Probing the activity of DUX4 in FSHD

摘要 FSHD在美国影响着超过25,000人。它是第三种最常见的肌营养不良症， 发病率，但可能是最常见的流行率(孤儿网，2008年)。与此相关的DNA损伤 疾病是在4q的端粒附近的一系列3.3kb重复序列(D4Z4重复)内的收缩。这个 收缩改变了4q35.2的染色质配置，导致编码基因的错误表达 在每个D4Z4重复序列中，DUX4。我们已经证明了当DUX4在细胞中高水平表达时具有细胞毒性 多种细胞模型系统，并在低水平表达时干扰肌源性基因的表达 卫星细胞和成肌细胞，并建立了一个动物模型，概括了 人类疾病：在几乎检测不到DUX4蛋白的情况下肌肉退化。然而， 从机制上讲，DUX4仍然没有被很好地理解，我们也不清楚肌肉中的哪种细胞类型 表达DUX4以及这种表达的后果是什么，这是一种解释肌肉的病理机制 损失仍然是难以捉摸的领域，我们也缺乏治疗FSHD的特效疗法。这项研究建议在 本申请通过以下方式解决这些问题：(1)探索DUX4介导的转录机制， 包括研究该转录的抑制剂(2)研究抑制p300途径的效果 从遗传学和药理学的角度研究DUX4在小鼠模型中的表达。 FSHD患者。这项研究将解决FSHD中的关键悬而未决的问题，将提出一种机械化的 在分子、细胞和组织水平上了解DUX4在FSHD中的作用，并可能导致新的治疗方法 方向。

Abstract FSHD affects over 25,000 individuals in the United States. It is the third most common muscular dystrophy by incidence but may be the most common by prevalence (Orphanet, 2008). The DNA lesion associated with this disease is a contraction within a series of 3.3 kb repeats (D4Z4 repeats) near the telomere of 4q. The contraction modifies the chromatin configuration of 4q35.2 which results in misexpression of a gene encoded within each D4Z4 repeat, DUX4. We have shown that DUX4 is cytotoxic when expressed at high levels in various cellular model systems, and interferes with myogenic gene expression when expressed at low levels in satellite cells and myoblasts, and have generated an animal model that recapitulates one key aspect of the human disease: muscle deterioration in the presence of barely-detectable DUX4 protein. However mechanistically, DUX4 is still not well understood, we do not have a clear picture of which cell types in muscle express DUX4 and what the consequence of that expression is, a pathological mechanism explaining muscle loss still eludes the field, and we suffer from a dearth of specific therapies for FSHD. The research proposed in this application addresses these issues by (1) probing the mechanism of DUX4-mediated transcription, including studying inhibitors of that transcription (2) investigating the effects of inhibiting the p300 pathway genetically and pharmacologically in the mouse model, and (3) studying DUX4 expression in primary cells from FSHD patients. This research will address key outstanding questions in FSHD, will advance a mechanistic understanding of DUX4 in FSHD at the molecular, cellular, and tissue levels, and may lead to new therapeutic directions.