Muscle Stem Cell Lineage

肌肉干细胞谱系

• 批准号: 8894836
• 负责人: CHEN-MING FAN
• 金额: $ 36.3万
• 依托单位: CARNEGIE INSTITUTION OF WASHINGTON, D.C.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8894836
• 关键词: Affect; Age; Alternative Splicing; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antisense Oligonucleotides; Basic Science; Biological Phenomena; Cell Lineage; Characteristics; Chronic; Clinical; Clinical Trials; Collaborations; Cytoskeleton; Data; Disease; Duchenne muscular dystrophy; Dystrophin; Endogenous Factors; Epitopes; Event; Exons; Extracellular Matrix; Fiber; Funding; Future; Genes; Hereditary Disease; Human; IL4 gene; In Vitro; Inflammation; Injection of therapeutic agent; Interleukin-13; Interleukin-4; Intramuscular Injections; Janus kinase 1; Link; Longevity; Mechanics; Methods; Modeling; Molecular; Movement; Muscle; Muscle Fibers; Muscle satellite cell; Muscular Dystrophies; Mutate; Mutation; Myoblasts; Names; Nature; Pathology; Patients; Pattern; Peptides; Process; Production; Proteins; RNA Splicing; Reading Frames; Research; Signal Transduction; Site; Skeletal Muscle; Testing; Therapeutic; Transcript; Translating; base; boys; design; epigenetic memory; exon skipping; improved; in vivo; mRNA Precursor; mdx mouse; mouse model; muscle degeneration; muscle regeneration; muscular system; novel; progenitor; programs; public health relevance; receptor; tibialis anterior muscle; transcription factor

 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.

 描述（由申请人提供）：人类的多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的缺失的患者会出现最严重的肌营养不良症，即杜兴氏肌营养不良症 (DMD)。 DMD 是一种 X 连锁隐性遗传疾病，约 3,500 名男孩中就有 1 人受到影响。在骨骼肌中，主要的 DMD 转录本包含 79 个外显子，并产生约 427 KD 的蛋白质，称为肌营养不良蛋白。肌营养不良蛋白在细胞骨架和细胞外基质之间提供了重要的联系，以维持肌肉的完整性。由于内部截短的肌营养不良蛋白具有部分功能，因此反义寡核苷酸指导的突变外显子跳跃以恢复 DMD 阅读框正在临床试验中，以改善该疾病。一种长期存在的 DMD 动物模型是 mdx 小鼠，它在同源 Dmd 基因的外显子 23 上携带无义突变。 DMD 患者和 mdx 小鼠的一个显着特征是与持续肌肉退化相关的慢性炎症。 IL4 和 IL13 是抗炎肽因子，也能促进肌肉再生。在之前/当前的资助期间，我们发现IL4或IL13可以诱导肌纤维表达截短的Dmd蛋白，类似于反义寡核苷酸引导的外显子跳跃所发现的蛋白。我们提出了三个目标来研究 IL4/13 诱导 Dmd 表达的机制： 目标 1：进一步表征 IL4 和 IL13 对 mdx 模型的影响。目标 2：检查 IL4/IL13 诱导的回复纤维的特征。目标 3：确定 IL4/IL13 诱导 Dmd 逆转的细胞机制。目标 4：探索 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，但我们的重点是揭示一种新的生物现象背后的机制。从本研究中获得的信息对于将本研究转化为临床应用至关重要。