Mitochondrial biogenesis in sepsis-induced organ dysfunction

描述(申请人提供)：我们建议调查线粒体生物发生在脓毒症器官功能障碍演变中的重要性。多器官功能障碍综合征(MODS)是脓毒症的常见并发症，虽然脓毒症的死亡率几乎与所涉及的器官数目呈线性关系，但器官衰竭的潜在发病机制及其解决办法尚不清楚。我们已经在脓毒症动物身上表明，组织中线粒体的破坏会导致细胞能量产生的异常，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，这是一种适应性程序，通过维护和修复线粒体组件以及合成新的细胞器来维持线粒体的能量生产能力。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发的MODS的严重程度。我们认为脓毒症时MODS的解决依赖于线粒体生物发生的启动。在脓毒症中，线粒体基因组是氧化损伤的一个特别敏感的靶点，因为它靠近氧化磷酸化的位置，并且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固有部分。为了确定它们如何与患者MODS的发生和解决相关，我们提出了以下特定目标：特定目标1.确定外周血单个核细胞(PBMC)中线粒体DNA损伤是否预测非糖尿病和糖尿病脓毒症患者器官功能障碍，特别是重症肌病变。具体目的2.确定PBMC中线粒体DNA复制和生物发生的分子机制的激活是否预示着脓毒症引起的器官功能障碍的恢复。具体目的3.确定特定的分子通路是否对解决野生型和糖尿病小鼠脓毒症引起的器官损伤至关重要。我们将对败血症患者PBMC中的线粒体进行表征，以确定线粒体DNA损伤和生物发生与疾病严重程度和预后的关系。利用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为影响脓毒症患者MODS恢复的可行靶点。这一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，对患者脓毒症并发症的风险进行分层，并利用该结果来增强现有的动物模型，并确定哪些患者可能受益于促进线粒体生物发生的治疗干预。公共卫生相关性：多器官功能障碍综合征(MODS)是严重感染引起的脓毒症的常见并发症，每年报告约75万例，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，并有望为促进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.