Messenger RNA Stability in Myotonic Dystrophy

描述(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。该病有两种形式：DM1是由Dystrophia Myotonica Protein Kinase(DMPK)基因3‘非翻译区的CUG重复扩增引起的；DM2是由锌指蛋白9(Zincinger Protein 9，ZNF9)基因内含子的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物种的积累引起的。突变的RNA隔离了Musclebindd，这是一种RNA结合蛋白，对处理临床相关的mRNAs很重要。此外，突变的RNA还通过未知的机制诱导另一种RNA结合蛋白CUGBP1的异常表达。这反过来会影响额外mRNAs的处理和衰退。我们将首先研究有毒的RNA物种是如何被细胞代谢的，以期最终提高其清除能力。然后，我们将继续研究CUGBP1对两组编码涉及肌肉发生和蛋白质分泌的蛋白质的mRNAs的影响。最后，我们将从患者肌肉细胞中产生新的细胞培养模型，并利用它们来发现在DM1中发生的mRNA稳定性的变化。总体而言，我们希望阐明强直性肌营养不良发生的基本分子变化，并为未来的治疗确定新的靶点。

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.