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

 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，死亡率为25%-40%，并且没有有效的药物治疗。我们最近在两个大型随机对照试验中确认并验证了ARDS的两种不同的亚型(也称为“内型”)的存在。在对这两个数据集的独立分析中，有强有力的证据表明，ARDS有两种不同的内型：高炎性内型和低炎性内型。这些内型具有显著不同的(1)临床特征、(2)生物标志物特征、(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，发现了显著的内型特异性治疗反应。然而，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床边；同样，这两种内型的生物学仍未完全了解。在这里提出的研究中，我们将检验创新的中心假设，即ARDS包含两种不同的内在型疾病，具有不同的临床和生物学特征，对治疗的反应也不同。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测试这一假设，利用随机化来确定内型特异性的治疗反应。在目标1中，我们将使用潜在类别分析来确定参加两项NHLBI资助的ARDS随机对照试验(他汀类药物治疗急性损伤肺(SAILS)临床试验已经完成，以及全身早期神经肌肉阻断(ROSE)临床试验正在进行中)的患者的ARDS内型，以确定内型对这些试验中测试的治疗是否有不同的反应。同样在目标1中，我们将 测试一个实用、简约的模型，以确定风帆和玫瑰以及加州大学旧金山分校更多样化的ARDS队列中的ARDS内型。在目标2中，我们将在ROSE试验的背景下，通过分析新的候选蛋白质、脂质和代谢物生物标记物以及高通量基因组测序，识别ARDS内型生物学上的特定差异。凭借我们在人类ARDS发病机制研究方面的专业知识、我们在该项目涉及的特定方法方面的经验以及我们有效合作的历史，我们的研究团队完全有资格进行这项研究。完成这些目标将 通过确定内型特异性的治疗反应，通过开发可直接转化为提高未来ARDS随机对照试验的效率和产量的实用方法，以及通过提高我们对人类ARDS的多样化生物学的理解，增加针对每种内型确定成功的新疗法的可能性，我们将产生很大的影响。

 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.