Investigating Individual Susceptibility and Host Response in Acute Respiratory Distress Syndrome

这项R35提案旨在支持一项强大的转化研究计划，重点关注脓毒症相关的急性 呼吸窘迫综合征（ARDS），解释个体风险和表征ARDS宿主免疫 为了鉴定可能对特定治疗有不同反应的分子性状，2020年 和SARS-CoV-2大流行使全球关注脓毒症相关的ARDS及其缺乏 药物治疗，超过40万美国人死亡。然而，即使在非大流行的年份， 使大约10%的重症监护病房入院复杂化，影响了近20万美国人。 ARDS的死亡率一直超过30%。我用我的翻译科学训练来扩展我们的 了解影响ARDS风险和解决的个体因素和途径，使用基因组工具， 推断哪些与ARDS相关的血浆标志物可能是导致ARDS风险和死亡的原因， 深入描述宿主对COVID-19 ARDS的反应。我建立了一个研究项目， 对超过3，500名患有败血症的危重人类受试者进行了仔细的表型分析，并在 多个时间点，以促进基因组和分子发现，同时有助于职业生涯 多个NHLBI资助的面向患者的研究人员的发展。在R35的支持下， 研究计划将集中在5个互补的主题，以改善患者的健康和风险， 脓毒症相关的ARDS。主题领域1集中于理解ARDS的个体风险， ARDS死亡率，将利用全基因组关联、表达和蛋白质数量性状位点 分析和遗传因果推理框架，以评估遗传风险，并确定哪些RNA和 血浆性状可能是ARDS发病的中间环节。区域2使用深呼吸， 免疫分析和综合分析，以表征和对比对细菌和病毒的反应 脓毒症相关的ARDS。在以后的几年里，无菌性ARDS将与感染性ARDS进行比较， 将检查活化的T细胞的贡献。区域3检查了ARDS和非肺 脓毒症期间的器官损伤，特别是急性肾损伤、谵妄和认知损伤，以及休克， 循环功能障碍我们将鉴定DNA、RNA、血浆和细胞计数特征， 失败并在多个器官系统中共享。R35计划还将催化两个新领域， 迈耶实验室的调查首先，我们将应用生物医学信息学技术来整合，可视化， 并分析多个数据网络-临床、基因组、转录组、蛋白质组、代谢组和细胞计数 - 以确定协调的反应模式及其与ARDS结局的关系。我们亦会研究 在恢复过程中对ARDS的纵向宿主反应，测试预测或保护后 重症监护综合征对我们研究项目的投资将促进预防和个性化 在肺健康研究方面促进培训和指导的同时，

This R35 proposal is to support a robust translational research program focused on sepsis-associated acute respiratory distress syndrome (ARDS), explaining individual risk and characterizing the ARDS host immune response in order to identify molecular traits that may respond differently to specific therapy. The year 2020 and the SARS-CoV-2 pandemic placed a global spotlight on sepsis-associated ARDS and its lack of pharmacologic treatments, with over 400,000 American deaths. Even in non-pandemic years, however, ARDS complicates approximately 10% of all intensive care unit admissions and impacts close to 200,000 Americans. Mortality for ARDS has stubbornly exceeded 30%. I have used my translational science training to extend our knowledge of individual factors and pathways that influence ARDS risk and resolution, use genomic tools to infer which ARDS-associated plasma markers may be causal contributors to ARDS risk and mortality, and deeply characterize the host response to COVID-19 ARDS. I have grown a research program that includes a carefully phenotyped cohort of over 3,500 human subjects critically ill with sepsis, and curated biosamples at multiple timepoints to facilitate genomic and molecular discoveries, while contributing to the career development of multiple NHLBI-funded patient-oriented researchers. With the support of the R35, the Meyer research program will focus on 5 complementary themes to improve the health of patients with and at risk for sepsis-associated ARDS. Thematic area 1 concentrates upon understanding individual risk for ARDS and ARDS mortality, which will utilize whole genome association, expression and protein quantitative trait locus analysis, and genetic causal inference frameworks to evaluate inherited risks and identify which RNA and plasma traits may be causal intermediates in ARDS. Area 2 addresses the host response to ARDS, using deep immune profiling and integrated analyses to characterize and contrast the response to bacterial and viral sepsis-associated ARDS. In later years, sterile ARDS will be compared to infectious ARDS, and the contribution of activated T cells will be examined. Area 3 examines the interplay between ARDS and non-lung organ injuries during sepsis, particularly acute kidney injury, delirium and cognitive injury, and shock and circulatory dysfunction. We will identify DNA, RNA, plasma, and cytometric features specific to individual organ failures and shared across multiple organ systems. The R35 program will also catalyze two new areas of investigation for the Meyer lab. First, we will apply biomedical informatics techniques to integrate, visualize, and analyze multiple data networks – clinical, genomic, transcriptomic, proteomic, metabolomic, and cytometric – to identify coordinated patterns of response and their association with ARDS outcome. We will also examine the longitudinal host response to ARDS during recovery, testing for responses that predict or protect from post- intensive care syndrome. An investment in our research program will advance the prevention and personalized treatment of ARDS while fostering training and mentorship in lung health research.