Copolymer-Based Sarcolemma Stabilization for Protecting Dystrophic Skeletal Muscles in Vivo

摘要 杜氏肌营养不良症（DMD）是一种毁灭性的和普遍致命的X-连锁隐性遗传疾病， 进行性横纹肌退化DMD男孩在生命早期有严重的骨骼肌萎缩， 通常在10-12岁时坐轮椅。DMD在青少年后期至20多岁之间是致命的， 和呼吸肌衰竭这些严峻的现实强调了发现和 实施可能影响DMD疾病进展和结局的新方法和疗法。 这个建议对NIH的意义是巨大的。DMD没有治愈方法，或任何有效的临床治疗方法。 治疗可以阻止或逆转疾病。该应用程序具有突出的健康意义， 通过专注于一流的合成膜稳定剂，直接针对主要生理 DMD的缺陷：严重的肌膜不稳定。膜稳定剂可显著保护 然而，到目前为止，营养不良的心肌，营养不良的骨骼肌没有得到明显的保护， 缓和了DMD领域对这类治疗的热情。据我们所知，我们第一次发现 药效学优化的膜稳定剂在营养不良肢体中具有显著的保护作用 体内骨骼肌。这一潜在的治疗突破对NIH作为一个新的 可行的方法来治疗营养不良的横纹肌。指导这一提议的首要假设是， 对合成嵌段共聚物的机械引导结构-功能分析将阐明新的基本原理 深入了解膜稳定性如何保护肌肉的细胞基础。这些机械引导的 研究具有巨大的潜在影响，因为它们为寻求有效的最终目标提供了必要的基础。 长期保护体内营养不良的横纹肌。

Abstract Duchenne muscular dystrophy (DMD) is a devastating and universally fatal X-linked recessive disease of progressive striated muscle deterioration. DMD boys have severe skeletal muscle wasting early in life and they are typically wheelchair bound by age 10-12. DMD is fatal by the late teens to mid-twenties due to cardiac muscle and respiratory muscle failure. These grim realities underscore the tremendous urgency to discover and implement new approaches and therapies that could impact disease progression and outcomes in DMD. Significance of this proposal to the NIH is tremendous. There is no cure for DMD, or any effective clinical treatment that can halt or reverse the disease. This application derives outstanding health significance and impact by focusing on first-in-class synthetic membrane stabilizers that directly target the primary physiological defect in DMD: severe muscle membrane instability. Membrane stabilizers confer marked protection to dystrophic cardiac muscle, however, until now, dystrophic skeletal muscles were not significantly protected, tempering enthusiasm in the DMD field for this class of therapy. Now, for the first time to our knowledge, we find that pharmacodynamically optimized membrane stabilizers have a dramatic protective effect in dystrophic limb skeletal muscles in vivo. This potential therapeutic breakthrough has great significance to the NIH as a new viable approach to treat dystrophic striated muscles. The overarching hypothesis directing this proposal is that mechanistically guided structure-function analysis of synthetic block copolymers will illuminate new fundamental insights into the cellular basis of how membrane stabilization protect muscles. These mechanistically guided studies have great potential impact as they serve the required foundation in seeking the ultimate goal of effective long-term protection to dystrophic striated muscles in vivo.