权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.