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: 10084061
• 负责人: ESPEN E SPANGENBURG
• 金额: $ 38.28万
• 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 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10084061
• 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; base; design; excitotoxicity; experience; experimental study; extensor digitorum; femoral artery; functional independence; gain of function; improved; in vivo; ischemic injury; limb injury; limb ischemia; 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，氧气 (O2) 是细胞/组织生存的绝对必要条件。我们最近有 发现了一种独特的骨骼肌，它能够显着且独特地抵抗缺血的负面影响。 这意味着与其他外周骨骼肌不同，这种肌肉具有独特的机制 使其能够耐受缺血条件。确定解释缺血的潜在机制 耐药性可能是解锁治疗靶点和/或改善组织存活的方法的关键 在 O2 暴露受到限制的条件下。缺血在许多临床中都会影响骨骼肌 疾病，包括各种肌病、外周动脉疾病（PAD）、筋膜室综合征、严重 肢体损伤等，更不用说心肌冠状动脉闭塞了。因此，识别一个机制 提供抗缺血能力将克服临床医生面临的长期挑战之一。 该项目的科学目标是采用综合实验设计来阐明独特的 功能、代谢和/或生物能量系统，解释了该肌肉在缺血状态下存活的能力 侮辱。该项目的长期目标是利用已确定的机制来治疗 和/或预防由缺血引起或加剧的肌病。该提案将利用分子、生物化学、 和生理学方法旨在解决基于这种独特肌肉的假设 必须能够满足能量需求并确保缺血期间肌膜的稳定性。因此， 实验方法旨在利用已经确定的基因，这些基因对于产生 三磷酸腺苷并操纵能够在缺血期间稳定肌膜的基因 防止兴奋性中毒的条件。使用功能增益或功能丧失方法设计的实验 该提案将确定该机制对于缺血生存是否必要，并评估是否 机制足以在缺血中生存。完成这项提案将挑战有关我们的教条 了解组织如何抵抗缺血性损伤并以重大方式推动该领域向前发展 由于抗缺血肌肉的识别。