Understanding and Preventing Disuse Atrophy

了解和预防废用性萎缩

• 批准号: 6686114
• 负责人: H Lee Sweeney
• 金额: $ 38.44万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6686114
• 关键词: BCL2 gene /protein; adeno associated virus group; apoptosis; atrophy; biological signal transduction; extracellular matrix; focal adhesion kinase; free radical oxygen; functional ability; gene targeting; gene therapy; genetically modified animals; insulinlike growth factor; laboratory mouse; muscle function; musculoskeletal disorder; musculoskeletal disorder therapy; recombinant virus; rehabilitation; striated muscles; suspensions

DESCRIPTION (provided by applicant): The major goals of this project are to prevent the loss of function that occurs in skeletal muscle during disuse and to increase the rate of recovery of muscle function upon reloading. Disuse atrophy is a major problem in the elderly and is one of the major hurdles that must be overcome for extended human exposure to microgravity (i.e. long periods in the space environment). We will take advantage of the ability of recombinant adeno-associated virus (AAV) to effect gene transfer in skeletal muscle. This work will lay the foundations for gene transfer therapies to reserve muscle function during periods of unloading and to increase the rate and extent of recovery upon reloading. Two major aims will be addressed: 1) preventing disuse atrophy; and 2) increasing the rate of functional recovery upon reloading. The first aim will dissect the signaling pathways that drive disuse atrophy and will address the hypothesis that both apoptotic and growth pathways are 'affected. The pivotal role of focal adhesion kinase in this process will be examined. The second aim addresses the hypothesis that following a period of disuse, the action of IGF-I will enhance the rate of recovery. Additionally, we will test the hypothesis that a large amount of the damage upon reloading is due to oxygen free radical injury. The experiments delineated under each aim will provide mechanistic insights into the multi-faceted problem of disuse atrophy. In addition, the experiments will provide the foundations for future gene transfer approaches aimed at ameliorating functional loss concomitant with disuse, for human exploration of space, and for a healthier life for the elderly on earth, we must understand and design measures to prevent disuse atrophy of skeletal muscle.

描述（由申请人提供）：该项目的主要目标是防止骨骼肌在废弃期间发生功能丧失，并提高重新加载时肌肉功能的恢复率。废用性萎缩是老年人的一个主要问题，也是人类长期暴露于微重力（即长时间处于太空环境中）必须克服的主要障碍之一。我们将利用重组腺相关病毒（AAV）的能力来影响骨骼肌中的基因转移。这项工作将为基因转移疗法奠定基础，以在卸载期间保留肌肉功能，并提高重新加载时的恢复速度和程度。将解决两个主要目标：1）防止废用性萎缩； 2) 提高重新加载时的功能恢复率。第一个目标将剖析驱动废用性萎缩的信号传导途径，并将解决细胞凋亡和生长途径都受到“影响”的假设。将检查粘着斑激酶在此过程中的关键作用。第二个目标提出这样的假设：停用一段时间后，IGF-I 的作用将提高恢复率。此外，我们将测试以下假设：重新加载时的大量损坏是由于氧自由基损伤造成的。每个目标下描述的实验将为废用性萎缩的多方面问题提供机制上的见解。此外，这些实验将为未来旨在改善废用性功能丧失的基因转移方法奠定基础，为了人类探索太空，为了地球上老年人的健康生活，我们必须了解和设计防止废用性萎缩的措施骨骼肌。