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

项目摘要 这个最大化研究者研究奖（MIRA）的主要目标是提供新的 关于烧伤创伤的代谢应激反应的机制性见解。具体而言，总体目标 这项研究计划的目的是阐明烧伤引起的高代谢中的作用， 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，烧伤幸存者忍受着漫长的恢复， 功能和生活质量不容易实现。因此，迫切需要新的战略 从而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介质。 事实上，生物能量学的改变被认为是烧伤后高代谢反应的原因， 烧伤引起的胰岛素抵抗、脂质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内稳态， 通过释放线粒体DNA（mtDNA）片段到烧伤的全身炎症反应中， 流通 该MIRA将支持同位素标记脂肪组织的创新啮齿动物模型的开发， 骨骼肌。这些模型将被用来追踪特定的生物体的周转、再分配和氧化。 对烧伤的反应。通过将这些新模型与体内氧化氘给药相结合， 我们将产生关于多种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对底物通量和线粒体载体蛋白的测量， 通过直接测量线粒体呼吸功能、质子漏、膜电位和 超氧化物的形成，我们将阐明改变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，质子载体和线粒体的效用 有针对性的抗氧化剂作为恢复烧伤后生物能量学和代谢功能的策略， 测试.此外，从烧伤患者采集的血液和组织样本将用于验证临床前 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后代谢应激反应的机械理解， 将贡献新的知识，可以利用，以减轻痛苦，促进恢复烧伤 幸存者此外，由于高代谢存在于其他形式的危重病中，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.