Project 2: Repeat derepression and RNA-mediated toxicity in FSHD

项目2：FSHD的重复去抑制和RNA介导的毒性 摘要 FSHD是由正常转录沉默的D4Z4基因座的体细胞去抑制引起的 随后表达的疾病基因DUX4。这个项目的广泛和长期目标是 确定D4Z4去阻抑基因下游可能针对延缓疾病的分子途径 促进或改善肌肉功能。这个项目的主要假设是重复性和 其他异常的RNA有助于DUX4的细胞毒性并改变FSHD的严重程度。的具体目标 该项目旨在确定异常RNA产生和细胞毒性的机制根源，以及 确定这些有毒的RNA是否会改变FSHD的外透性。这将通过以下方式实现：目标1， 确定DUX4介导的抑制RNA监视的分子机制；目的2， 确定DUX4诱导的被主动翻译的RNA的子集，并测试这些 异常RNA在表达DUX4的细胞中产生异常蛋白质或新的多肽；目的3， 确定遗传变异是否影响重复的RNA表达以改变FSHD的外显率。 总之，这些目标将确定促进重复和其他基因稳定表达的机制 异常RNA，从而导致DUX4毒性并作为FSHD的新修饰物 洞察力。这些研究的意义在于它们将确定下游的分子途径。 D4Z4去阻滞性，介导DUX4毒性，并有助于FSHD的可变外显性。这个 与健康相关的是，RNA介导的毒性机制可能为 D4Z4去阻抑下游的治疗干预。

PROJECT 2: Repeat derepression and RNA-mediated toxicity in FSHD Abstract FSHD is caused by somatic derepression of the normally transcriptionally silent D4Z4 locus and subsequent expression of the disease gene DUX4. The broad and long-term goal of this project is to identify molecular pathways downstream of D4Z4 derepression that may be targeted to slow disease progression or improve muscle function. The major hypothesis of this project is that repetitive and other aberrant RNAs contribute to DUX4 cytotoxicity and modify FSHD severity. The specific goal of the project is to identify the mechanistic origins of aberrant RNA production and cytotoxicity, and determine whether these toxic RNAs modify FSHD penetrance. This will be accomplished by: Aim 1, Determine the molecular mechanisms of DUX4-mediated inhibition of RNA surveillance; Aim 2, Determine the subset of DUX4-induced RNAs that are actively translated, and test whether these aberrant RNAs produce abnormal proteins or novel peptides in DUX4-expressing cells; Aim 3, Determine whether genetic variation influences repetitive RNA expression to modify FSHD penetrance. Together, these aims will identify mechanisms that promote stable expression of repetitive and other aberrant RNAs, thereby contributing to DUX4 toxicity and acting as a novel modifier of FSHD penetrance. The significance of these studies is that they will identify molecular pathways downstream of D4Z4 derepression that mediate DUX4 toxicity and contribute to variable penetrance of FSHD. The health relatedness is that RNA-mediated mechanisms of toxicity may provide opportunities for therapeutic intervention downstream of D4Z4 derepression.