FSHD iPS Cells: Genetic Correction and Myogenesis

描述（由申请人提供）：FSHD影响美国超过25，000人。按发病率计算，它是第三常见的肌营养不良症，但按患病率计算，它可能是最常见的（Orphanet，2008）。引起这种疾病的DNA损伤是在4q端粒附近的一系列3.3kb重复序列（D4Z4重复序列）内的收缩。这种收缩改变了4q35.2的染色质构型，导致每个D4Z4重复序列中编码的基因DUX4的错误表达。DUX4在各种细胞模型系统中过表达时具有细胞毒性。然而，病理机制仍然回避该领域。我们没有一个清晰的图片，肌肉中的哪些细胞类型表达DUX4，也没有表达在发育过程中启动，也没有转录活性D4Z4阵列如何影响发育，肌肉生理学或再生。此外，对如此大的缺失进行遗传校正是不可能的。 琐碎的。为了解决这些问题，我们从FSHD患者和对照中获得了iPS细胞系。我们提出了一系列的研究，针对创新的方法，遗传校正这个位点（目的1），并制定一个更好地了解肌生成和FSHD的病理机制（目的2）。

DESCRIPTION (provided by applicant): 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 causing 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. DUX4 is cytotoxic when overexpressed in various cellular model systems. However a pathological mechanism still eludes the field. We do not have a clear picture of which cell types in muscle express DUX4, nor when expression is initiated during development, nor how a transcriptionally active D4Z4 array affects development, muscle physiology, or regeneration. In addition, genetic correction of such a large deletion is not trivial. To address these questions, we have derived iPS cell lines from FSHD patients and controls. We propose a series of studies directed towards innovative approaches to genetic correction of this locus (Aim 1) and to developing a better understanding of myogenesis and the mechanism underlying the pathology in FSHD (Aim 2).