FSHD iPS Cells: Genetic Correction and Myogenesis

FSHD iPS 细胞：基因校正和肌生成

基本信息

批准号：
9057625
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
项目类别：
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/9057625
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 cassette DNA lesion Defect Development Disease Duchenne muscular dystrophy Engraftment Facioscapulohumeral Muscular Dystrophy Future Gene Conversion Gene Targeting Genes Genetic Genetic Transcription Grant Health 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 arm base cell type cytotoxic design dystroglycanopathy functional improvement improved in vivo induced pluripotent stem cell injured innovation insight muscle degeneration mutant myogenesis overexpression progenitor programs research study telomere transcription activator-like effector nucleases transcriptome sequencing vector zinc finger nuclease

项目摘要

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 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）。导致这种疾病的 DNA 损伤是 4q 端粒附近一系列 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 的染色质构型，导致每个 D4Z4 重复序列（DUX4）内编码的基因错误表达。 DUX4 在各种细胞模型系统中过度表达时具有细胞毒性。然而，该领域仍不清楚病理机制。我们不清楚肌肉中哪些细胞类型表达 DUX4，也不清楚发育过程中何时启动表达，也不清楚转录活性 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基因校正并不可行。琐碎的。为了解决这些问题，我们从 FSHD 患者和对照中衍生出 iPS 细胞系。我们提出了一系列研究，旨在通过创新方法对该基因座进行遗传校正（目标 1），并更好地了解 FSHD 的肌发生和病理机制（目标 2）。