Probing the activity of DUX4 in FSHD

摘要 FSHD影响美国超过25，000人。这是第三个最常见的肌肉萎缩症， 发病率，但可能是最常见的患病率（孤儿院，2008年）。与此相关的DNA损伤 疾病是在4q端粒附近的一系列3.3kb重复（D4Z4重复）内的收缩。的 收缩改变了4q35.2的染色质构型，这导致编码4q35.2的基因的错误表达。 在每个D4Z4重复中，DUX4。我们已经证明，DUX4在大肠杆菌中高水平表达时具有细胞毒性。 在各种细胞模型系统中，当肌源性基因在低水平表达时， 卫星细胞和成肌细胞，并产生了一个动物模型，概括了一个关键方面， 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仍然没有得到很好的理解，我们不清楚肌肉中的细胞类型 表达DUX4以及这种表达的后果是什么，这是一种解释肌肉组织的病理机制， 损失仍然回避该领域，我们遭受缺乏FSHD的特定疗法。该研究在 本申请通过（1）探测DUX4介导的转录的机制， 包括研究该转录的抑制剂（2）研究抑制p300通路的作用 在小鼠模型中进行遗传学和免疫学研究，以及（3）研究DUX4在来自 FSHD患者。这项研究将解决FSHD中关键的突出问题，将推进一个机制， 在分子、细胞和组织水平上了解FSHD中的DUX 4，并可能带来新的治疗方法 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.