Project 1 Abstract In muscular dystrophies, such as Duchenne muscular dystrophy (DMD), in which there are ongoing bouts of degeneration followed by regeneration, muscle repair is achieved by activated muscle stem cells. Over time, fibrosis accumulates in the muscle, largely driven by increased TGF-?1, contributed by ongoing inflammation. Fibrosis itself is believed to contribute to failed regeneration, and as fibrosis accumulates regeneration is further depressed. Fibrosis can arise from a combination of cell types including resident fibroblasts, fibro-fatty precursor (FAP) cells, satellite cells themselves, and as we hypothesize in this proposal, from invading mesothelial precursor cells. Stem cells can also be directed into fat, creating a fibro-fatty matrix that gradually replaces the muscle cells. In this proposal, we will investigate the interaction betweens modulators of inflammation, fibrosis and cell fate to ultimately gain insight into the interplay of how these factors contributes to failed regeneration and how therapeutics can alter this process. The proposed studies will use a new, severe mouse model of Duchenne muscular dystrophy, the mdx mouse on the DBA background. The investigations are organized into three aims: (1) Delineation of the cells that contribute to fibrosis and fat; (2) Impact of genetic modifiers of inflammation and fibrosis on the cells involved in fibrosis; and (3) Modulation of fibrosis using therapeutics to decrease inflammatory and fibrotic responses and TGF-?1 signaling on the DBA background.

Public Health Relevance

In many types of muscular dystrophy, muscle fails to repair itself, and is gradually lost and replaced with fat and connective tissue. This project is designed to uncover the nature of the disease processes that prevent muscle repair and maintenance, and to evaluate therapeutics that will alter the course of disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AR052646-13
Application #
9330684
Study Section
Special Emphasis Panel (ZHD1)
Project Start
2005-09-25
Project End
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
13
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Florida
Department
Type
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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
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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