Protease inhibition as possible therapy for muscular dystrophyThe major goals of this project are to slow the loss of skeletal muscle mass and function that occurs as aconsequence of the dystrophic process. Informs of muscular dystrophy in which the dystrophin andassociated complex are defective (e.g. DMD, LGMD2C) or in which muscle repair is impaired (e.g. dysferlindefects), activation of muscle protein breakdown is greatly elevated. The fundamental hypothesis of thisproposal is that targeted inhibition of specific proteases can reduce this elevated turnover, leading toincreased muscle mass and strength. There are a number of potential targets, including intracellularproteases that are up-regulated as part of the inflammatory response, calpain and even specific arms of theubiquitin-proteosome pathway. These pathways will be inhibited with specific drugs, alone and incombination in mouse models of muscular dystrophies.As muscular dystrophy progresses, the rate of loss of muscle accelerates as inactivity is imposed. Disuseatrophy has at its basis three major underlying causes; increased protein degradation, decreased proteinsynthesis and a transient component of apoptosis. These likely will greatly accelerate muscle loss on adystrophic background. Using drugs to target specific proteases may lead to a sparing of the disuse atrophyas well as the muscle loss associated with the dystrophy itself. This will be evaluated in dystrophic micesubjected to hindlimb suspension.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AR052646-04
Application #
7648211
Study Section
Special Emphasis Panel (ZNS1)
Project Start
2008-06-01
Project End
2010-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
4
Fiscal Year
2008
Total Cost
$470,464
Indirect Cost
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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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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