Mitochondrial biogenesis in sepsis-induced organ dysfunction

描述（由申请人提供）：我们建议研究线粒体生物发生在败血症器官功能障碍进化中的重要性。多器官功能障碍综合征（MODS）是脓毒症的常见并发症，尽管脓毒症死亡率随着受累器官数量的增加几乎呈线性增加，但器官衰竭的潜在发病机制及其如何解决尚不清楚。我们已经在患有败血症的动物身上证明，组织中线粒体的损伤会导致细胞能量产生异常，当修复机制失效时，会导致细胞死亡和器官功能障碍（6-12）。这是由线粒体生物发生平衡的，线粒体生物发生是一种适应性程序，通过线粒体成分的维护和修复以及新细胞器的合成来维持线粒体能量生产的能力。我们假设线粒体损伤是严重脓毒症患者的早期发现，线粒体损伤的程度可以预测脓毒症诱导的MODS的严重程度。我们认为，脓毒症中MODS的解决取决于线粒体生物发生的开始。线粒体基因组是脓毒症中氧化损伤的一个特别敏感的靶点，因为它位于氧化磷酸化位点附近，相对不受抗氧化防御的保护（13-15）。我们的初步数据表明，线粒体DNA （mtDNA）损伤和生物发生是宿主对严重感染反应的内在组成部分。为了确定这些与患者MODS的发展和消退之间的关系，我们提出以下具体目标：确定外周血单个核细胞（PBMC）线粒体DNA损伤是否预测非糖尿病和糖尿病脓毒症患者的器官功能障碍，特别是危重症肌病。具体目标2。确定PBMC中线粒体DNA复制和生物发生的分子机制激活是否能预测败血症诱导的器官功能障碍的恢复。具体目标3。确定特定的分子途径是否对野生型和糖尿病小鼠脓毒症诱导的器官损伤的解决至关重要。我们将对脓毒症患者PBMC中的线粒体进行表征，以确定mtDNA损伤和生物发生与疾病严重程度和预后之间的关系。通过临床相关的脓毒症动物模型，我们将研究线粒体生物发生和器官功能恢复的重要途径，并确定这些途径是否可以作为脓毒症患者MODS恢复的可行靶点。该研究结果将为脓毒症期间能量衰竭的临床评估提供一种新的方法，对脓毒症并发症的患者风险进行分层，并使用该结果来增强现有的动物模型，并确定可能从促进线粒体生物发生的治疗干预中受益的患者。公共卫生相关性：多器官功能障碍综合征（MODS）是严重感染引起的败血症的常见并发症，每年约有75万例报告病例，总死亡率约为30%。死亡率与器官衰竭的严重程度直接相关，但根本原因和决定解决的因素尚不清楚。这些研究将探讨线粒体损伤和生物发生在脓毒症器官功能障碍发病机制中的作用，并为脓毒症器官功能衰竭的恢复提供新的治疗方法。

DESCRIPTION (provided by applicant): We propose to investigate the importance of mitochondrial biogenesis in the evolution of organ dysfunction in sepsis. Multiple organ dysfunction syndrome (MODS) is a frequent complication of sepsis, and although sepsis mortality increases almost linearly with the number of organs involved, the underlying pathogenesis of organ failure and how it resolves are not understood. We have shown in animals with sepsis that damage to mitochondria in tissues contributes to abnormalities in cellular energy production and, when repair mechanisms fail, to cell death and organ dysfunction (6-12). This is balanced by mitochondrial biogenesis, the adaptive program that maintains the capacity for mitochondrial energy production through maintenance and repair of mitochondrial components and through synthesis of new organelles. We hypothesize that mitochondrial damage is an early finding in patients with severe sepsis and that the extent of mitochondrial injury predicts the severity of sepsis-induced MODS. We propose that the resolution of MODS in sepsis depends on the initiation of mitochondrial biogenesis. The mitochondrial genome is a particularly sensitive target for oxidative injury in sepsis because it is located close to the site of oxidative phosphorylation and is relatively unprotected by anti-oxidant defenses (13-15). Our preliminary data show that mitochondrial DNA (mtDNA) injury and biogenesis are an intrinsic part of the host response to severe infection. To determine how these relate to the development and resolution of MODS in patients, we propose the following Specific Aims: Specific Aim 1. Determine if mitochondrial DNA damage in peripheral blood mononuclear cells (PBMC) predicts organ dysfunction in non-diabetic and diabetic septic patients, especially critical care myopathy. Specific Aim 2. Determine if activation of the molecular mechanisms of mitochondrial DNA replication and biogenesis in PBMC predicts recovery from sepsis-induced organ dysfunction. Specific Aim 3. Determine whether specific molecular pathways are critical to resolution of sepsis- induced organ injury in wild type and diabetic mice. We will characterize mitochondria in PBMC from septic patients to determine the relationship between mtDNA damage and biogenesis to disease severity and outcome. Using a clinically relevant animal model of sepsis, we will investigate pathways important for mitochondrial biogenesis and recovery of organ function and determine whether these are feasible targets for effecting recovery of MODS in septic patients. The results will provide a new approach to the clinical assessment of energy failure during sepsis, stratify patient risk for sepsis complications and use the results to enhance existing animal models, and identify patients who might benefit from therapeutic interventions that promote mitochondrial biogenesis. PUBLIC HEALTH RELEVANCE: The multiple organ dysfunction syndrome (MODS) is a frequent complication of sepsis from severe infections, with ~750,000 reported cases per year and an overall mortality rate of about 30%. Mortality is directly related to severity of organ failure, but the underlying causes and what determines resolution are not understood. These studies will investigate the role of mitochondrial injury and biogenesis in the pathogenesis of organ dysfunction in sepsis, and should lead to new therapies to enhance recovery from organ failures in sepsis.