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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要在Covid-19之前，每年有超过15万名美国人在急性呼吸窘迫综合症（ARDS）中幸存下来。迄今为止，超过500,000名美国人在Covid-19 Ards中幸存下来。至少一半的ARDS幸存者有持续的肌肉无力导致残疾，医疗保健成本和死亡率增加。没有有针对性的疗法可以改善ARDS幸存者的肌肉力量和身体恢复，因为这些身体障碍和恢复不良的机制尚不清楚。总体该项目的假设是急性ARDS中发生的多系统失调，医院后仍然存在持续的身体损害的人出院，并在身体康复的人中解决。总体该项目的目的是确定单核细胞失调，合成代谢的持续炎症是否存在出院后3个月，激素缺乏症和肌肉线粒体功能障碍分别 ARDS幸存者中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的病例对照研究。我们将前瞻性地招募345个ARDS幸存者，以12-- 约翰·霍普金斯大学和哥伦比亚大学医院的纵向随访。三个月住院后，我们将对180个ARDS幸存者进行面对面的嵌套病例对照研究，并拥有案件状态定义为未经新残疾的重组。炎症，合成代谢激素缺乏症和肌肉线粒体功能障碍随着衰老和合并症的增加而增加，老年人ARDS幸存者较少可能比年轻，更健康的人康复。因此，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，我们将比较来自国家心脏肺和血液的精心匹配的社区成年人的ARDS幸存者动脉粥样硬化（MESA）和哥伦比亚大学梅里特中心的多民族研究学院（NHLBI）肌肉生物库。在整个队列中，我们已经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，针对性血浆代谢组学，血液的高维流式细胞术以及肌肉活检线粒体功能和基因表达分析以实现我们的三个目标：（1）确定单核细胞功能在从ARDS幸存者中的残疾中恢复；（2）确定合成代谢激素缺乏在恢复中的作用来自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骨骼肌线粒体功能障碍和ARDS幸存者的残疾恢复相关。这总体目标是进行EPI机械研究，该研究将为未来的明式壁板随机试验提供针对性的目标抗炎疗法，荷尔蒙补充疗法和肌肉线粒体疗法的目标为了改善ARDS幸存者的身体功能，NHBLI研究的优先级。