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，首要目标是 这项研究的目的是阐明线粒体在烧伤诱导的高代谢和 代谢功能障碍。烧伤是美国非致命性创伤的主要原因。今天，即使是 大多数严重烧伤是可以存活的。然而，烧伤幸存者需要忍受漫长的恢复，在那里恢复 功能和生活质量是不容易实现的。因此，迫切需要新的战略。 这降低了发病率，加速了烧伤幸存者的康复。 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，并可能起到作用 可导致烧伤后的胰岛素抵抗、脂代谢改变和肌肉萎缩。此外，线粒体应激 似乎通过氧自由基的形成影响烧伤后的细胞动态平衡，并可能参与 通过释放线粒体DNA片段(MtDNA)到烧伤后的全身炎症反应 发行量。 该MIRA将支持开发同位素标记脂肪组织的创新啮齿动物模型，并 骨骼肌。这些模型将被用来追踪特定行业的周转、再分配和氧化 对烧伤做出反应的底物。通过将这些新模型与体内的氧化氢剂量相结合， 我们将生成关于多个组织中关键线粒体蛋白质合成速率的重要数据 对烧伤创伤的反应。通过匹配底物通量和线粒体载体蛋白的测量 周转率直接测量线粒体呼吸功能、质子泄漏、膜电位和 超氧化物的形成，我们将阐明改变的生物能量学和代谢的机制基础 对烧伤的反应。此外，环境温度、原生团和线粒体的利用 作为恢复烧伤后生物能量和代谢功能的策略的靶向抗氧化剂也将严格 测试过。此外，从烧伤患者身上收集的血液和组织样本将用于验证临床前 并探讨线粒体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械理解，这项研究计划 将提供新的知识，可用于减轻痛苦和促进烧伤的恢复 幸存者。此外，由于高代谢存在于其他形式的危重疾病中，新的信息 这项研究计划产生的结果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.