Project 2. Cell damage and remodeling pathways in Duchenne muscular dystrophy [ Duchenne muscular dystrophy (DMD) is a progressive muscle disease caused by dystrophin deficiency. Although Duchenne dystrophy muscle shows myofiber damage and necrosis at all ages, the ensuing endomysial fibrosis and gradual failure of muscle regeneration in DMD are believed to be downstream or secondary consequences of dystrophin deficiency. Here, we focus on two key tissue damage and remodeling pathways that we show differentially regulated as a function of age in Duchenne dystrophy;Tolllike receptor/NF-KB and TGF-?. Our preliminary studies show that the activation of macrophages, tissue dendritic cells and associated NF-KB pathway occurs as early as the neonatal period and remains relatively constant in activity throughout the course of the pathology. On the other hand, we show activation of the TGF-? pathway only later in the disease process, and this is commensurate with both endomysial fibrosis and a metabolic crisis.
The specific aims are focused on isolating each of these pathways, and determining cause/effect consequences of pathway modulation.
Aim 1 builds out the TGF-? pathway, using both in vivo and in vitro models to determine interactions between TGF-?, and two key modulatory proteins (IGFBP3 and AML1).
Aim 2 focuses on Toll-like receptor/NF-KB, pathways that we show are commensurate with very early inflammation in dystrophin deficient muscle (8-10 month old DMD patients).
This aim will dissect this complex tissue damage and remodeling pathway, bringing expanding knowledge of this cascade in other tissues to bear on muscle pathology. This project draws upon the expertise of the co-investigators in muscle immunology (Dr. Nagaraju), molecular pathology and muscle remodeling (Drs. Chen and Nagaraju), and the extensive pre-existing. mRNA profiling muscle data sets held by the Center (-800 profiles). This permits rapid assessment of disease specificity, as we show in preliminary data for TLR7 and DMD. The proposed studies take a """"""""pathway oriented"""""""" approach to pathophysiology of Duchenne'dystrophy, with the goal of defining cause/effect pathway modulation specific for stages of the human disease, and provide pathwaybased targets for future design of human clinical trials in DMD. ]

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZNS1)
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Children's Research Institute
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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
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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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