The Role of the Mitochondrion in the Metabolic Stress Response to Burn Trauma

项目总结 这一最大化调查人员研究奖(MIRA)的主要目标是提供新的 烧伤创伤时代谢应激反应的机械论洞察。具体地说，最重要的 这项研究计划的目的是阐明线粒体在烧伤诱导中的作用 高代谢和代谢功能障碍。烧伤是美国非致命性创伤的主要原因。 各州。今天，即使是最严重的烧伤也能存活下来。然而，烧伤幸存者忍受着旷日持久的 恢复，功能恢复和生活质量不容易实现。相应地，有一个 迫切需要新的战略，以降低发病率并加速烧伤幸存者的康复。 最近的数据表明，线粒体是烧伤后代谢应激反应的中介。 事实上，改变的生物能量学被认为是烧伤后高代谢反应的基础，并且可能 会导致烧伤引起的胰岛素抵抗、脂肪代谢改变和肌肉萎缩。此外， 线粒体应激似乎通过氧的形成影响烧伤后的细胞内稳态 自由基，并可能通过释放碎片促进全身炎症反应。 线粒体DNA(MtDNA)进入循环。 该MIRA将支持开发同位素标记脂肪的创新啮齿动物模型 组织和骨骼肌。这些模型将被用来跟踪营业额、再分配和 烧伤时特定底物的氧化反应。通过将这些新模型与 在体内添加氧化氢，我们将产生关于关键合成速率的重要数据 烧伤后多种组织中线粒体蛋白的变化。通过将测量结果与 直接测量线粒体呼吸的底物通量和线粒体载体蛋白周转率 功能，质子泄漏，膜电位和超氧化物生成，我们将阐明其机制 烧伤后生物能量学和代谢改变的基础。此外，环境的效用 温度、原基团和线粒体靶向抗氧化剂作为恢复 烧伤后的生物能量学和代谢功能也将进行严格的测试。此外，血液和组织 从烧伤患者身上收集的样本将被用于验证临床前数据，并探索 线粒体DNA在烧伤全身炎症反应中的作用 通过改善我们对烧伤的代谢应激反应的机制的理解，这项研究 计划将贡献新的知识，这些知识可能被用来减轻痛苦并促进 烧伤幸存者的康复。此外，由于高代谢存在于其他形式的危重疾病中， 这项研究计划产生的新信息可能会产生更广泛的科学和临床影响。

PROJECT SUMMARY The main objective of this Maximizing Investigators' Research Award (MIRA) is to provide new mechanistic insight regarding the metabolic stress response to burn trauma. Specifically, the overarching goal of this research program is to elucidate the role of the mitochondrion in burn-induced hypermetabolism and metabolic dysfunction. Burns are a leading cause of non-fatal trauma in the United States. Today, even the most severe burns are survivable. However, burn survivors endure a protracted recovery, where restoration of function and quality of life are not readily achieved. Accordingly, there is a pressing need for new strategies that reduce morbidity and hasten the recovery of burn survivors. Recent data have implicated mitochondria as mediators of the metabolic stress response to burn trauma. Indeed, altered bioenergetics are thought underlay the hypermetabolic response to burns, and may contribute to burn-induced insulin resistance, altered lipid metabolism and muscle wasting. Further, mitochondrial stress appears to impact cellular homeostasis post burn through the formation of oxygen radicals, and may contribute to the systemic inflammatory response to burns by releasing fragments of mitochondrial DNA (mtDNA) into the circulation. This MIRA will support the development of innovative rodent models of isotopically labeled adipose tissue and skeletal muscle. These models will be leveraged to trace the turnover, redistribution and oxidation of specific substrates in response to burn injury. By combining these novel models with deuterium oxide dosing in vivo, we will generate important data regarding synthesis rates of key mitochondrial proteins in multiple tissues in response to burn trauma. By dovetailing measurements of substrate flux and mitochondrial carrier protein turnover with direct measures of mitochondrial respiratory function, proton leak, membrane potential and superoxide formation, we will elucidate the mechanistic basis of altered bioenergetics and metabolism in response to burn injury. In addition, the utility of ambient temperature, protonophores and mitochondrial targeted antioxidants as strategies to restore bioenergetics and metabolic function post burn will also rigorously tested. Furthermore, blood and tissue samples collected from burn patients will be used to validate preclinical data and to probe the role of mtDNA in the systemic inflammatory response to burn injury. By bettering our mechanistic understanding of the metabolic stress response to burns this research program will contribute new knowledge that may be leveraged to lessen the suffering and promote the recovery of burn survivors. Moreover, since hypermetabolism is present in other forms critical illness, the new information generated by this research program may have broader scientific and clinical impact.