Genetic Modifiers of Duchenne Muscular Dystrophy
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PROVIDER: PRJNA1124393 | ENA |
REPOSITORIES: ENA
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Project description:Large animal models for Duchenne muscular dystrophy (DMD) are indispensible for preclinical evaluation of novel diagnostic procedures and treatment strategies. To evaluate functional consequences of Duchenne muscular dystrophy (DMD) in skeletal muscle and myocardium, we used a new genetically engineered dystrophin KO pig model displaying hallmarks of human DMD. Heart and skeletal muscle tissue samples of DMD pigs and wild-type (WT) controls at three different ages were analyzed by label-free proteomics.
2021-12-01 | PXD027772 | Pride
Project description:Three subjects with Duchenne muscular dystrophy (8.3, 10.4, and 16.7 years old) were studied. Baseline studies included stable isotope infusion followed by gastrocnemius muscle biopsy to determine myosin heavy chain synthesis rates. RNA was isolated from the muscle biopsy as well. The subjects were then treated for 3 months with oxandrolone (a synthetic anabolic steroid, 0.1 mg/kg/day) and the studies repeated. Keywords = muscle Keywords = Duschenne muscular dystrophy Keywords = oxandrolone Keywords = androgen Keywords: parallel sample
2004-10-15 | GSE1764 | GEO
Project description:Skeletal muscle wasting results from numerous pathological conditions impacting both the musculoskeletal and nervous systems. A unifying feature of these pathologies is the upregulation of members of the E3 ubiquitin ligase family, resulting in increased proteolytic degradation of target proteins. Despite the critical role E3 ubiquitin ligases in regulating muscle mass, the specific proteins they target for degradation and the mechanisms by which they regulate skeletal muscle homeostasis remain ill-defined. Here, using zebrafish loss of function models combined with in vivo cell biology and proteomic approaches, we identified the endoplasmic reticulum chaperone, BiP, as a novel target of the E3 ubiquitin ligase atrogin-1. A loss in atrogin-1 results in an accumulation of BiP, leading to impaired mitochondrial dynamics and a subsequent loss in muscle fibre integrity. We further implicate a disruption in atrogin-1 mediated BiP regulation in the pathogenesis of Duchenne Muscular Dystrophy. We reveal that BiP is not only upregulated in Duchenne Muscular Dystrophy, but its inhibition using pharmacological strategies, or by upregulating atrogin-1, significantly ameliorates pathology in a zebrafish model of Duchenne Muscular Dystrophy. Collectively, our data implicates a novel disease axis in the pathogenesis of Duchenne Muscular Dystrophy, and highlights atrogin-1’s essential role in maintaining muscle homeostasis.
2024-03-07 | PXD038406 | Pride
Project description:Duchenne muscular dystrophy (DMD) is caused by genetic deficiency of dystrophin and characterized by massive structural and functional changes of skeletal muscle tissue, leading to terminal muscle failure. In this project, proteomics data from skeletal muscle of a genetically engineered DMD pig model were investigated in order to confirm muscular fibrosis and MSOT signals.
2020-01-09 | PXD016003 | Pride
Project description:Duchenne muscular dystrophy is an X-linked monogenic disease caused by mutations in the dystrophin gene (DMD) and characterized by progressive muscle weakness leading to loss of ambulation and significantly decreased life expectancy. Since the current standard of care for Duchenne muscular dystrophy is to merely treat symptoms, there is a dire need for novel treatment modalities that can correct the underlying genetic mutations. While several gene replacement therapies are being explored in clinical trials, one emerging approach that can directly correct mutations in genomic DNA is base editing. We have recently developed CRISPR-SKIP, a base editing strategy to induce permanent exon skipping by introducing C>T or A>G mutations at splice acceptors in genomic DNA, which can be utilized therapeutically to recover dystrophin expression when a genomic deletion leads to an out-of-frame DMD transcript. We now demonstrate that CRISPR-SKIP can be adapted to correct some forms of Duchenne muscular dystrophy by disrupting the splice acceptor in human DMD exon 45 with high efficiency, which enables open reading frame recovery and restoration of dystrophin expression. We also demonstrate that AAV-delivered split-intein base editors edit the splice acceptor of DMD exon 45 in cultured human cells and in vivo, highlighting the therapeutic potential of this strategy.
2023-07-20 | GSE235673 | GEO
Project description:Eosinophils are implicated in the development of many chronic diseases. However, their function in muscular dystrophy is understudied. Here we demonstrate that muscle hyper-eosinophilia could be a marker of poor outcomes in Duchenne Muscular Dystrophy.
2022-03-14 | GSE189846 | GEO
Project description:Muscle wasting in Duchenne Muscular Dystrophy is caused by myofiber fragility and poor regeneration that leads to chronic inflammation and muscle replacement by fibrofatty tissue. Our recent findings demonstrated that Resolvins, a class bioactive lipids derived from omega-3 fatty acids, have the capacity to dampen inflammation and stimulate muscle regeneration to alleviate disease progression. This therapeutic avenue has many advantages compared to glucocorticoids, the current gold-standard treatment for Duchenne Muscular Dystrophy. However, the use of bioactive lipids as therapeutic drugs also faces many technical challenges such as their short-half life. Here, we explored the potential of synthetic agonist of bioactive lipid receptor, namely the Gpr18 agonist PSB-KD107, as a therapeutic alternative for Duchenne Muscular Dystrophy. We showed that PSB-KD107 can stimulate the myogenic capacity of human iPSC-derived myoblasts in vitro. RNAseq analysis revealed an enrichment in biological processes related to lipid metabolism, small molecule biosynthesis, and steroid-related processes in PSB-KD107-treated cells, as well as pathways related to fatty acid signaling such as Peroxisome proliferator-activated receptors, AMP-activated protein kinase, and sphingolipid signaling pathways. In vivo, the treatment of dystrophic mdx mice with PSB-KD107 resulted in reduced inflammation, enhanced myogenesis, and improved muscle function compared to vehicle-treated mice. Overall, our findings identified a novel therapeutic target for the treatment of Duchenne Muscular Dystrophy.
2023-08-04 | GSE222773 | GEO
Project description:Three subjects with Duchenne muscular dystrophy (8.3, 10.4, and 16.7 years old) were studied. Baseline studies included stable isotope infusion followed by gastrocnemius muscle biopsy to determine myosin heavy chain synthesis rates. RNA was isolated from the muscle biopsy as well. The subjects were then treated for 3 months with oxandrolone (a synthetic anabolic steroid, 0.1 mg/kg/day) and the studies repeated.
2007-08-25 | E-GEOD-1764 | biostudies-arrayexpress
Project description:Noninvasive Prenatal Diagnosis of Duchenne Muscular Dystrophy: Comprehensive Genetic Diagnosis in Carrier, Proband, and Fetus.
| PRJEB7629 | ENA
Project description:Duchenne muscular dystrophy (DMD) is caused by genetic deficiency of dystrophin and characterized by massive structural and functional changes of skeletal muscle tissue, leading to terminal muscle failure. In this project, proteomics data from skeletal muscle of a genetically engineered DMD pig model treated by somatic gene editing are shown.
2020-02-05 | PXD014893 | Pride