FSHD iPS Cells: Genetic Correction and Myogenesis

描述（由申请人提供）：FSHD在美国影响超过25,000人。就发病率而言，它是第三种最常见的肌肉萎缩症，但就患病率而言，它可能是最常见的（Orphanet, 2008）。导致这种疾病的DNA损伤是在4q端粒附近的一系列3.3 kb重复序列（D4Z4重复序列）内的收缩。这种收缩改变了4q35.2的染色质结构，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，其病理机制尚不明确。我们不清楚肌肉中哪些细胞类型表达DUX4，也不清楚在发育过程中何时开始表达，也不清楚转录活性D4Z4阵列如何影响发育、肌肉生理或再生。此外，基因校正如此大的缺失是不可能的

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).