DUX4 and the P53 pathway in FSHD pathogenesis

描述（由申请人提供）：20年前，面部肩胛骨肱肌营养不良症（FSHD）与染色体4q35上D4Z4重复数的收缩有关。这些收缩不会完全去除或突变任何基因，自从这种基因异常被发现以来，解决它们如何导致FSHD的核心谜团一直是该领域最关键的需求。最近的工作给人们带来了希望，即致病机制正在成为人们关注的焦点。一些已发表的研究，包括我们的研究，支持FSHD发病模型涉及d4z4定位DUX4基因的过表达，该基因编码转录因子。这些发现加强了FSHD领域的关注，现在有越来越多的动力来了解DUX4生物学及其可能促进FSHD发展的机制。在我们最初的工作中，我们证明了DUX4在动物肌肉中的肌病潜能，并表明DUX4的毒性依赖于其结合DNA和激活p53依赖性细胞死亡途径的能力。在本研究中，我们将验证DUX4和p53通路在FSHD发病机制中的机制作用。这些研究将有助于确定FSHD的致病损伤，这最终是治疗发展所必需的。

DESCRIPTION (provided by applicant): Facioscapulohumeral muscular dystrophy (FSHD) was linked to contractions in the number of D4Z4 repeats on chromosome 4q35 two decades ago. These contractions do not completely remove or mutate any genes, and solving the central mystery of how they lead to FSHD has been the most critical need in the field since this genetic abnormality was discovered. Recent work provides hope that the pathogenic mechanisms are coming into focus. Several published studies, including ours, support an FSHD pathogenesis model involving over- expression of the D4Z4-localized DUX4 gene, which encodes a transcription factor. These findings have sharpened the focus of the FSHD field, and there is now growing momentum to understand DUX4 biology and the mechanisms by which it may contribute to FSHD development. In our initial work, we demonstrated the myopathic potential of DUX4 in animal muscle, and showed that DUX4 toxicity was dependent upon its ability to bind DNA and activate p53-dependent cell death pathways. In this proposal, we will test several hypotheses addressing the mechanistic role of DUX4 and the p53 pathway in FSHD pathogenesis. These studies will help define the pathogenic insults underlying FSHD, which is ultimately necessary for therapeutic development.