This MDCRC is organized around the concept that limiting fibrosis in the muscular dystrophies will help extend the period of successful regeneration via the patients'own satellite cell repair, increase the benefits associated with therapies that increase the patients'muscle repair capacity, and will extend the age at which patients can benefit from eventual viral gene or stem cell therapies. Thus the primary objectives of this MDCRC are to facilitate the attainment of clinically useful pharmacological means of inhibiting fibrosis and to identify the best existing pharmacological inhibitors of fibrosis, as well as drive the development of new classes of inhibitors. Our further goal is to develop non-invasive imaging techniques to assess the progression of fibro-fatty replacement of skeletal and cardiac muscles. In Project 1, Drs. Sweeney and Spencer (in collaboration with Drs. McNally, Barton, Miceli, Discher and Epstein) will follow the fate of satellite cells during the progression of disease in mdx and A/J mice, while characterizing changes in muscular tissue, fibrosis and fat. The project will go on to analyze inhibitors of inflammation and/or fibrosis and their impact on disease pathology in mdx and A/J mice. In Project 2, Dr. McNally will search for modifiers of cardiac fibrosis by examining mouse models of muscular dystrophy on different genetic backgrounds. Stan Nelson (UCLA) will collaborate on Project 2. In Project 3, Drs. Walter and Vandenborne will continue their project focused on the development of non-invasive monitoring of disease progression in muscular dystrophy. They will be aided and advised in this effort by Drs. Bonnemann, Finkel, McNally, Sweeney and Byrne. An Administrative Core (Core A) will support all projects, as well as provide the administrative support for our symposia and bi-annual international muscular dystrophy meeting, and to oversee the use of non-NIH funding for the Center. The Center will also have a major training and educational component, under the direction of Drs. Ostap and Finkel (Core B: Training and Education Core). A Physiological Assessment Core (Core C) will support Project 1 and continue as a national source for evaluating therapeutic inten/entions in mouse models of Muscular Dystrophy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AR052646-07
Application #
8128671
Study Section
Special Emphasis Panel (ZNS1-SRB-S (22))
Program Officer
Nuckolls, Glen H
Project Start
2005-04-01
Project End
2015-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
7
Fiscal Year
2011
Total Cost
$1,586,518
Indirect Cost
Name
University of Pennsylvania
Department
Physiology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Quattrocelli, Mattia; Spencer, Melissa J; McNally, Elizabeth M (2017) Outside in: The matrix as a modifier of muscular dystrophy. Biochim Biophys Acta 1864:572-579
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
McNally, Elizabeth M (2017) Cardiomyopathy in Muscular Dystrophy: When to Treat? JAMA Cardiol 2:199
Hammers, David W; Merscham-Banda, Melissa; Hsiao, Jennifer Ying et al. (2017) Supraphysiological levels of GDF11 induce striated muscle atrophy. EMBO Mol Med 9:531-544
Demonbreun, Alexis R; McNally, Elizabeth M (2017) Muscle cell communication in development and repair. Curr Opin Pharmacol 34:7-14
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
Capote, Joana; Kramerova, Irina; Martinez, Leonel et al. (2016) Osteopontin ablation ameliorates muscular dystrophy by shifting macrophages to a pro-regenerative phenotype. J Cell Biol 213:275-88
Kramerova, Irina; Ermolova, Natalia; Eskin, Ascia et al. (2016) Failure to up-regulate transcription of genes necessary for muscle adaptation underlies limb girdle muscular dystrophy 2A (calpainopathy). Hum Mol Genet 25:2194-2207
Quattrocelli, Mattia; McNally, Elizabeth M (2016) BMP and WNT: the road to cardiomyocytes is paved with precise modulation. Stem Cell Investig 3:21
Demonbreun, Alexis R; Quattrocelli, Mattia; Barefield, David Y et al. (2016) An actin-dependent annexin complex mediates plasma membrane repair in muscle. J Cell Biol 213:705-18

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