A variety of mutations in humans cause muscular dystrophies. Among these genetic disorders, patients carrying non-sense mutations in the DMD gene or deletions that disrupt the reading frame present the most severe form of muscular dystrophies, i.e. Duchene's Muscular Dystrophy (DMD). DMD is an X-linked recessive disorder that affects ~ 1 in 3,500 boys. In the skeletal muscle, the primary DMD transcripts contain 79 exons and produce a protein of ~427 KD named Dystrophin. Dystrophin provides an essential linkage between cytoskeleton and extracellular matrix to maintain muscle integrity. Because internally truncated Dystrophin are partially functional, anti-sense oligonucleotide-directed skipping of mutated exon to restore DMD reading frame is in clinical trial to ameliorate the disease. A long-standing animal model for DMD is the mdx mouse, which carries a non-sense mutation in exon 23 of the homologous Dmd gene. A prominent feature in DMD patients and mdx mice are chronic inflammation associated with continuous muscle degeneration. IL4 and IL13 are anti-inflammatory peptide factors that also promote muscle regeneration. During the previous/current funding period, we found that IL4 or IL13 can induce muscle fibers to express truncated Dmd proteins, similar to those found by anti-sense oligonucleotide-directed exon skipping. We propose three aims to investigate the mechanisms which underlie IL4/13-inducible Dmd expression:
Aim 1 : Further characterizing the effects of IL4 and IL13 on mdx models.
Aim 2 : Examining the characteristics of IL4/ IL13-induced revertant fibers.
Aim 3 : Defining the cellular mechanism underlying IL4/IL13-induced Dmd reversion.
Aim 4 : Exploring the molecular mechanism underlying IL4/IL13-induced Dmd reversion. While our proposed research has exciting clinical implications to DMD patients, we focus on uncovering the mechanism underlying a novel biological phenomenon. Information gained from this study is essential for translating this study to clinical use.

Public Health Relevance

Duchenne Muscular Dystrophy affects ~ 1 in 3,500 boys due to mutations in the DMD gene causing no Dystrophin expression. The mdx mouse is an animal model for this disorder. We find that IL4 and IL13 can induce expression of internally truncated Dystrophin in the mdx mouse - such forms of Dystrophin can be functional. We propose to investigate the mechanisms underlying IL4/IL13- induced Dystrophin expression. Results from our research should provide critical information for translating our finding into a therapeutic method for Duchenne Muscular Dystrophy patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR060042-07
Application #
9068812
Study Section
Skeletal Muscle Biology and Exercise Physiology Study Section (SMEP)
Program Officer
Boyce, Amanda T
Project Start
2010-08-15
Project End
2020-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
7
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Carnegie Institution of Washington, D.C.
Department
Type
DUNS #
072641707
City
Washington
State
DC
Country
United States
Zip Code
20005
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