DUX4 and the P53 pathway in FSHD pathogenesis

DUX4 和 P53 通路在 FSHD 发病机制中的作用

• 批准号: 8731070
• 负责人: Scott Q Harper
• 金额: $ 32.08万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8731070
• 关键词: 4q35; Address; Affect; Animals; Apoptosis; Binding Sites; Biochemical; Biology; Biopsy; CMV promoter; Cell Death; Chromosomes; D4Z4; DNA Binding; Data; Development; Disease; Elements; Event; Face; Facioscapulohumeral Muscular Dystrophy; Gene Silencing; Genes; Homologous Gene; Human; Knowledge; Lead; Length; Limb structure; Link; Measures; Modeling; Molecular; Molecular Abnormality; Mus; Muscle; Muscle Cells; Muscular Dystrophies; Mutagenesis; Mutate; Myoblasts; Myopathy; Pathogenesis; Pathology; Pathway interactions; Patients; Publishing; Relative (related person); Reporter; Research; Role; Shoulder; Skeletal Muscle; TP53 gene; Testing; Toxic effect; Transactivation; Transcript; Transgenic Organisms; Translational Research; Work; caspase-3; effective therapy; in vivo; novel; overexpression; programs; promoter; protein expression; therapeutic development; transcription factor

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.

描述（由申请人提供）：面肩肱型肌营养不良症（FSHD）与20年前染色体4q35上D4Z4重复序列数量的收缩有关。这些收缩不会完全消除或突变任何基因，并且解决它们如何导致FSHD的核心谜团一直是该领域最关键的需求，因为这种遗传异常被发现。最近的工作提供了希望，致病机制正在成为焦点。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，DUX4基因编码一种转录因子。这些发现使FSHD领域的焦点更加突出，现在越来越多的人开始了解DUX4生物学及其可能有助于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。在这个建议中，我们将测试几个假设解决机制的作用DUX4和p53通路在FSHD发病机制。这些研究将有助于确定FSHD潜在的致病性损伤，这是治疗发展的最终必要条件。