Duchenne muscular dystrophy is the most common and devastating of the muscular dystrophies. The only effective therapy to date is chronic use of corticosteroids, yet patients respond variably to treatment and the basis of this benefit is not understood. The theme of the proposed Center application is to increase our understanding of the pathophysiology of Duchenne muscular dystrophy at multiple complementary yet interacting levels. The proposed research projects propose to break down the complex disease pathophysiology into component biochemical pathways, each of which shows evidence of cross-talk. This cross-talk in pathways leads to a synergism of projects and expertise in the proposed Center. Project 1 proposes to study genetic modifiers of Duchenne dystrophy, taking advantage of extensive patient resources available through the Cooperative International Neuromuscular Research Group (CINRG). This is the """"""""clinical project"""""""" for the Center. Project 2 studies cell damage and remodeling pathways as. a function of age and disease progression in human patients, with pathophysiological models tested in transgenic mice. Project 3 studies the issues of satellite cell characterization and activation as a function of age in the mdx mouse model. The proposed Center is centered in the Research Center for Genetic Medicine, a interdisciplinary group of -70 scientists with a major focus on the muscular dystrophies at all levels from clinics, clinical trials, molecular biology, and ethics. The three proposed projects are supported by three Cores; an Administrative Core, a Human Clinical Core (CINRG), and a Bioinformatics and Computing Core. This Center application has been extensively revised to respond to the previous critiques, including new published manuscripts addressing technical concerns regarding feasibility. The key personnel of the proposed Center (Drs. Hoffman, Escolar, Partridge, Chen, Nagaraju, Pegoraro, Leshner) have continued their strong publication record in neuromuscular disease and the topics of the proposal, with 129 manuscripts over the last 5 years, including 18 co-authored by two or more key personnel. ]

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HD053177-03
Application #
7294908
Study Section
Special Emphasis Panel (ZNS1-SRB-S (08))
Program Officer
Hanson, James W
Project Start
2005-09-30
Project End
2010-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
3
Fiscal Year
2007
Total Cost
$1,540,856
Indirect Cost
Name
Children's Research Institute
Department
Type
DUNS #
143983562
City
Washington
State
DC
Country
United States
Zip Code
20010
Jain, Harsh V; Boehler, Jessica F; Nagaraju, Kanneboyina et al. (2018) Synthesis, Characterization, and Function of an RNA-Based Transfection Reagent. Curr Protoc Nucleic Acid Chem 72:4.81.1-4.81.29
Anderson, Julia; Seol, Haeri; Gordish-Dressman, Heather et al. (2017) Interleukin 1 Receptor-Like 1 Protein (ST2) is a Potential Biomarker for Cardiomyopathy in Duchenne Muscular Dystrophy. Pediatr Cardiol 38:1606-1612
Jain, H V; Boehler, J F; Verthelyi, D et al. (2017) An amphipathic trans-acting phosphorothioate RNA element delivers an uncharged phosphorodiamidate morpholino sequence in mdx mouse myotubes. RSC Adv 7:42519-42528
Echigoya, Yusuke; Lim, Kenji Rowel Q; Trieu, Nhu et al. (2017) Quantitative Antisense Screening and Optimization for Exon 51 Skipping in Duchenne Muscular Dystrophy. Mol Ther 25:2561-2572
Coley, William D; Bogdanik, Laurent; Vila, Maria Candida et al. (2016) Effect of genetic background on the dystrophic phenotype in mdx mice. Hum Mol Genet 25:130-45
Nagaraju, Kanneboyina; Ghimbovschi, Svetlana; Rayavarapu, Sree et al. (2016) Muscle myeloid type I interferon gene expression may predict therapeutic responses to rituximab in myositis patients. Rheumatology (Oxford) 55:1673-80
Vila, Maria Candida; Klimek, Margaret Benny; Novak, James S et al. (2015) Elusive sources of variability of dystrophin rescue by exon skipping. Skelet Muscle 5:44
Hathout, Yetrib; Brody, Edward; Clemens, Paula R et al. (2015) Large-scale serum protein biomarker discovery in Duchenne muscular dystrophy. Proc Natl Acad Sci U S A 112:7153-8
Bello, Luca; Kesari, Akanchha; Gordish-Dressman, Heather et al. (2015) Genetic modifiers of ambulation in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study. Ann Neurol 77:684-96
Dillingham, Blythe C; Benny Klimek, Margaret E; Gernapudi, Ramkishore et al. (2015) Inhibition of inflammation with celastrol fails to improve muscle function in dysferlin-deficient A/J mice. J Neurol Sci 356:157-62

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