Smad8 is a driver of Duchenne muscular dystrophy pathology via myomiR repression

项目概述：该项目提出研究Smad 8和肌肉富集microRNA的作用，已知 在杜氏肌营养不良症中，杜氏肌营养不良症是一种骨骼肌萎缩 至少部分由肌营养不良蛋白缺失引起的膜脆性的继发效应介导的疾病。 这些继发性影响包括肌肉增殖、分化和再生的损伤， 通过炎症传播。该项目已经鉴定了TGF β 1相关转录因子Smad 8， 在Duchenne型肌营养不良症骨骼肌中， 肌肉.因此，该提案将使用细胞培养和杜氏肌营养不良症的小鼠模型， 分子图谱Smad 8在骨骼肌功能和疾病中的作用。 短期目标是确定TGF β 1/Smad 8信号可能促进营养不良的机制。 通过了解其与myomiRs抑制的联系，以确定新的途径， 潜在的治疗干预。例如，我们将研究过表达和敲低 Smad 8对肌肉增殖、分化和骨骼肌再生等关键途径的作用。我们还将 研究Smad 8调节对myomiRs及其下游mRNA通路的影响。长期目标是 扩大我们对骨骼肌功能中TGF β/Smad 8细胞信号传导和microRNA生物学的理解 健康和疾病。

Project Summary: This project proposes to study the role of Smad8 and muscle-enriched microRNAs, known as myomiRs, in Duchenne muscular dystrophy. Duchenne muscular dystrophy is a skeletal muscle wasting disease that is at least in part mediated by secondary effects from membrane fragility due to loss of dystrophin. These secondary effects include impairments in muscle proliferation, differentiation, and regeneration that are propagated by inflammation. This project has identified the TGF-associated transcription factor, Smad8, as markedly elevated and associated with the repression of myomiRs in Duchenne muscular dystrophy skeletal muscles. As such, the proposal will use cell culture and mouse models of Duchenne muscular dystrophy to molecularly map the role of Smad8 in skeletal muscle function and disease. The short-term goal is to identify the mechanisms by which TGF / Smad8 signaling might promote dystrophic processes by understanding its connection to myomiRs repression with a goal of identifying novel pathways for potential therapeutic intervention. For example, we will study the effects of over-expression and knockdown of Smad8 on key pathways like muscle proliferation, differentiation, and skeletal muscle regeneration. We will also study impact of Smad8 modulation on myomiRs and their downstream mRNA pathways. The long-term goal is to expand our understanding of TGF / Smad8 cell signaling and microRNA biology in skeletal muscle function in health and disease.