DUX4 and the P53 pathway in FSHD pathogenesis

描述（由申请人提供）：二十年前，面肩肱型肌营养不良症（FSHD）与染色体 4q35 上 D4Z4 重复次数的收缩有关。这些收缩不会完全消除或突变任何基因，自从发现这种遗传异常以来，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。最近的工作为致病机制逐渐成为人们关注的焦点提供了希望。包括我们在内的几项已发表的研究支持 FSHD 发病机制模型，该模型涉及 D4Z4 定位的 DUX4 基因的过度表达，该基因编码转录因子。这些发现加深了 FSHD 领域的关注，现在了解 DUX4 生物学及其可能有助于 FSHD 发展的机制的势头越来越大。在我们的初步工作中，我们证明了 DUX4 在动物肌肉中的肌病潜力，并表明 DUX4 毒性取决于其结合 DNA 和激活 p53 依赖性细胞死亡途径的能力。在本提案中，我们将测试几个假设，以解决 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 背后的致病性损伤，这对于治疗开发至关重要。

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.