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 #
5U54AR052646-09
Application #
8543510
Study Section
Special Emphasis Panel (ZNS1-SRB-S)
Project Start
2013-08-01
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
9
Fiscal Year
2013
Total Cost
$315,816
Indirect Cost
$128,129
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Quattrocelli, Mattia; McNally, Elizabeth M (2016) BMP and WNT: the road to cardiomyocytes is paved with precise modulation. Stem Cell Investig 3:21
DiFranco, Marino; Kramerova, Irina; Vergara, Julio L et al. (2016) Attenuated Ca(2+) release in a mouse model of limb girdle muscular dystrophy 2A. Skelet Muscle 6:11
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
Demonbreun, Alexis R; Allen, Madison V; Warner, James L et al. (2016) Enhanced Muscular Dystrophy from Loss of Dysferlin Is Accompanied by Impaired Annexin A6 Translocation after Sarcolemmal Disruption. Am J Pathol 186:1610-22
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
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
Vohra, Ravneet S; Mathur, Sunita; Bryant, Nathan D et al. (2016) Age-related T2 changes in hindlimb muscles of mdx mice. Muscle Nerve 53:84-90
Woodall, Benjamin P; Woodall, Meryl C; Luongo, Timothy S et al. (2016) Skeletal Muscle-specific G Protein-coupled Receptor Kinase 2 Ablation Alters Isolated Skeletal Muscle Mechanics and Enhances Clenbuterol-stimulated Hypertrophy. J Biol Chem 291:21913-21924
Demonbreun, Alexis R; McNally, Elizabeth M (2016) Plasma Membrane Repair in Health and Disease. Curr Top Membr 77:67-96
Smith, Lucas R; Hammers, David W; Sweeney, H Lee et al. (2016) Increased collagen cross-linking is a signature of dystrophin-deficient muscle. Muscle Nerve 54:71-8

Showing the most recent 10 out of 115 publications