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

项目2：FSHD中的重复去阻遏和RNA介导的毒性 摘要 FSHD由正常转录沉默的D4 Z4基因座的体细胞去阻遏引起， 疾病基因DUX 4的后续表达。该项目的广泛和长期目标是 鉴定D4 Z4去阻遏下游的分子途径，其可能靶向减缓疾病 改善或改善肌肉功能。该项目的主要假设是， 其它异常RNA有助于DUX 4细胞毒性并改变FSHD的严重性。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起源， 确定这些有毒RNA是否修饰FSHD转录。这将通过以下方式实现：目标1， 确定DUX 4介导的RNA监视抑制的分子机制;目的2， 确定DUX 4诱导的活跃翻译的RNA的子集，并测试这些RNA是否 异常RNA在DUX 4表达细胞中产生异常蛋白质或新肽; Aim 3， 确定遗传变异是否影响重复RNA表达，以改变FSHD突变率。 总之，这些目标将确定机制，促进稳定表达的重复和其他 异常RNA，从而导致DUX 4毒性并作为FSHD的新型修饰剂 外显率这些研究的意义在于，它们将确定下游的分子通路 D4 Z4去阻遏介导DUX 4毒性并导致FSHD的可变表达率。的 健康相关性是RNA介导的毒性机制可能提供机会， D4 Z4去阻遏下游的治疗干预。

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.