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（由适用提供）：人类的多种突变引起肌肉营养不良。在这些遗传疾病中，在DMD基因中携带非义突变的患者或破坏阅读框的缺失呈现出最严重的肌肉营养不良形式，即Duchene的肌肉营养不良（DMD）。 DMD是一种X连锁的隐性疾病，影响了3500名男孩中约1个。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。肌肉蛋白肌骨骼和细胞外基质之间提供了一个必不可少的联系，以维持肌肉完整性。因为内部截短的肌营养不良蛋白是部分功能性的，因此在临床试验中，突变外显子的反义寡核苷酸指导的跳过以恢复DMD阅读框，可以改善该疾病。 DMD的长期动物模型是MDX小鼠，该模型在同源DMD基因的外显子23中带有非义突变。 DMD患者和MDX小鼠的突出特征是与连续肌肉变性有关的慢性炎症性。 IL4和IL13是抗炎肽因子，也促进肌肉再生。在上一个/当前的资金期间，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指导的外显子跳过的肌肉。我们提出了三个旨在研究IL4/13诱导DMD表达基础的机制：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诱导的恢复纤维的特性。 AIM 3：定义IL4/IL13诱导的DMD反向的细胞机制。 AIM 4：探索IL4/IL13诱导的DMD恢复基础的分子机制。尽管我们提出的研究对DMD患者具有令人兴奋的临床意义，但我们着重于揭示新型生物学现象的基础机制。从这项研究中获得的信息对于将这项研究转化为临床使用至关重要。