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

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无力和变性。无论潜在的原因是什么，所有患有这组疾病的人都可以从改善肌肉力量和增强再生能力的药物中受益。这项资助的目标是确定最好的IGF-I亚型，以对抗所有肌营养不良症常见的虚弱和变性，并开发基于内源性表达的E肽的新的力量促进疗法。为了实现这些目标，将在两种不同的肌营养不良症动物模型中使用三种不同IGF-I亚型的定向表达，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指标。其次，为了排除潜在的有害物质，将检查IGF-I对心脏的影响，并在Tg-rasH 2小鼠中评价致瘤性。接下来，将利用体外研究仔细检查IGF-I同种型产生的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肽的鉴定，并有助于优化IGF-I亚型，以对抗与肌营养不良症相关的常见病理。 相关性：肌营养不良症没有既定的治疗方法，虽然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性。因此，非常需要维持或至少减缓肌肉萎缩的进展，以便为开发有效的治疗赢得时间。生长促进策略是对抗这种肌肉力量损失的一种方法，可以为所有患有这些肌肉疾病的人提供益处。

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.