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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要急性呼吸衰竭 (ARF) 的幸存者往往面临着恢复正常生活的艰巨任务，因为他们患有严重的超过一半的患者永远无法重返工作岗位，并且常常难以维持生活。目前有可靠的算法来预测长期身体功能。我们之前描述了代谢组学如何预测脓毒症和 ARF 的急性结局。许多代谢组学变化与 β-氧化、柠檬酸循环 (TAC) 和烟酰胺腺嘌呤二核苷酸（NADH）代谢障碍现在被认为是一种线粒体功能障碍。败血症结果的主要驱动因素，并可能在败血症引起的肌肉功能障碍中发挥作用。线粒体 DNA (mtDNA) 损伤相关分子模式 (DAMP) 可预测患者的预后我们开发了一种新颖且创新的 RNA 靶饵捕获深度测序。和生物信息学方案，用于准确定量和区分 mtDNA DAMP 和核线粒体假基因，mtDNA 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，也可以预测身体状况为了支持这一假设，我们在一项小型试点研究中发现，患者出院时测量的线粒体相关代谢物与六种患者的身体功能不良相关在这项研究中，我们建议通过以下方式扩展代谢组学和 mtDNA 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维克森林浸信会医疗中心（TARGET；ClinicalTrials.gov 标识符：NCT00976833）。旨在测试在 ICU 中启动的物理治疗是否会缩短 ICU 住院时间并提高长期质量 - 在目标 1 中，我们将确定无细胞血浆中 mtDNA DAMP 的浓度增加。目标 2 将调查 ARF 幸存者的身体功能。线粒体相关的生物能代谢物和无细胞血浆中 mtDNA DAMP 的丰度。这项研究的结果将为 mtDNA DAMP 的作用提供新的病理生理学见解， ARF 引起的身体功能不良中线粒体相关代谢物的新药物疗法。有潜力通过改善线粒体功能、生物发生和减少 mtDNA DAMP，而 NAD 衍生物或雄激素类固醇补充可以改善身体状况强度和功能。