Messenger RNA stability in myotonic dystrophy

描述（由申请人提供）：强直性肌营养不良（DM）是一种遗传性疾病，主要影响骨骼肌。该疾病有两种形式：DM 1是由肌强直性肌营养不良蛋白激酶（DMPK）基因3'非翻译区的CUG重复扩增引起的，而DM 2是由锌指蛋白9（ZNF 9）基因内含子中的CCUG重复扩增引起的。在这两种情况下的发病机制主要是由含有扩增重复序列的有毒RNA物质的积累引起的。突变的RNA螯合肌盲，一种对临床相关mRNA的加工很重要的RNA结合蛋白。此外，突变RNA通过未知机制诱导另一种RNA结合蛋白CUGBP1的异常表达。这反过来又影响额外mRNA的加工和降解。 我们将首先研究有毒的RNA物质是如何被细胞代谢的，以期最终提高其去除率。然后，我们将继续研究CUGBP1对两组编码蛋白质的mRNA的影响，这些蛋白质参与肌生成和蛋白质分泌。最后，我们将从患者肌肉细胞中产生新的细胞培养模型，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，并为未来的治疗确定新的靶点。 公共卫生相关性：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。突变基因产生一种有毒的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.