Muscle Stem Cell Lineage

肌肉干细胞谱系

基本信息

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
项目类别：
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

项目摘要

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营养不良症，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。肌营养不良症 (DMD) 是一种 X 连锁隐性遗传疾病，约 3,500 名男孩中就有 1 人患有骨骼肌疾病，这是原发性 DMD。转录物包含 79 个外显子，并产生约 427 KD 的蛋白质，称为肌营养不良蛋白，在细胞骨架和细胞外基质之间提供重要的连接，以维持肌肉完整性，因为内部截短的肌营养不良蛋白具有部分功能，因此反义寡核苷酸引导突变的外显子跳跃以恢复。 DMD 阅读框正在进行临床试验，以改善这种疾病。mdx 小鼠是一种长期存在的 DMD 动物模型，它携带有 DMD 基因。同源 Dmd 基因的外显子 23 发生无义突变，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。目前的资助期间，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。我们提出了三种。目的是研究 IL4/13 诱导的 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。 IL4/IL13 诱导 Dmd 逆转的细胞机制目标 4：探索 IL4/IL13 诱导的分子机制。 DMD 逆转：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学现象背后的机制，对于将这项研究转化为临床应用至关重要。