Mitochondrial Determinants of Cognitive Outcomes in ARDS and Sepsis

ARDS 和脓毒症认知结果的线粒体决定因素

• 批准号: 9883826
• 负责人: Timothy D Girard
• 金额: $ 38.29万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9883826
• 关键词: Acute; Adult Respiratory Distress Syndrome; Affect; African American; Animals; Apoptosis; Arteries; Biogenic Amines; Brain; Caring; Cell Proliferation; Cell Respiration; Cells; Citric Acid Cycle; Cognition; Cognitive; Complication; Computerized Medical Record; Confusion; Critical Illness; DNA; DNA Databases; Data; Delirium; Dementia; Enrollment; F2-Isoprostanes; Functional disorder; Funding; Future; Genotype; Glutamates; Glutamine; Goals; Haplogroup; Hospitals; Human; Impaired cognition; Impairment; Infection; Inflammatory; Inflammatory Response; Injury; Internal jugular vein structure; Ketones; Kidney; Lead; Length of Stay; Life; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Mitochondrial DNA; Myocardium; Organ; Outcome; Oxidants; Oxygen; Oxygen Consumption; Participant; Patients; Plasma; Play; Populations at Risk; Production; Prospective cohort; Pyruvate; Reactive Oxygen Species; Research Project Grants; Role; Sepsis; Sepsis Syndrome; Specimen; Stress; Survivors; Symptoms; Syndrome; Testing; Tissues; United States National Institutes of Health; Upper Extremity; Work; base; biological adaptation to stress; brain dysfunction; brain metabolism; caucasian American; cognitive function; confusion assessment method; improved; lung injury; metabolomics; mitochondrial dysfunction; mortality; nutrient metabolism; preservation; prevent; prospective; septic patients

PROJECT SUMMARY Acute respiratory distress syndrome (ARDS) and sepsis claim the lives of hundreds of thousands of patients worldwide each year. Improved care has reduced mortality due to ARDS and sepsis, but up to 80% of ARDS/sepsis patients develop acute brain dysfunction in the form of delirium, a major complication associated with prolonged ICU and hospital stays and increased mortality. Even when delirium symptoms resolve, many patients never regain normal cognition, instead struggling with an acquired, dementia-like, long-term cognitive impairment. With a limited understanding of the pathophysiology of brain dysfunction due to ARDS and sepsis, there are currently no cognition-preserving therapies for ARDS/sepsis patients. Animal and human studies have shown that the inflammatory response of ARDS/sepsis imposes a stress on cells and tissues characterized by increased production of reactive oxygen species (ROS), decreased oxygen delivery, impaired oxygen consumption, metabolic reprogramming increasing lactate production, and dysregulation of cell proliferation/apoptosis. This stress response is mediated by mitochondria, which produce ROS, regulate oxygen and nutrient metabolism, and control initiation of apoptosis. Mitochondrial dysfunction has been implicated in sepsis-induced injury of lung (i.e., ARDS) as well as heart, muscle, and kidneys, but the most metabolically vulnerable organ—the brain—remains poorly studied in this context. We hypothesize that mitochondrial function and key variables that impact it, e.g., mitochondrial DNA (mtDNA) haplogroup, are major determinants of delirium and long-term cognitive impairment due to ARDS and sepsis. To test this central hypothesis, we will complete the following Aims: (1) Test the hypotheses that specific mtDNA haplogroups are independently associated with delirium and long-term cognitive impairment due to ARDS and sepsis; (2) test the hypotheses that alterations in mitochondrial oxidative metabolism, systemic oxidant injury, and mitochondrial injury are predicted by mtDNA haplogroup and are independently associated with delirium and long-term cognitive impairment due to ARDS and sepsis; and (3) test the hypotheses that alterations in multiple specific metabolic pathways affected by mitochondrial dysfunction in the brain are independently associated with delirium and long-term cognitive impairment due to ARDS and sepsis. We will complete Aim 1 using Vanderbilt’s BioVU DNA Databank and electronic medical record as well as data and DNA collected during the NIH-funded BRAIN-ICU study, Aim 2 using data and specimens collected in the BRAIN-ICU study, and Aim 3 using data and specimens collected from a prospective cohort of patients with ARDS and/or sepsis. By elucidating the pathophysiology of ARDS/sepsis-associated brain dysfunction, this work will in due course lead to strategies that preserve cognitive function for millions who will suffer from ARDS or sepsis in the future.

项目摘要 急性呼吸窘迫综合征（ARDS）和脓毒症夺去了数十万患者的生命 全球每年都有。改善的护理降低了ARDS和败血症的死亡率，但高达80%的 ARDS/脓毒症患者以谵妄的形式发展急性脑功能障碍，这是一种主要的并发症， ICU和住院时间延长，死亡率增加。即使谵妄症状消失，许多 患者永远不会恢复正常的认知，而是与获得性的、类似痴呆的、长期的认知障碍作斗争。 损伤由于对ARDS和脓毒症引起的脑功能障碍的病理生理学了解有限， 目前还没有用于ARDS/脓毒症患者的认知保留疗法。动物和人类研究 已经表明，ARDS/脓毒症的炎症反应对细胞和组织施加了压力， 其特征在于活性氧（ROS）的产生增加，氧输送减少， 氧消耗、代谢重编程增加乳酸产生和细胞失调 增殖/凋亡。这种应激反应是由线粒体介导的，线粒体产生ROS， 氧和营养代谢，并控制细胞凋亡的启动。线粒体功能障碍一直是 与脓毒症诱导的肺损伤有关（即，ARDS）以及心脏、肌肉和肾脏，但最重要的是 代谢脆弱的器官-大脑-在这方面的研究仍然很少。我们假设 线粒体功能和影响它的关键变量，例如，线粒体DNA（mtDNA）单倍型群，是主要的 谵妄和长期认知障碍的决定因素，由于ARDS和败血症。为了测试这个中央 假设，我们将完成以下目的：（1）检验特定mtDNA单倍型群是 与ARDS和脓毒症引起的谵妄和长期认知障碍独立相关;（2）测试 线粒体氧化代谢的改变，全身氧化损伤， 线粒体损伤是由mtDNA单倍型群预测的，并且与谵妄独立相关， 由于ARDS和脓毒症引起的长期认知功能障碍;（3）测试以下假设： 受脑中线粒体功能障碍影响的多种特定代谢途径独立地 与谵妄和ARDS和脓毒症引起的长期认知障碍相关。我们将完成目标1 利用范德比尔特的BioVU DNA数据库和电子病历以及收集的数据和DNA 在NIH资助的BRAIN-ICU研究中，目标2使用BRAIN-ICU研究中收集的数据和标本， 和目标3使用从患有ARDS和/或脓毒症的患者的前瞻性队列收集的数据和样本。 通过阐明ARDS/脓毒症相关脑功能障碍的病理生理学，这项工作将在适当的时候 从而为数百万未来将遭受ARDS或败血症的患者提供保护认知功能的策略。