Mitochondrial biogenesis in sepsis-induced organ dysfunction

脓毒症引起的器官功能障碍中的线粒体生物发生

• 批准号: 8021807
• 负责人: CLAUDE A PIANTADOSI
• 金额: $ 31.65万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8021807
• 关键词: Animal Model; Animals; Antioxidants; Biogenesis; Biopsy; Case Study; Cell Death; Clinical assessments; Complication; Critical Care; Critical Pathways; DNA Damage; DNA biosynthesis; Data; Development; Diabetes Mellitus; Diabetic mouse; Disease Outcome; Elderly; Equilibrium; Evolution; Failure; Functional disorder; Health; Homeostasis; Immune response; Infection; Injury; Lead; Maintenance; Measures; Metabolic; Mitochondria; Mitochondrial DNA; Molecular; Multiple Organ Failure; Myopathy; Organ; Organ failure; Organelles; Oxidative Phosphorylation; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Production; Recovery; Regulation; Resolution; Risk; Role; Sepsis; Severities; Severity of illness; Signal Transduction; Site; Skeletal Muscle; Therapeutic Intervention; Tissues; clinically relevant; diabetic; high risk; mitochondrial genome; mortality; non-diabetic; novel strategies; oxidative damage; programs; repaired; restoration; septic

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.

描述（由申请人提供）：我们建议研究线粒体生物合成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随着受累器官的数量几乎呈线性增加，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中表明，组织中线粒体的损伤有助于细胞能量产生的异常，并且当修复机制失败时，导致细胞死亡和器官功能障碍（6-12）。这通过线粒体生物发生来平衡，线粒体生物发生是一种适应性程序，通过维持和修复线粒体组分以及通过合成新的细胞器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预测脓毒症诱导的MODS的严重程度。我们认为脓毒症MODS的解决依赖于线粒体生物合成的启动。线粒体基因组是脓毒症中氧化损伤的特别敏感的靶标，因为它位于氧化磷酸化位点附近，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）损伤和生物合成是宿主对严重感染反应的内在组成部分。为了确定这些如何与患者MODS的发展和解决有关，我们提出了以下具体目标：具体目标1。确定外周血单个核细胞（PBMC）中线粒体DNA损伤是否可预测非糖尿病和糖尿病脓毒症患者的器官功能障碍，尤其是重症监护肌病。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的激活是否预示着脓毒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解决野生型和糖尿病小鼠中脓毒症诱导的器官损伤至关重要。我们将描述脓毒症患者PBMC中线粒体的特征，以确定线粒体DNA损伤和生物发生与疾病严重程度和结果之间的关系。使用临床相关的脓毒症动物模型，我们将研究线粒体生物合成和器官功能恢复的重要途径，并确定这些是否是影响脓毒症患者MODS恢复的可行靶点。这些结果将为脓毒症期间能量衰竭的临床评估提供一种新方法，对脓毒症并发症的患者风险进行分层，并使用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合成的治疗干预中受益的患者。公共卫生关系：多器官功能障碍综合征（MODS）是严重感染败血症的常见并发症，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方案的因素尚不清楚。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，并将导致新的治疗方法，以提高脓毒症器官功能衰竭的恢复。