This is a renewal application to study the sarcoglycan complex in striated muscle, and specifically the role of this complex in promoting sarcolemmal stability. Mutations in the genes encoding the sarcoglycan subunits produce a fragile sarcolemma that is susceptible to disruption. Sarcolemmal disruption is a hallmark feature associated with many different etiologies of muscle and heart injury. In the case of primary sarcoglycan gene mutations, there is ongoing injury to striated muscle, both heart and skeletal muscle. In skeletal muscle, where regeneration is robust, there is insufficient regeneration to keep pace with injury, and ultimately there is replacement of myocytes and cardiomyocytes by fibrosis, leading to weakness. The process of sarcolemmal instability is seen in humans with sarcoglycan gene mutations, as it is in those with dystrophin gene mutations, since the sarcoglycans are dystrophin-associated proteins. This proposal for continued work is justified by the need to develop approaches to stabilize the sarcolemma. Such approaches, if successful, are expected to provide a potential therapeutic for individuals with sarcoglycan gene mutation. Importantly, understanding mechanisms to stabilize the sarcolemma of heart and muscle could also potential yield improved approaches towards treating or preventing other defects that compromise sarcolemmal integrity. In the prior funding period, we proposed to use an unbiased genomewide approach to map modifiers of muscular dystrophy. We successfully did this, identifying Ltbp4, the latent TGFbeta binding protein, as a modifier for murine muscular dystrophy. We extended these findings by showing that LTBP4 also modifies walking in Duchenne Muscular Dystrophy, highlighting the importance and relevance of this approach. As proposed, we used the superhealing MRL strain to identify genetic loci that modify muscle and heart function in mouse models of muscular dystrophy. We now outline experiments to study candidate modifier genes from a chromosome 9 locus that regulates the heart in muscular dystrophy. Identifying modifiers for muscular dystrophy and cardiomyopathy points to pathways that we can exploit for prognosis and ultimately for therapy since these pathways, by design, can influence the outcome of disease. Additionally, during the prior funding period, we developed significant preliminary data identifying a minimal unit of gamma-sarcoglycan that is sufficient to improve muscle and heart function. The rationale for developing and testing this minimal unit of gamma- sarcoglycan, which we termed mini-gamma, is to justify the use of exon skipping as a treatment for LGMD2C.
This proposal outlines experiments to continue work to identify modifiers of muscular dystrophy and cardiomyopathy. Genetic modifiers are genes that alter the outcome of genetic diseases and identifying modifiers points to pathways that could be used to treat these disorders. We are also conducting experiments to determine whether exon skipping is feasible for limb girdle muscular dystrophy.
|Kim, Ellis Y; Page, Patrick; Dellefave-Castillo, Lisa M et al. (2016) Direct reprogramming of urine-derived cells with inducible MyoD for modeling human muscle disease. Skelet Muscle 6:32|
|McNally, Elizabeth M; Wyatt, Eugene J (2016) Welcome to the splice age: antisense oligonucleotide-mediated exon skipping gains wider applicability. J Clin Invest 126:1236-8|
|Gardner, Brandon B; Swaggart, Kayleigh A; Kim, Gene et al. (2015) Cardiac function in muscular dystrophy associates with abdominal muscle pathology. J Neuromuscul Dis 2:39-49|
|Vo, Andy H; McNally, Elizabeth M (2015) Modifier genes and their effect on Duchenne muscular dystrophy. Curr Opin Neurol 28:528-34|
|McNally, Elizabeth M; George Jr, Alfred L (2015) New approaches to establish genetic causality. Trends Cardiovasc Med 25:646-52|
|Gao, Quan Q; McNally, Elizabeth M (2015) The Dystrophin Complex: Structure, Function, and Implications for Therapy. Compr Physiol 5:1223-39|
|Ferlini, Alessandra; Flanigan, Kevin M; Lochmuller, Hanns et al. (2015) 204th ENMC International Workshop on Biomarkers in Duchenne Muscular Dystrophy 24-26 January 2014, Naarden, The Netherlands. Neuromuscul Disord 25:184-98|
|Gao, Quan Q; Wyatt, Eugene; Goldstein, Jeff A et al. (2015) Reengineering a transmembrane protein to treat muscular dystrophy using exon skipping. J Clin Invest 125:4186-95|
|McNally, Elizabeth M; Kaltman, Jonathan R; Benson, D Woodrow et al. (2015) Contemporary cardiac issues in Duchenne muscular dystrophy. Working Group of the National Heart, Lung, and Blood Institute in collaboration with Parent Project Muscular Dystrophy. Circulation 131:1590-8|
|McNally, Elizabeth M; Barefield, David Y; Puckelwartz, Megan J (2015) The genetic landscape of cardiomyopathy and its role in heart failure. Cell Metab 21:174-82|
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