Defects in dystrophin are thought to disrupt a mechanical link between the cytoskeleton, the membrane and the extracellular matrix of muscle cells resulting in muscular dystrophy and cardiomyopathy. Dystrophin binds a complex of proteins that anchor its attachment to the muscle membrane and in turn, bind the extracellular matrix protein, laminin. Laminin mutations also result in myopathy, but the membrane in laminin-deficient muscle does not seem to be as physically disrupted as dystrophin-deficient membranes implying a distinct molecular mechanism. Within the dystrophin-glycoprotein complex is a multisubunit protein, sarcoglycan, that is secondarily decreased when dystrophin is mutated. Recently, it was discovered that mutations in sarcoglycan genes are a primary cause of human myopathy. The function of sarcoglycan is unknown and its predicted structure suggests a cell surface receptor. To investigate membrane defects in muscle lacking sarcoglycan, we are using homologous recombination in embryonic stem cells to generate mice lacking different subunits of sarcoglycan. gamma-sarcoglycan and delta-sarcoglycan are related 35 kDa glycosylated, transmembrane proteins normally expressed in cardiac and skeletal muscle. We have generated mice lacking gamma-sarcoglycan and embryonic stem cells heterozygously lacking delta-sarcoglycan. Preliminary data indicate mice lacking gamma-sarcoglycan show a severe dystrophic pattern that resembles human myopathy arising from sarcoglycan mutations. Sarcoglycan-deficient mice will be characterized using a variety of immunocytochemical approaches. Changes in gene expression that result from sarcoglycan deficiency will be investigated. Lastly, we will perform genetic experiments aimed at disrupting multiple membrane-extracellular matrix connections to assess the relative contribution of these different attachments and their role in normal and abnormal heart and muscle function.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL061322-03
Application #
6390090
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Fakunding, John
Project Start
1999-07-01
Project End
2004-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
3
Fiscal Year
2001
Total Cost
$274,808
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
Fallon, Justin R; McNally, Elizabeth M (2018) Non-Glycanated Biglycan and LTBP4: Leveraging the extracellular matrix for Duchenne Muscular Dystrophy therapeutics. Matrix Biol 68-69:616-627
Ohiri, Joyce C; McNally, Elizabeth M (2018) Gene Editing and Gene-Based Therapeutics for Cardiomyopathies. Heart Fail Clin 14:179-188
Wyatt, Eugene J; Demonbreun, Alexis R; Kim, Ellis Y et al. (2018) Efficient exon skipping of SGCG mutations mediated by phosphorodiamidate morpholino oligomers. JCI Insight 3:
McNally, Elizabeth M; Wyatt, Eugene J (2017) Mutation-Based Therapy for Duchenne Muscular Dystrophy: Antisense Treatment Arrives in the Clinic. Circulation 136:979-981
McNally, Elizabeth M; Mestroni, Luisa (2017) Dilated Cardiomyopathy: Genetic Determinants and Mechanisms. Circ Res 121:731-748
Quattrocelli, Mattia; Barefield, David Y; Warner, James L et al. (2017) Intermittent glucocorticoid steroid dosing enhances muscle repair without eliciting muscle atrophy. J Clin Invest 127:2418-2432
Demonbreun, Alexis R; McNally, Elizabeth M (2017) Muscle cell communication in development and repair. Curr Opin Pharmacol 34:7-14
McNally, Elizabeth M (2017) Gene Editing for the Heart: Correcting Dystrophin Mutations. Circ Res 121:896-898
Quattrocelli, Mattia; Salamone, Isabella M; Page, Patrick G et al. (2017) Intermittent Glucocorticoid Dosing Improves Muscle Repair and Function in Mice with Limb-Girdle Muscular Dystrophy. Am J Pathol 187:2520-2535
Giacomazzi, Giorgia; Holvoet, Bryan; Trenson, Sander et al. (2017) MicroRNAs promote skeletal muscle differentiation of mesodermal iPSC-derived progenitors. Nat Commun 8:1249

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