Molecular Endotypes of ARDS: Identification, Biology, and Differential Response to Therapy

ARDS 的分子内型：鉴定、生物学和对治疗的差异反应

• 批准号: 9233792
• 负责人: Carolyn Calfee
• 金额: $ 40.01万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-15 至 2018-01-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9233792
• 关键词: Acute; Acute respiratory failure; Adrenal Cortex Hormones; Adult Respiratory Distress Syndrome; Asthma; Biologic Characteristic; Biological Markers; Biology; Blood specimen; Catheters; Characteristics; Clinical; Clinical Trials; Collaborations; Conceptions; Consensus; Critical Illness; Data; Data Set; Development; Disease; Enrollment; Fluid Therapy; Funding; Future; Genomics; Goals; Heterogeneity; High-Throughput RNA Sequencing; Hormone Receptor; Human; Human Biology; Individual; Induction of neuromuscular blockade; Inflammatory; Inflammatory Response; Injury; Interleukin-13; Kidney; Lipids; Liquid substance; Lung; Mediating; Methods; Modeling; Molecular; National Heart, Lung, and Blood Institute; Outcome; Pathogenesis; Patients; Pharmacotherapy; Phase II/III Trial; Placebos; Plasma; Pneumonia; Prevention strategy; Preventive therapy; Proteins; Publishing; Randomized; Randomized Controlled Trials; Recording of previous events; Research; Research Personnel; Respiratory Failure; Risk Factors; Sepsis; Syndrome; Testing; Translating; Trauma; United States National Institutes of Health; Whole Blood; Work; base; biological heterogeneity; clinical care; clinical risk; cohort; experience; improved; injured; innovation; lung injury; malignant breast neoplasm; mortality; neutrophil; novel; novel therapeutics; predictive modeling; public health relevance; response; rosuvastatin; success; targeted treatment; treatment response; treatment strategy; treatment trial

 DESCRIPTION (provided by applicant): The acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure in critically ill patients, with nearly 200,000 cases per year in the US alone, mortality rates of 25-40%, and no effective pharmacotherapies. We recently identified and validated the presence of two distinct subphenotypes (also known as "endotypes") of ARDS in two large randomized controlled trials. In an independent analysis of both datasets, there was strong evidence that there are two different endotypes within ARDS: a hyper-inflammatory endotype and a hypo-inflammatory endotype. These endotypes had strikingly different (1) clinical characteristics, (2) biomarker profiles, (3) clinical outcomes, and (4) treatment responses. Most notably, significant endotype-specific treatment responses were identified within a clinical trial previously thought to be "negative." However, what remains unknown is whether these endotypes respond differently to other ARDS treatments and how to translate these promising findings to the bedside; likewise, the biology of the two endotypes remains incompletely understood. In the research proposed here, we will test the innovative central hypothesis that ARDS contains two distinct endotypes of disease, with different clinical and biologic characteristics and differing responses to therapy. We propose to test this hypothesis primarily within the framework of completed and ongoing NHLBI-funded ARDS randomized controlled trials, leveraging randomization to identify endotype-specific therapeutic responses. In Aim 1, we will use latent class analysis to identify ARDS endotypes in patients enrolled in two NHLBI-funded ARDS randomized controlled trials (the Statins for Acutely Injured Lungs (SAILS) clinical trial, already complete, and the Reevaluation Of Systemic Early neuromuscular blockade (ROSE) clinical trial, ongoing), in order to determine whether the endotypes respond differently to the therapies being tested in these trials. Also in Aim 1, we will test a practical, parsimonious model to identify ARDS endotypes in SAILS and ROSE, as well as in a more diverse ARDS cohort at UCSF. In Aim 2, we will identify specific differences in the biology of ARDS endotypes through analysis of novel candidate protein, lipid and metabolite biomarkers as well as high-throughput genomic sequencing, in the setting of the ROSE trial. Our research group is well-qualified to conduct this research by virtue of our expertise in pathogenesis-focused studies of human ARDS, our experience with the specific methods involved in the project, and our history of effective collaboration. Completion of these aims will have a high impact by identifying endotype-specific therapeutic responses, by developing practical approaches to endotype identification that can be directly translated to increase the efficiency and yield of future randomized controlled trials in ARDS, and by improving our understanding of the diverse biology of human ARDS, enhancing the likelihood that successful new therapeutics will be identified for each endotype.

 描述（申请人提供）：急性呼吸窘迫综合征（ARDS）是危重患者呼吸衰竭的常见原因，仅在美国每年就有近20万例病例，死亡率为25-40%，并且没有有效的药物治疗。我们最近在两项大型随机对照试验中鉴定并验证了 ARDS 两种不同亚表型（也称为“内型”）的存在。在对两个数据集的独立分析中，有强有力的证据表明 ARDS 中有两种不同的内型：高炎症内型和低炎症内型。这些内型具有显着不同的（1）临床特征，（2）生物标志物概况，（3）临床结果和（4）治疗反应。最值得注意的是，在一项先前被认为是“阴性”的临床试验中发现了显着的内型特异性治疗反应。然而，目前尚不清楚的是这些内型对其他 ARDS 治疗的反应是否不同，以及如何将这些有希望的发现转化为临床；同样，这两种内型的生物学仍然不完全清楚。在此提出的研究中，我们将测试创新的中心假设，即 ARDS 包含两种不同的疾病内型，具有不同的临床和生物学特征以及对治疗的不同反应。我们建议主要在已完成和正在进行的 NHLBI 资助的 ARDS 随机对照试验的框架内检验这一假设，利用随机化来确定内型特异性治疗反应。在目标 1 中，我们将使用潜在类别分析来识别参加两项 NHLBI 资助的 ARDS 随机对照试验（已完成的他汀类药物治疗肺急性损伤 (SAILS) 临床试验和正在进行的全身性早期神经肌肉阻滞 (ROSE) 临床试验）的患者的 ARDS 内型，以确定内型是否对这些试验中正在测试的疗法有不同的反应。 试验。同样在目标 1 中，我们将 测试一个实用、简约的模型来识别 SAILS 和 ROSE 以及 UCSF 更多样化的 ARDS 队列中的 ARDS 内型。在目标 2 中，我们将在 ROSE 试验中通过分析新型候选蛋白质、脂质和代谢物生物标志物以及高通量基因组测序来确定 ARDS 内型生物学的具体差异。我们的研究小组凭借我们在人类 ARDS 发病机制研究方面的专业知识、我们对项目所涉及的具体方法的经验以及我们有效合作的历史，完全有资格进行这项研究。 完成这些目标将 通过识别内型特异性治疗反应，开发实用的内型识别方法（可以直接转化为提高未来 ARDS 随机对照试验的效率和产量），并通过提高我们对人类 ARDS 多样化生物学的理解，提高为每种内型识别成功的新疗法的可能性，产生重大影响。

项目成果

Personalized medicine for ARDS: the 2035 research agenda.

• DOI: 10.1007/s00134-016-4331-6
• 发表时间: 2016-05
• 期刊: Intensive care medicine
• 影响因子: 38.9
• 作者: Beitler JR;Goligher EC;Schmidt M;Spieth PM;Zanella A;Martin-Loeches I;Calfee CS;Cavalcanti AB;ARDSne(x)t Investigators
• 通讯作者: ARDSne(x)t Investigators