Muscle Stem Cell Lineage

 描述(申请人提供)：人类的各种突变会导致肌肉营养不良。在这些遗传性疾病中，携带DMD基因无义突变或破坏阅读框架的缺失的患者呈现最严重的肌肉营养不良，即Duchene肌营养不良(DMD)。DMD是一种X连锁的隐性疾病，每3,500名男孩中就有1人受到影响。在骨骼肌中，初级DMD转录本包含79个外显子，产生一种~427kD的蛋白质，称为dystrophin。肌营养不良蛋白在细胞骨架和细胞外基质之间起着至关重要的作用，以维持肌肉的完整性。由于内部截短的Dystrophin是部分功能的，反义寡核苷酸指导跳过突变的外显子以恢复DMD读框正在进行临床试验，以改善疾病。长期存在的DMD动物模型是MDX小鼠，它携带同源DMD基因外显子23的无义突变。DMD患者和MDX小鼠的一个显著特征是与持续性肌肉退化相关的慢性炎症。白介素4和白介素13是抗炎肽因子，也能促进肌肉再生。在之前/现在的资助期，我们发现IL4或IL13可以诱导肌肉纤维表达截短的DMD蛋白，类似于反义寡核苷酸导向的外显子跳跃。我们提出了三个目的来研究IL4/13诱导DMD表达的机制：目的1：进一步研究IL4和IL13对MDX模型的影响。目的：检测IL4/IL13诱导的可逆性纤维的特性。目的3：明确IL4/IL13诱导DMD逆转的细胞机制。目的4：探讨IL4/IL13诱导DMD逆转的分子机制。虽然我们提出的研究对DMD患者具有令人兴奋的临床意义，但我们专注于揭示一种新的生物现象背后的机制。从这项研究中获得的信息对于将这项研究转化为临床应用是必不可少的。

 DESCRIPTION (provided by applicant): A variety of mutations in humans cause muscular dystrophies. Among these genetic disorders, patients carrying non-sense mutations in the DMD gene or deletions that disrupt the reading frame present the most severe form of muscular dystrophies, i.e. Duchene's Muscular Dystrophy (DMD). DMD is an X-linked recessive disorder that affects ~ 1 in 3,500 boys. In the skeletal muscle, the primary DMD transcripts contain 79 exons and produce a protein of ~427 KD named Dystrophin. Dystrophin provides an essential linkage between cytoskeleton and extracellular matrix to maintain muscle integrity. Because internally truncated Dystrophin are partially functional, anti-sense oligonucleotide-directed skipping of mutated exon to restore DMD reading frame is in clinical trial to ameliorate the disease. A long-standing animal model for DMD is the mdx mouse, which carries a non-sense mutation in exon 23 of the homologous Dmd gene. A prominent feature in DMD patients and mdx mice are chronic inflammation associated with continuous muscle degeneration. IL4 and IL13 are anti-inflammatory peptide factors that also promote muscle regeneration. During the previous/current funding period, we found that IL4 or IL13 can induce muscle fibers to express truncated Dmd proteins, similar to those found by anti-sense oligonucleotide-directed exon skipping. We propose three aims to investigate the mechanisms which underlie IL4/13-inducible Dmd expression: Aim 1: Further characterizing the effects of IL4 and IL13 on mdx models. Aim 2: Examining the characteristics of IL4/ IL13-induced revertant fibers. Aim 3: Defining the cellular mechanism underlying IL4/IL13-induced Dmd reversion. Aim 4: Exploring the molecular mechanism underlying IL4/IL13-induced Dmd reversion. While our proposed research has exciting clinical implications to DMD patients, we focus on uncovering the mechanism underlying a novel biological phenomenon. Information gained from this study is essential for translating this study to clinical use.