Great Lakes Clinical Center of the Acute Respiratory Distress Syndrome, Pneumonia and Sepsis (APS) Consortium

项目总结 急性呼吸窘迫综合征(ARDS)、肺炎和脓毒症都是危及生命的疾病 其临床和生物学表现经常相互交织：肺炎是一种常见的 脓毒症，两者都是ARDS的易感条件。虽然在降低死亡率方面取得了进展 这些条件，其显著的异质性是限制治疗进展的一个主要因素。未来 干预措施必须通过更好地了解这些细胞的表型和内型 更好地设计临床试验的条件。拟建的ARDS五大湖临床中心， 肺炎和败血症(APS)联盟，由密歇根大学、亨利·福特医院、 辛辛那提大学和芝加哥大学将进行筛选、招生、收集数据和传输 在这项为期6年的5000名患者的观察性研究中，至少有1000名患者使用了生物胺类药物。 从指数住院和长期随访中获得的临床信息和生物标本 将收取12个月的费用。生物标本将包括血液、粪便、咽拭子和气管内。 吸气。标本将被运送到临床协调中心进行储存和未来分析。 我们提出的丰富的数据库将为研究人员提供无数的生物学机会 询问APS患者的异质性。这个数据库中包括调查人员有机会 研究临床疾病轨迹；血液细胞因子、DNA、RNA和代谢物；胃肠道和 呼吸微生物区系；以及胸部和身体成像。此外，我们还提出了两个独特数据收集方案 方法：CT图像的形态特征(严格表征身体成分)和 鼻上皮刮除(研究宿主在呼吸道内的转录反应)。 我们还提出了一项针对中心的研究，将阐明微生物组在发育中的作用， 轨迹，以及ARDS、肺炎和败血症的康复。微生物组是一个重要但不完整的 了解生物异质性的来源，代表了一个非常有希望的治疗目标。然而，我们缺乏 对其在这些情况下所扮演的角色的可操作的理解。我们的团队将利用上述 利用实地领先的方法专长收集样本和数据，以(目标1)通过以下方式确定途径 哪些肠道和呼吸道微生物区系参与了脓毒症、ARDS和 肺炎和(目标2)确定肠道微生物区系影响的微生物和代谢途径 在这些情况下的长期复苏。我们将使用尖端的分子技术来表征 微生物组及其代谢产物，我们将使用复杂的因果推理分析来研究 微生物组在临床结果中的中介作用。通过询问微生物群在生物多样性中的作用 这些条件的发展、轨迹和恢复，这个项目将促进 微生物群靶向疗法用于预防和治疗。

PROJECT SUMMARY The Acute Respiratory Distress Syndrome (ARDS), pneumonia and sepsis are life-threatening conditions whose clinical and biological manifestations are frequently interwoven: pneumonia is a common cause of sepsis, and both are predisposing conditions for ARDS. While progress has been made to reduce mortality in these conditions, their significant heterogeneity is a major factor limiting therapeutic progress. Future interventions must be informed by an improved understanding of phenotypes and endotypes within these conditions to better design clinical trials. The proposed Great Lakes Clinical Center (GLCC) of the ARDS, Pneumonia and Sepsis (APS) Consortium, consisting of the University of Michigan, Henry Ford Hospital, the University of Cincinnati, and the University of Chicago will screen, enroll, collect data and transport biospecimens on at least 1000 patients of this 5000-patient observational study over a 6-year period. Clinical information and biospecimens from the index hospitalization and from long-term follow up at 3, 6 and 12 months will be collected. Biospecimens will include blood, stool, pharyngeal swabs, and endotracheal aspirates. Specimens will be transported to the Clinical Coordinating Center for storage and future analysis. The rich database we propose will provide investigators with innumerable opportunities to biologically interrogate the heterogeneity of APS patients. Included in this database are opportunities for investigators to study clinical disease trajectories; blood cytokines, DNA, RNA, and metabolites; gastrointestinal and respiratory microbiota; and chest and body imaging. In addition, we propose two unique data collection approaches: morphometric characterization of CT images (to rigorously characterize body composition) and nasal epithelial curettage (to study the host transcriptomic response within the respiratory tract). We also propose a Center-specific study that will elucidate the role of the microbiome in the development, trajectory, and recovery of ARDS, pneumonia, and sepsis. The microbiome is an important yet incompletely understood source of biologic heterogeneity, and represents a highly promising treatment target. Yet we lack an actionable understanding of its role in these conditions. Our team will leverage the above-described specimen and data collection with field-leading methodological expertise to (Aim 1) identify the pathways by which gut and respiratory microbiota participate in the acute development and trajectory of sepsis, ARDS, and pneumonia and (Aim 2) determine the microbial and metabolic pathways by which gut microbiota influence long-term recovery after these conditions. We will use cutting-edge molecular techniques to characterize the microbiome and its metabolic products, and we will use sophisticated causal inference analyses to study the mediating role of the microbiome in clinical outcomes. By interrogating the role of the microbiome in the development, trajectory, and recovery of these conditions, this project will facilitate the development of microbiome-targeted therapies for their prevention and treatment.