Messenger RNA stability in myotonic dystrophy

描述（由申请人提供）：强直性肌营养不良（DM）是一种主要影响骨骼肌的遗传性疾病。该疾病有两种形式：DM1 是由肌强直蛋白激酶 (DMPK) 基因 3' 非翻译区的 CUG 重复扩增引起的，而 DM2 是由锌指蛋白 9 (ZNF9) 基因内含子中的 CCUG 重复扩增引起的。这两种情况的发病机制主要是由含有扩展重复序列的有毒 RNA 物质的积累引起的。突变体 RNA 隔离了 Muscleblind，这是一种对临床相关 mRNA 加工非常重要的 RNA 结合蛋白。此外，突变的RNA通过未知的机制诱导另一种RNA结合蛋白CUGBP1的异常表达。这反过来又会影响其他 mRNA 的加工和衰变。 我们将首先研究细胞如何代谢有毒 RNA，以期最终增强其去除能力。然后我们将继续研究 CUGBP1 对编码参与肌生成和蛋白质分泌的蛋白质的两组 mRNA 的影响。最后，我们将从患者肌肉细胞中生成新的细胞培养模型，并利用它们来发现 DM1 中发生的 mRNA 稳定性变化。 总的来说，我们希望阐明强直性肌营养不良中发生的基本分子变化，并确定未来治疗的新靶点。 公众健康相关性：强直性肌营养不良是一种主要影响骨骼肌的衰弱性遗传性疾病。突变基因产生有毒RNA，影响其他基因的表达。我们的研究将确定突变 RNA 毒性背后的分子机制，并表征对其他临床相关基因表达的影响。我们希望找到治疗干预的新途径。

DESCRIPTION (provided by applicant): Myotonic dystrophy (DM) is an inherited disease primarily affecting skeletal muscle. There are two forms of the disease: DM1 is caused by a CUG repeat expansion in the 3' untranslated region of the Dystrophia Myotonica Protein Kinase (DMPK) gene while DM2 results from a CCUG repeat expansion in an intron of the Zinc Finger Protein 9 (ZNF9) gene. Pathogenesis in both cases is caused principally by accumulation of toxic RNA species containing the expanded repeat. The mutant RNA sequesters Muscleblind, an RNA-binding protein important for processing of clinically relevant mRNAs. In addition, the mutant RNA induces aberrant expression of another RNA-binding protein, CUGBP1 through an unknown mechanism. This in turn impacts processing and decay of additional mRNAs. We will first examine how the toxic RNA species is metabolized by the cell with a view to eventually enhancing its removal. We will then move on to investigate the effects of CUGBP1 on two sets of mRNAs encoding proteins involved in myogenesis and in protein secretion. Finally, we will generate novel cell culture models from patient muscle cells and utilize them to discover changes in mRNA stability that occur in DM1. Overall, we hope to elucidate the fundamental molecular changes that occur in myotonic dystrophy and identify novel targets for future therapeutics. PUBLIC HEALTH RELEVANCE: Myotonic dystrophy is a debilitating inherited disease primarily affecting skeletal muscle. The mutant gene produces a toxic RNA that impacts expression of other genes. Our research will determine the molecular mechanisms behind the toxicity of the mutant RNA and characterize the effects on expression of other clinically relevant genes. We hope to identify new avenues for therapeutic intervention.