PROJECT 1: Assessing and modulating the role of inflammation and fibrosis in the dystrophic process. Project 1 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. Lastly, the project will examine the combined effects of combined anti-inflammatory or anti-fibrotic drugs and myostatin inhibitors. The fundamental concept driving this project is 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 project are the attainment of clinically useful pharmacological means of inhibiting fibrosis by identifying the best existing pharmacological inhibitors of fibrosis, as well as driving the development of new classes of inhibitors.

Public Health Relevance

Fibrosis ultimately limits repair of skeletal muscle in the muscular dystrophies and will limit the success of viral gene transfer and stem cell therapies. By slowing fibrosis, the overall disease progression can be slowed and functional muscle can be better maintained and treated

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AR052646-10
Application #
8722304
Study Section
Special Emphasis Panel (ZNS1-SRB-S)
Project Start
2014-08-01
Project End
2015-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
10
Fiscal Year
2014
Total Cost
$387,985
Indirect Cost
$136,497
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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
Batra, Abhinandan; Harrington, Ann; Lott, Donovan J et al. (2018) Two-Year Longitudinal Changes in Lower Limb Strength and Its Relation to Loss in Function in a Large Cohort of Patients With Duchenne Muscular Dystrophy. Am J Phys Med Rehabil 97:734-740
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
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

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