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
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Daniel, Bence; Nagy, Gergely; Czimmerer, Zsolt et al. (2018) The Nuclear Receptor PPAR? Controls Progressive Macrophage Polarization as a Ligand-Insensitive Epigenomic Ratchet of Transcriptional Memory. Immunity 49:615-626.e6
Willcocks, Rebecca J; Triplett, William T; Lott, Donovan J et al. (2018) Leg muscle MRI in identical twin boys with duchenne muscular dystrophy. Muscle Nerve :
Aartsma-Rus, Annemieke; Ferlini, Alessandra; McNally, Elizabeth M et al. (2018) 226th ENMC International Workshop:: Towards validated and qualified biomarkers for therapy development for Duchenne muscular dystrophy 20-22 January 2017, Heemskerk, The Netherlands. Neuromuscul Disord 28:77-86
Barthélémy, Florian; Defour, Aurélia; Lévy, Nicolas et al. (2018) Muscle Cells Fix Breaches by Orchestrating a Membrane Repair Ballet. J Neuromuscul Dis 5:21-28
Smith, Lucas R; Barton, Elisabeth R (2018) Regulation of fibrosis in muscular dystrophy. Matrix Biol 68-69:602-615
Hicks, Michael R; Hiserodt, Julia; Paras, Katrina et al. (2018) ERBB3 and NGFR mark a distinct skeletal muscle progenitor cell in human development and hPSCs. Nat Cell Biol 20:46-57
Barnard, Alison M; Willcocks, Rebecca J; Finanger, Erika L et al. (2018) Skeletal muscle magnetic resonance biomarkers correlate with function and sentinel events in Duchenne muscular dystrophy. PLoS One 13:e0194283
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
McNally, Elizabeth M; Wyatt, Eugene J (2017) Mutation-Based Therapy for Duchenne Muscular Dystrophy: Antisense Treatment Arrives in the Clinic. Circulation 136:979-981

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