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

摘要/项目摘要 Dogma告诉我们，氧气(O2)是细胞/组织生存的绝对要求。我们最近做了 发现了一种独特的骨骼肌，对缺血的负面影响具有显着和独特的抵抗力。 这意味着，与其他外周骨骼肌不同，这种肌肉具有一种独特的机制，即 使其能够耐受缺血条件。确定解释缺血的潜在机制(S) 耐药性可能是解锁治疗靶点和/或提高组织存活率的方法的关键 在氧气暴露有限的条件下。缺血在许多临床上影响骨骼肌 各种情况，包括各种肌病、外周动脉疾病(PAD)、间隔室综合征、严重 肢体损伤等，更不用说心肌冠状动脉闭塞了。因此，一种机制的识别 这提供了缺血抵抗将克服临床医生面临的最长的长期挑战之一。 使用综合实验设计，这个项目的科学目标是阐明独特的 功能、代谢和/或生物能量系统，解释了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(S)进行治疗性治疗 和/或防止因缺血引起或加重的肌病。该提案将使用分子、生化、 以及旨在解决假说的生理学方法，这些假说基于这样一种想法，即这种独特的肌肉 必须能够满足能量需求，并确保缺血期间的肌膜稳定性。因此， 实验方法寻求利用已经识别的基因，这些基因对产生 三磷酸腺苷和操纵能够在缺血时稳定肌膜的基因 防止兴奋性毒性的条件。使用增益或损耗函数接近于中设计的实验 该提案将确定该机制是否对缺血存活是必要的，并还将评估是否 机制足以在缺血状态下存活。这项提案的完成将挑战关于我们的 了解组织如何抵抗缺血损伤并以显著的方式推进磁场 因为鉴定出了一块耐缺血的肌肉。

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.