Modulation of muscle regeneration by growth factors

生长因子调节肌肉再生

• 批准号: 8122854
• 负责人: Elisabeth R Barton
• 金额: $ 6.5万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8122854
• 关键词: Acute; Adolescent; Animal Model; Blood Circulation; Canis familiaris; Clinic; Clinical Trials; Complement; Complex; Development; Duchenne muscular dystrophy; Elderly; Evaluation; Gene Delivery; Gene Expression; Genetic; Goals; Growth; Growth Factor; Hepatocyte; Hereditary Disease; Human; Injury; Insulin-Like Growth Factor I; Lead; Messenger RNA; Mitotic; Muscle; Muscle Fibers; Muscle rehabilitation; Muscular Dystrophies; Musculoskeletal; Myoblasts; Myopathy; Myotonic Dystrophy; Natural regeneration; New Agents; New Jersey; Nuclear; Patients; Peptides; Phase; Phase I Clinical Trials; Phase I/II Trial; Population; Process; Production; Property; Protein Biosynthesis; Proteins; Recombinant IGF-I; Regenerative Medicine; Regulation; Research; Research Personnel; Resolution; Risk; Signal Transduction; Skeletal Muscle; Skin Tissue; Source; Specificity; Stem cells; Symptoms; Technology; Therapeutic; Tissue Engineering; Tissues; Toxic effect; Toxicology; Transgenes; Translational Research; Translations; Untranslated Regions; Up-Regulation; Viral; Viral Genes; Work; adeno-associated viral vector; age related; boys; collagenase 3; interest; mdx mouse; muscle regeneration; pre-clinical; prevent; promoter; repaired; sarcopenia; satellite cell; skeletal muscle growth; small molecule; therapeutic target

DESCRIPTION (provided by applicant): Enhancement of skeletal muscle growth and repair is a central therapeutic target for the muscular dystrophies, sarcopenia, and muscle rehabilitation after disuse or acute injury. Insulin-like growth factor I (IGF-I) has long been recognized as one of the critical factors for promoting muscle growth and enhancing muscle regeneration through its regulation of protein synthesis and of satellite cell actions. Because muscle fibers are post-mitotic, repair must rely on satellite cells, a stem cell-like population residing close to muscle fibers as a source for replenishing nuclear content of the muscle. Satellite cells are normally quiescent unless triggered by signals such as IGF-I that are increased during muscle growth or after damage. In addition to IGF-I, a newly identified partner in the resolution of muscle damage is matrix-metalloproteinase 13 (MMP-13). We have found that increased IGF-I production by skeletal muscle also drives MMP-13 expression, and so these proteins may complement each other in the repair process. The current status of IGF-I therapeutics is founded on systemic delivery of recombinant IGF-I. However, because IGF-I is a potent growth factor in many tissues of the body and poses a potential carcinogenic risk, investigators have introduced IGF-I in limiting amounts. Thus, clinical trials have produced mixed results because the ability for IGF-I to provide any benefit to skeletal muscle is constrained by both the low level of protein administered, as well as the limited distribution of IGF-I to the muscle by the circulation. In our earlier work (Barton-Davis, et al 1998; Barton et al, 2002; Barton, 2006), this was circumvented by gene delivery allowing expression of IGF-I under a muscle-specific promoter. We now seek to define in a large animal model (dog), the optimal IGF-I related therapeutic for delivery in a viral (AAV) vector). We also seek to recapitulate this specificity viral gene expression with a small molecule therapeutic. Differential screens were set up to find compounds that can modulate IGF-I levels in skeletal muscle cells, but not in hepatocytes. Such molecules have been identified by working closely with a small New Jersey biotech company (PTC Therapeutics) that has developed proprietary technology to screen for small molecules that can selectively modulate translation of target mRNA (screens involve targeting the 5' and 3' UTRs). PUBLIC HEALTH RELEVANCE: Skeletal muscle repair occurs after acute injury and is an ongoing symptom associated with genetic muscle disease, specifically in the muscular dystrophies. Therefore, the therapies that enhance muscle regeneration can benefit patients suffering from genetic disease, those recovering from muscle injury, and the elderly. Development of new agents that can enhance muscle regeneration, and evaluation of these agents in animal models is a critical step for translation to the clinic.

描述（由申请人提供）：骨骼肌生长和修复的增强是肌肉营养不良，肌肉减少症和废弃或急性损伤后的肌肉营养不良，肌肉减少症和肌肉康复的核心。胰岛素样生长因子I（IGF-I）长期以来一直被认为是通过调节蛋白质合成和卫星细胞作用来促进肌肉生长和增强肌肉再生的关键因素之一。由于肌肉纤维是有丝分裂后的，因此维修必须依靠卫星细胞，卫星细胞像干细胞一样，居住在肌肉纤维附近，作为补充肌肉核含量的来源。卫星细胞通常是静止的，除非在肌肉生长或损害后增加的信号（例如IGF-I）触发。除IGF-I外，在肌肉损伤的分辨率方面，新确定的伴侣是基质 - 绝素蛋白酶13（MMP-13）。我们发现，骨骼肌增加的IGF-I产生也可以驱动MMP-13表达，因此这些蛋白质可能在修复过程中相互补充。 IGF-I治疗剂的当前状态建立在重组IGF-I的全身性递送基础上。但是，由于IGF-I是人体许多组织中的有效生长因子，并带来了潜在的致癌风险，因此研究人员在限制量中引入了IGF-I。因此，临床试验产生了混合的结果，因为IGF-I为骨骼肌提供任何益处的能力受到低水平的蛋白质的限制，以及通过循环的IGF-I对肌肉的分布有限。在我们较早的工作（Barton-Davis等，1998; Barton等，2002; Barton，2006）中，通过基因递送允许在肌肉特异性启动子下表达IGF-I的基因表达。现在，我们试图在大型动物模型（DOG）中定义，这是用于在病毒（AAV）载体中输送的最佳IGF-I相关治疗方法。我们还试图用小分子治疗概括这种特异性病毒基因表达。设置了差分筛选，以找到可以调节骨骼肌细胞中IGF-I水平的化合物，但不能在肝细胞中调节IGF-I水平。通过与一家新泽西州生物技术公司（PTC TherapeiTics）紧密合作，该分子已经确定了，该公司开发了专有技术以筛选可以选择性地调节目标mRNA翻译的小分子（筛选涉及针对5'和3'UTRS的筛选）。 公共卫生相关性：急性损伤后发生骨骼肌修复，是与遗传肌肉疾病有关的持续症状，特别是在肌肉营养不良中。因此，增强肌肉再生的疗法可以使患有遗传疾病的患者，从肌肉损伤中康复的患者和老年人受益。开发可以增强肌肉再生的新药物，并在动物模型中评估这些药物是转化为诊所的关键步骤。