Immune, hormonal, and muscle mitochondrial determinants of recovery in Acute Respiratory Distress Syndrome survivors

急性呼吸窘迫综合征幸存者康复的免疫、激素和肌肉线粒体决定因素

• 批准号: 10659639
• 负责人: Matthew R Baldwin
• 金额: $ 75.46万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659639
• 关键词: Acute; Acute Respiratory Distress Syndrome; Acute respiratory failure; Adult; Affect; Age; Aging; American; Amino Acids; Anti-Inflammatory Agents; Bioenergetics; Biological; Biological Markers; Biopsy; Blood Flow Cytometry; COVID-19; COVID-19 survivors; COVID-19/ARDS; Clinic; Clinical; Cohort Studies; Communities; Data; Dehydroepiandrosterone Sulfate; Elderly; Enrollment; Future; GDF15 gene; Gene Expression Profiling; Goals; Growth Factor; Health Care Costs; Hormonal; Hormones; Hospitals; Immune; Impairment; Inflammation; Insulin; Interleukin-6; Intervention; Limb structure; Lung; Messenger RNA; Mitochondria; Mitochondrial Myopathies; Morphology; Multi-Ethnic Study of Atherosclerosis; Muscle; Muscle Mitochondria; Muscle Weakness; National Heart, Lung, and Blood Institute; Nested Case-Control Study; Outcome; Patients; Persons; Physical Function; Plasma; Process; Recovery; Research Priority; Role; Serum; Skeletal Muscle; Source; Supplementation; Survivors; TNFRSF1A gene; Testosterone; Time; Universities; University Hospitals; Walking; Work; biobank; cohort; comorbidity; coronavirus disease; critical period; cytokine; disability; follow-up; high dimensionality; hormone deficiency; improved; inhibitor; interest; lung injury; metabolomics; mitochondrial dysfunction; monocyte; mortality; muscle strength; novel; physically handicapped; prospective; randomized trial; sociodemographics; systemic inflammatory response; targeted therapy trials; targeted treatment; therapeutic target; vastus lateralis

PROJECT SUMMARY Prior to COVID-19, over 150,000 Americans survived Acute Respiratory Distress Syndrome (ARDS) each year. To date, more than 500,000 Americans have survived COVID-19 ARDS. At least half of ARDS survivors have persistent muscle weakness that results in increased disability, healthcare costs, and mortality. There are no targeted therapies to improve muscle strength and physical recovery in ARDS survivors, because the mechanisms underlying these physical impairments and poor recovery are not well understood. The overall hypothesis of the project is that multi-systemic dysregulation that occurs in acute ARDS, persists after hospital discharge in those with persistent physical impairment, and resolves in those who recover physically. The overall objective of the project is to determine whether persistent inflammation from dysregulated monocytes, anabolic hormone deficiencies, and muscle mitochondrial dysfunction at 3 months after hospital discharge are each treatment targets for physical disability in ARDS survivors. To achieve our objective, we will conduct a nested case-control study of cohorts. We will prospectively enroll 345 ARDS survivors at hospital discharge with 12- month longitudinal follow-up from Johns Hopkins University and Columbia University hospitals. Three months after hospital discharge, we will conduct an in-person nested case-control study of 180 ARDS survivors, with case status defined as not-recovered from new disability. Inflammation, anabolic hormone deficiencies, and muscle mitochondrial dysfunction increase with aging and comorbidity, and older adult ARDS survivors are less likely to recover than those who are younger and healthier. Therefore, to determine biomarker levels and muscle mitochondrial dysfunction that are associated with ARDS, independent of age or comorbidity, we will compare ARDS survivors with carefully matched community-dwelling adults from the National Heart Lung and Blood Institute (NHLBI) Multi-Ethnic Study of Atherosclerosis (MESA) and the Columbia University Merritt Center muscle biobank. Across the cohorts, we have carefully coordinated sociodemographic, clinical, and functional assessments to facilitate careful matching. We will conduct rigorous serum biomarker assessments, targeted plasma metabolomics, high dimensional flow cytometry of blood, and muscle biopsy mitochondrial function and gene expression analyses to accomplish our three Aims: (1) to determine the role of monocyte function in recovery from disability in ARDS survivors; (2) to determine the role of anabolic hormone deficiencies in recovery from disability in ARDS survivors; and (3), to determine how plasma biomarkers of mitochondrial myopathy associate with skeletal muscle mitochondrial dysfunction and recovery from disability in ARDS survivors. The overall goal is to conduct epi-mechanistic studies that will inform future post-ARDS randomized trials of targeted anti-inflammatory therapies, hormone supplementation therapies, and muscle mitochondrial therapies that aim to improve physical function in ARDS survivors, a NHBLI research priority.

项目概要 在 COVID-19 之前，每年有超过 150,000 名美国人死于急性呼吸窘迫综合症 (ARDS)。 迄今为止，已有超过 500,000 名美国人在 COVID-19 ARDS 中幸存。至少一半的 ARDS 幸存者 持续性肌肉无力会导致残疾、医疗费用和死亡率增加。没有 靶向治疗可改善 ARDS 幸存者的肌肉力量和身体恢复，因为 这些身体损伤和恢复不良的机制尚不清楚。整体 该项目的假设是，急性 ARDS 中发生的多系统失调在住院后持续存在 那些身体持续受损的人会出院，而身体康复的人会消退。整体 该项目的目标是确定单核细胞失调、合成代谢失调是否会导致持续性炎症 出院后 3 个月时激素缺乏和肌肉线粒体功能障碍分别为 ARDS 幸存者身体残疾的治疗目标。为了实现我们的目标，我们将进行嵌套 队列病例对照研究。我们将前瞻性地招募 345 名出院的 ARDS 幸存者，其中 12- 约翰·霍普金斯大学和哥伦比亚大学医院进行了一个月的纵向随访。三个月 出院后，我们将对 180 名 ARDS 幸存者进行面对面的巢式病例对照研究，其中 病例状态定义为未从新的残疾中恢复。炎症、合成代谢激素缺乏和 肌肉线粒体功能障碍随着年龄的增长和合并症而增加，老年 ARDS 幸存者较少 比那些更年轻、更健康的人更有可能恢复。因此，为了确定生物标志物水平和肌肉 与 ARDS 相关的线粒体功能障碍，与年龄或合并症无关，我们将进行比较 ARDS 幸存者与来自国家心肺血液中心的社区居民仔细匹配 动脉粥样硬化研究所 (NHLBI) 多种族研究 (MESA) 和哥伦比亚大学梅里特中心 肌肉生物库。在各个队列中，我们仔细协调了社会人口统计学、临床和功能 评估以促进仔细匹配。我们将进行严格的血清生物标志物评估，有针对性 血浆代谢组学、血液高维流式细胞术和肌肉活检线粒体功能和 基因表达分析来实现我们的三个目标：（1）确定单核细胞功能在 ARDS 幸存者的残疾康复； (2)确定合成代谢激素缺乏在恢复中的作用 ARDS 幸存者的残疾； (3) 确定线粒体肌病的血浆生物标志物如何 与 ARDS 幸存者骨骼肌线粒体功能障碍和残疾恢复有关。这 总体目标是进行表观机制研究，为未来的 ARDS 后随机试验提供信息 抗炎疗法、激素补充疗法和肌肉线粒体疗法 改善 ARDS 幸存者的身体功能，这是 NHBLI 的研究重点。