FSHD iPS Cells: Genetic Correction and Myogenesis

FSHD iPS 细胞：基因校正和肌生成

• 批准号: 8556649
• 负责人: Michael Kyba
• 金额: $ 33.25万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8556649
• 关键词: Address; Affect; Alleles; Biological Models; Candidate Disease Gene; Cell Line; Cell Therapy; Cell model; Cells; Chromatin; Chromosomes; Chromosomes, Human, Pair 4; D4Z4; DNA; DNA lesion; Defect; Development; Disease; Duchenne muscular dystrophy; Engraftment; Future; Gene Conversion; Gene Targeting; Genes; Genetic; Genetic Transcription; Grant; Immunodeficient Mouse; In Vitro; Incidence; Individual; Institution; Laboratories; Lead; Loss of Heterozygosity; Methods; Molecular Profiling; Muscle; Muscle Development; Muscle Fibers; Muscular Dystrophies; Mutation; Natural regeneration; Paraxial Mesoderm; Pathology; Pathway interactions; Patients; Phenotype; Physiology; Population; Population Control; Prevalence; Research; Resistance; Resources; Series; Skin; Small RNA; Specificity; Staging; Technology; Testing; Transplantation; Undifferentiated; United States; United States National Institutes of Health; Zinc Fingers; arm; base; cell type; cytotoxic; design; dystroglycanopathy; functional improvement; improved; in vivo; induced pluripotent stem cell; injured; innovation; insight; muscle degeneration; mutant; myogenesis; nuclease; overexpression; progenitor; programs; public health relevance; research study; telomere; transcriptome sequencing; vector

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).

描述(由申请人提供)：FSHD在美国影响超过25,000人。按发病率计算，它是第三种最常见的肌营养不良症，但按患病率计算可能是最常见的(Orphanet，2008)。引起本病的DNA损伤是4Q端粒附近一系列3.3kb重复序列(D4Z4重复)内的收缩。这种收缩改变了4q35.2的染色质配置，导致每个D4Z4重复序列DUX4编码的基因错误表达。当在各种细胞模型系统中过表达时，DUX4具有细胞毒性。然而，病理机制仍不清楚。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，也不清楚转录活性的D4Z4阵列如何影响发育、肌肉生理或再生。此外，如此大的缺失的遗传校正并不是 微不足道。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。我们提出了一系列研究，旨在通过创新的方法对该基因座进行遗传纠正(目标1)，并更好地了解FSHD的肌肉发生和潜在的病理机制(目标2)。