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

基于共聚物的肌膜稳定保护体内营养不良的骨骼肌

基本信息

批准号：
9923445
负责人：
JOSEPH Mark METZGER
金额：
$ 46.63万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9923445
关键词：
Acute Age Cardiac Chemical Engineering Chemicals Clinical Treatment Clinical Trials DNA Sequence Alteration Data Defect Disease Disease Outcome Disease Progression Dissection Duchenne muscular dystrophy Exons Failure Foundations Genes Genetic Goals Health Immunosuppression Investigation Lesion Life Limb structure Link Membrane Modeling Molecular Muscle Muscular Atrophy Muscular Dystrophies Mutation Myocardium Nonsense Mutation Oxidative Stress Pathway interactions Patients Pharmacodynamics Physiological Progressive Disease Respiratory Muscles Sarcolemma Skeletal Muscle Striated Muscles Structure Teenagers Testing Therapeutic Time Treatment Efficacy United States National Institutes of Health Wheelchairs base boys clinical application copolymer design effective therapy in vivo insight mitochondrial dysfunction novel novel strategies novel therapeutics preclinical study preservation protective effect public health relevance respiratory skeletal muscle wasting

Acute Age Cardiac Chemical Engineering Chemicals Clinical Treatment Clinical Trials DNA Sequence Alteration Data Defect Disease Disease Outcome Disease Progression Dissection Duchenne muscular dystrophy Exons Failure Foundations Genes Genetic Goals Health Immunosuppression Investigation Lesion Life Limb structure Link Membrane Modeling Molecular Muscle Muscular Atrophy Muscular Dystrophies Mutation Myocardium Nonsense Mutation Oxidative Stress Pathway interactions Patients Pharmacodynamics Physiological Progressive Disease Respiratory Muscles Sarcolemma Skeletal Muscle Striated Muscles Structure Teenagers Testing Therapeutic Time Treatment Efficacy United States National Institutes of Health Wheelchairs base boys clinical application copolymer design effective therapy in vivo insight mitochondrial dysfunction novel novel strategies novel therapeutics preclinical study preservation protective effect public health relevance respiratory skeletal muscle wasting

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项目摘要

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.

抽象的 Duchenne肌肉营养不良（DMD）是一种毁灭性且普遍致命的X连锁隐性疾病进行性横纹肌肉恶化。 DMD男孩在生命的早期就有严重的骨骼肌浪费通常是由10-12岁的轮椅约束。十几岁的DMD由于心肌而致命到二十多岁和呼吸肌肉衰竭。这些严峻的现实强调了发现和实施可能影响DMD疾病进展和结果的新方法和疗法。该提议对NIH的意义是巨大的。无法治愈DMD或任何有效的临床可以停止或扭转疾病的治疗。该应用程序具有出色的健康意义，并且通过关注直接针对主要生理的一流合成膜稳定剂来影响 DMD缺陷：严重的肌肉膜不稳定性。膜稳定器授予标志性保护然而，到目前为止，营养不良的心肌肌肉尚未受到显着保护，骨骼肌肉尚未受到显着保护此类治疗的DMD领域中的回火热情。现在，据我们所知，我们第一次发现该药物动力学优化的膜稳定剂对营养不良的肢体具有巨大的保护作用体内骨骼肌。这种潜在的治疗突破对NIH具有重要意义可行的治疗营养不良的肌肉的方法。指导这一建议的总体假设是合成块共聚物的机械指导结构功能分析将阐明新的基本深入了解膜稳定如何保护肌肉的细胞基础。这些机械指导研究在寻求有效的最终目标时为基础提供了巨大的潜在影响长期保护体内营养不良的肌肉肌肉。