Metabolic Energy Crisis Signature Predicts Quality of Life in Survivors of Acute Respiratory Failure

代谢能量危机特征可预测急性呼吸衰竭幸存者的生活质量

• 批准号: 10390486
• 负责人: Raymond Julian Langley
• 金额: $ 20.08万
• 依托单位: UNIVERSITY OF SOUTH ALABAMA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10390486
• 关键词: 2019-nCoV; Acute; Acute respiratory failure; Algorithms; Baptist Church; Bioenergetics; Biogenesis; Bioinformatics; Biological Markers; Carnitine; Cells; Citric Acid Cycle; Clinical; Complex; Coronavirus; Critical Care; Critical Illness; DNA; DNA Damage; Data; Development; Disease; Electron Transport; Enrollment; Evaluation; Exercise Therapy; Face; Fatigue; Feasibility Studies; Financial Hardship; Functional disorder; Genome; Goals; Hospitals; Immune response; Impairment; Inflammatory Response; Injury; Kynurenine; Length of Stay; Life; Link; Lung; Measurement; Measures; Mechanical ventilation; Mediating; Medical center; Medicine; Metabolic; Metabolism; Methods; Mitochondria; Mitochondrial DNA; Molecular; Multienzyme Complexes; Muscle; Muscle Weakness; Neurocognitive; Nicotinamide adenine dinucleotide; Nuclear; Outcome; Oxidative Phosphorylation; Oxidative Stress; Pathway interactions; Patient Discharge; Patient-Focused Outcomes; Patients; Pattern; Peripheral; Physical Function; Physical Performance; Physical therapy; Pilot Projects; Plasma; Play; Protocols documentation; Pseudogenes; Quality of life; RNA; Randomized Clinical Trials; Reactive Oxygen Species; Rehabilitation therapy; Reporting; Resolution; Retrospective cohort; Risk; Role; SARS-CoV-2 infection; Sampling; Sentinel; Sepsis; Severities; Skeletal Muscle; Standardization; Steroids; Survivors; Testing; Time; Trauma; Trauma patient; Tricarboxylic Acids; Work; acylcarnitine; androgenic; care outcomes; deep sequencing; design; economic impact; experimental study; forest; improved; innovation; insight; metabolomics; mitochondrial dysfunction; mortality; novel; outcome prediction; oxidation; pandemic disease; predictive marker; predictive signature; severe COVID-19; skeletal muscle wasting

Project Summary/Abstract Survivors of acute respiratory failure (ARF) often face a daunting return to normal life as they have significant impairment of physical function. Over half of these patients are never able to return to work and often sustain significant skeletal muscle loss. Reliable algorithms to predict long-term physical function are currently unavailable. We previously described how metabolomics are predictive of acute outcomes in sepsis and ARF. Many of these metabolomic changes are related to dysfunction of β-oxidation, the citric acid cycle (TAC) and nicotinamide adenine dinucleotide (NADH) metabolism. Mitochondrial dysfunction is now considered to be a major driver of sepsis outcomes and may play a role in sepsis-induced muscle dysfunction. Furthermore, mitochondrial DNA (mtDNA) damage-associated molecular patterns (DAMPs) predicts patient outcomes in critical illness and trauma. We have developed a novel and innovative RNA target-bait capture deep sequencing and bioinformatics protocol for accurate quantitation and differentiation of mtDNA DAMPs and nuclear mitochondrial pseudogenes We hypothesize that mtDNA damage-associated molecular patterns (DAMPs) or metabolomic changes are reflective of mitochondrial-related bioenergetic status, and will also predict physical function in six-month survivors of ARF. In support of this hypothesis, we found in a small pilot study that mitochondrial related metabolites measured at patient discharge correlated with poor physical function in six- month survivors of ARF. In this study, we propose to expand upon the metabolomic and mtDNA results by leveraging patient data and plasma samples that were collected within the single center, randomized clinical trial at Wake Forest Baptist Medical Center (TARGET; ClinicalTrials.gov Identifier: NCT00976833). This study was designed to test if physical therapy initiated in the ICU reduced ICU length-of-stay and improved longterm quality- of-life in survivors. In Aim 1, we will establish that increased concentrations of mtDNA DAMPs in cell-free plasma predict physical function in survivors of ARF. Aim 2 will investigate the link between the concentration of mitochondrial-related bioenergetics metabolites and the abundance of mtDNA DAMPs in cell-free plasma. The results from this study will provide new pathophysiologic insight into the role of mtDNA DAMPs and mitochondrial-associated metabolites in ARF-induced poor physical function. New pharamcological therapies have the potential to improve physical function through improved mitochondrial function, biogenesis, and reduction of mtDNA DAMPs, while NAD-derivatives or androgenic steroid repletion could improve physical strength and function.

项目摘要/摘要 急性呼吸衰竭(ARF)的幸存者通常面临着恢复正常生活的艰巨任务，因为他们有重要的 身体机能受损。这些患者中有一半以上永远不能重返工作岗位，而且经常 严重的骨骼肌萎缩。预测长期身体机能的可靠算法目前 不可用。我们先前描述了代谢组学如何预测脓毒症和ARF的急性结局。 这些代谢变化中的许多都与β氧化、柠檬酸循环和 烟酰胺腺嘌呤二核苷酸(NADH)代谢。线粒体功能障碍现在被认为是一种 脓毒症预后的主要驱动因素，并可能在脓毒症引起的肌肉功能障碍中发挥作用。此外， 线粒体DNA(MtDNA)损伤相关分子模式(DAMPS)预测患者预后 危重疾病和创伤。我们开发了一种新颖而创新的RNA靶标-诱饵捕获深度测序 和生物信息学方法，用于准确定量和区分mtDNA dAMPS和核 线粒体假基因我们假设线粒体DNA损伤相关分子模式(DAMP)或 代谢组学的变化反映了线粒体相关的生物能量状态，并将预测物理 急性肾衰6个月存活者的功能。为了支持这一假设，我们在一项小规模的试点研究中发现 出院时测量的线粒体相关代谢物与六名患者的身体功能不良相关 ARF的一个月幸存者。在这项研究中，我们建议通过以下方式扩展代谢和mtdna的结果 利用在单中心随机临床试验中收集的患者数据和血浆样本 在维克森林浸信会医疗中心(TARGET；ClinicalTrials.gov身份识别：NCT00976833)。这项研究是 旨在测试在ICU开始的物理治疗是否减少了ICU的住院时间并提高了长期质量- 生还者的生命。在目标1中，我们将确定线粒体DNA浓度的增加抑制了无细胞血浆中的线粒体DNA 预测ARF存活者的身体功能。目标2将调查两种物质浓度之间的联系 线粒体相关的生物能量代谢产物和线粒体DNA的丰度在无细胞血浆中受到抑制。这个 这项研究的结果将为线粒体DNA阻滞剂的作用提供新的病理生理见解 线粒体相关代谢产物在急性肾功能衰竭中的作用。新的药物学疗法 有可能通过改善线粒体功能、生物发生和 线粒体DNA减少抑制，而NAD-衍生物或雄激素补充可以改善身体状况 力量和功能。