IGF-I isoforms: a source for new agents to counter muscular dystrophy pathology

IGF-I 亚型：对抗肌营养不良症病理学的新药物来源

基本信息

批准号：
7575778
负责人：
Elisabeth R Barton
金额：
$ 17.33万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-26 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7575778
关键词：
Alternative Splicing Animal Model Animals Attention Biological Availability C-terminal Carcinogens Clinical Trials Complex Development Disease Duchenne muscular dystrophy Dystrophin Evaluation Extracellular Matrix Genes Glycoproteins Goals Grant Growth Health Heart Hereditary Disease In Vitro Insulin-Like Growth Factor I Maintenance Mus Muscle Muscle Weakness Muscle function Muscular Dystrophies Mutation Myopathy Myotonic Dystrophy New Agents Nuclear Envelope Outcome Measure Pathology Patients Pattern Peptides Physiological Protein Isoforms Proteins Quality of life RNA Splicing Recombinant Insulin-Like Growth Factor Research Risk Severities Skeletal Muscle Source Spliced Genes Symptoms Therapeutic Time Tissues Transgenic Mice Transgenic Organisms Tumorigenicity base combat effective therapy experience improved in vivo muscle form muscle regeneration muscle strength novel novel strategies peptide E (adrenal medulla)regenerative repaired research study response therapy design tumorigenic wasting

项目摘要

DESCRIPTION (provided by applicant): The common thread for all muscular dystrophies is progressive muscle weakness and degeneration. Regardless of the underlying cause, all people who suffer from this group of diseases can benefit from agents which improve muscle strength and enhance regenerative capacity. The goals of this grant are to identify the best IGF-I isoform to counter weakness and degeneration common to all muscular dystrophies and to develop new strength-promoting therapies based on the endogenously expressed E peptides. To achieve these goals, directed expression of three different IGF-I isoforms will be utilized in two different animals models for muscular dystrophy, and the effects on muscle function, mass, and stabilization will be examined as outcome measures for efficacy. Second, to exclude potentially harmful agents, the effects of IGF-I on the hearts will be examined, and tumorigenicity will be evaluated in the Tg-rasH2 mouse. Next, in vitro studies will be utilized to carefully examine the therapeutic potential of the E-peptide extensions produced by the IGF-I isoforms. The dual approach of in vivo and in vitro experiments will accelerate the identification of novel peptides and help to optimize the IGF-I isoform to counter the common pathologies associated with muscular dystrophy. Relevance: The muscular dystrophies have no established cure, and although the diseases has many different causes, all patients suffer from muscle weakness and fragility. Therefore, there is a significant need to maintain or at least slow the progression of muscle wasting to buy time for an effective therapy to be developed. Growth promoting strategies are one way to combat this loss of muscle strength, and can provide benefit to all people suffering from these muscle diseases.

描述（由申请人提供）：所有肌营养不良症的共同点是进行性肌肉无力和退化。无论根本原因如何，所有患有此类疾病的人都可以从提高肌肉力量和增强再生能力的药物中受益。这笔资助的目标是确定最佳的 IGF-I 同工型，以对抗所有肌营养不良症常见的无力和退化，并开发基于内源表达的 E 肽的新的增强力量的疗法。为了实现这些目标，将在两种不同的肌营养不良动物模型中利用三种不同 IGF-I 同种型的定向表达，并将检查对肌肉功能、质量和稳定性的影响作为疗效的结果测量。其次，为了排除潜在的有害物质，将检查 IGF-I 对心脏的影响，并评估 Tg-rasH2 小鼠的致瘤性。接下来，将利用体外研究来仔细检查 IGF-I 亚型产生的 E 肽延伸的治疗潜力。体内和体外实验的双重方法将加速新型肽的鉴定，并有助于优化 IGF-I 同工型，以对抗与肌营养不良症相关的常见病理。相关性：肌营养不良症尚无确定的治疗方法，尽管这些疾病有许多不同的原因，但所有患者都患有肌肉无力和脆弱的症状。因此，非常需要维持或至少减缓肌肉萎缩的进展，为开发有效的疗法赢得时间。生长促进策略是对抗肌肉力量损失的一种方法，并且可以为所有患有这些肌肉疾病的人带来好处。