. Preliminary data demonstrates that a novel, muscle-specific form of SSPN is expressed in skeletal and cardiac muscles. We hypothesize that mutations within muscle-SSPN may cause novel forms of muscular dystrophy. Identification and characterization of this muscle-sarcospan will advance our understanding of the role of the dystrophin-glycoprotein complex in normal muscle and in the pathogenesis of muscular dystrophy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR048179-04
Application #
6786775
Study Section
Special Emphasis Panel (ZRG1-CDF-5 (02))
Program Officer
Nuckolls, Glen H
Project Start
2001-09-24
Project End
2006-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
4
Fiscal Year
2004
Total Cost
$339,975
Indirect Cost
Name
University of California Los Angeles
Department
Miscellaneous
Type
Schools of Arts and Sciences
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Gibbs, Elizabeth M; Crosbie-Watson, Rachelle H (2017) A Simple and Low-cost Assay for Measuring Ambulation in Mouse Models of Muscular Dystrophy. J Vis Exp :
Peter, Angela K; Miller, Gaynor; Capote, Joana et al. (2017) Nanospan, an alternatively spliced isoform of sarcospan, localizes to the sarcoplasmic reticulum in skeletal muscle and is absent in limb girdle muscular dystrophy 2F. Skelet Muscle 7:11
McMorran, Brian J; McCarthy, Francis E; Gibbs, Elizabeth M et al. (2016) Differentiation-related glycan epitopes identify discrete domains of the muscle glycocalyx. Glycobiology 26:1120-1132
Gibbs, Elizabeth M; Marshall, Jamie L; Ma, Eva et al. (2016) High levels of sarcospan are well tolerated and act as a sarcolemmal stabilizer to address skeletal muscle and pulmonary dysfunction in DMD. Hum Mol Genet 25:5395-5406
Marshall, Jamie L; Oh, Jennifer; Chou, Eric et al. (2015) Sarcospan integration into laminin-binding adhesion complexes that ameliorate muscular dystrophy requires utrophin and ?7 integrin. Hum Mol Genet 24:2011-22
Parvatiyar, Michelle S; Marshall, Jamie L; Nguyen, Reginald T et al. (2015) Sarcospan Regulates Cardiac Isoproterenol Response and Prevents Duchenne Muscular Dystrophy-Associated Cardiomyopathy. J Am Heart Assoc 4:
Marshall, Jamie L; Crosbie-Watson, Rachelle H (2013) Sarcospan: a small protein with large potential for Duchenne muscular dystrophy. Skelet Muscle 3:1
Marshall, Jamie L; Kwok, Yukwah; McMorran, Brian J et al. (2013) The potential of sarcospan in adhesion complex replacement therapeutics for the treatment of muscular dystrophy. FEBS J 280:4210-29
Cabrera, Paula V; Pang, Mabel; Marshall, Jamie L et al. (2012) High throughput screening for compounds that alter muscle cell glycosylation identifies new role for N-glycans in regulating sarcolemmal protein abundance and laminin binding. J Biol Chem 287:22759-70
Marshall, Jamie L; Holmberg, Johan; Chou, Eric et al. (2012) Sarcospan-dependent Akt activation is required for utrophin expression and muscle regeneration. J Cell Biol 197:1009-27

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