In skeletal muscle, the dystrophin-glycoprotein complex is located at the sarcolemma and is composed of peripheral and integral membrane proteins. As a whole, this complex links the extracellular matrix to the intracellular actin cytoskeleton and provides structural stability to the sarcolemma during muscle contraction. Duchenne muscular dystrophy, the most common form of dystrophy, is caused by mutations in the dystrophin gene that result in loss of dystrophin protein and the entire dystrophin-glycoprotein complex. My research group has pioneered several key discoveries related to the function of sarcospan, an integral component of the dystrophin-glycoprotein complex. We have shown that sarcospan plays an important role in mediating protein interactions within this complex. Sarcospan affects communication between the dystrophin-glycoprotein complex and the extracellular matrix. Importantly, we demonstrate that mild sarcospan over-expression in mdx mice, which possess a mutation in the murine dystrophin gene, rescues muscular dystrophy by stabilizing expression of a complex of proteins that is functionally analogous to the dystrophin-glycoprotein complex. We propose to investigate the molecular mechanism(s) of SSPN-mediated amelioration of mdx phenotype and reveal the compensatory mechanisms that may mask a potentially interesting and enlightening phenotype in the SSPN-null mice. We will also complete our characterization of SSPN's `rescue effect'by examining muscle mechanics. Our hypothesis provides a mechanism for cross-talk between transmembrane/cytoskeletal complexes (i.e. integrins and DGC) that may illuminate how compensatory mechanisms are regulated. Results from each of the Aims will provide new information on the role of sarcospan as an important structural element within the dystrophin-glycoprotein complex and uncover new information on sarcospan's function in signaling and disease.
Our proposal addresses questions related to how disruption of the dystrophin-glycoprotein complex causes Duchenne muscular dystrophy. During our previous funding period, we discovered that sarcospan, an integral component of the dystrophin-glycoprotein complex, is able to ameliorate dystrophin-deficient muscular dystrophy in mice. We plan to test the physiological properties of these mice and investigate the mechanisms of sarcospan amelioration.
|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|
|Marshall, Jamie L; Chou, Eric; Oh, Jennifer et al. (2012) Dystrophin and utrophin expression require sarcospan: loss of ?7 integrin exacerbates a newly discovered muscle phenotype in sarcospan-null mice. Hum Mol Genet 21:4378-93|
|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|
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