Walk this way: leveraging of a unique skeletal muscle that is resistant to ischemic injury

沿着这条路走：利用独特的抗缺血性损伤的骨骼肌

• 批准号: 10897684
• 负责人: ESPEN E SPANGENBURG
• 金额: $ 37.75万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-19 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10897684
• 关键词: ATP Hydrolysis; Acute; Address; Adenosine Triphosphate; Affect; Age; Annexins; Binding Proteins; Biochemical; Bioenergetics; Biological; Blood flow; Cells; Charge; Clinical; Compartment syndromes; Coronary Occlusions; Data; Development; Distal; Drops; Dyes; Ensure; Evans blue stain; Exhibits; Experimental Designs; Exposure to; Flexor; Free Energy; Generations; Genes; Genetic; Glycogen; Goals; Grant; Hemorrhage; Hindlimb; Hour; Human; Hypoxia; Ischemia; Limb structure; Longevity; Maintenance; Membrane; Metabolic; Modeling; Molecular; Muscle; Muscle function; Myoblasts; Myocardium; Myopathy; Necrosis; Oxygen; Pathology; Patients; Peripheral; Peripheral arterial disease; Phenotype; Physiological; Play; Pre-Clinical Model; Predisposition; Production; Proteins; Proteomics; Reaction; Regulation; Resistance; Role; SLC2A1 gene; Sarcolemma; Site; Skeletal Muscle; Soleus Muscle; System; Therapeutic; Tissue Survival; Tissues; Walking; artery occlusion; critical limb Ischemia; design; efficacy evaluation; excitotoxicity; experience; experimental study; extensor digitorum; femoral artery; functional independence; gain of function; genetic manipulation; improved; in vivo; ischemic injury; limb injury; loss of function; mortality; mouse model; new therapeutic target; novel; novel therapeutic intervention; preservation; prevent; skeletal muscle wasting; therapeutic target

Abstract/Project Summary Dogma tells us that oxygen (O2) is an absolute requirement for cell/tissue survival. We have recently discovered a unique skeletal muscle that is remarkably and uniquely resistant to negative effects of ischemia. The implication is that unlike other peripheral skeletal muscles, this muscle has a distinct mechanism that allows it to tolerate ischemic conditions. Identifying the underlying mechanism(s) that explain the ischemia resistance could hold the key to unlocking therapeutic targets and/or approaches for improving tissue survival under conditions where O2 exposure is limiting. Ischemia affects skeletal muscle in numerous clinical conditions, including various myopathies, peripheral artery disease (PAD), compartment syndrome, severe limb injury, etc., not to mention coronary occlusion in cardiac muscle. Thus, the identification of a mechanism that provides ischemia resistance would overcome one of the longest standing challenges faced by clinicians. Using an integrative experimental design, the scientific goal of this project is to elucidate the unique functional, metabolic, and/or bioenergetic systems that account for the ability of this muscle to survive ischemic insults. The long-term goal of the project is to leverage the identified mechanism(s) to therapeutically treat and/or prevent myopathies induced or exacerbated by ischemia. The proposal will use molecular, biochemical, and physiological approaches designed to address hypotheses grounded in the idea that this unique muscle must be able to meet energetic demands and ensure sarcolemmal stability during ischemia. Thus, the experimental approach seeks to leverage already identified genes that are critical to the generation of adenosine triphosphate and manipulate genes that are able to stabilize the sarcolemma during ischemic conditions to prevent excitotoxicity. Using gain-of or loss-of function approaches the experiments designed in the proposal will determine if the mechanism is necessary for ischemia survival and also assess if the mechanism is sufficient to survive ischemia. Completion of this proposal will challenge dogma concerning our understanding of how tissue can resist ischemic insults and advance the field forward in a significant fashion due to the identification of an ischemia-resistant muscle.

摘要/项目摘要 教条告诉我们，氧（O2）是细胞/组织存活的绝对要求。我们最近有 发现了一种独特的骨骼肌，对缺血的负面影响具有显着且独特的抵抗力。 这意味着与其他外围骨骼肌不同，该肌肉具有独特的机制 允许它耐受性缺血状况。识别解释缺血的基本机制 抗性可以保持解锁治疗靶标和/或改善组织存活的方法 在O2暴露限制的条件下。缺血会影响众多临床的骨骼肌 疾病，包括各种肌病，周围动脉疾病（PAD），室综合征，严重 肢体损伤等，更不用说心脏肌肉中的冠状动脉阻塞了。因此，识别机制 提供缺血性的抗药性将克服临床医生面临的最长的挑战之一。 使用综合实验设计，该项目的科学目标是阐明独特的 功能性，代谢和/或生物能源系统，这些系统可以说明这种肌肉能够生存的缺血性 侮辱。该项目的长期目标是利用确定的机制进行治疗 和/或预防缺血引起或加剧的肌病。该提案将使用分子，生化， 以及旨在解决这种独特肌肉以下的假设的生理方法 必须能够满足能量的需求并确保缺血期间的肌膜稳定性。因此， 实验方法试图利用已经确定的对产生至关重要的基因 三磷酸腺苷和操纵基因，能够在缺血期间稳定肌膜 防止兴奋性毒性的条件。使用功能丧失方法的实验在 该提案将确定该机制是否需要缺血生存，并评估是否是否 机制足以生存缺血。该提案的完成将挑战教条关于我们的 了解组织如何抵抗缺血性侮辱并以重大方式前进 由于鉴定出抗缺血的肌肉。