Investigating Individual Susceptibility and Host Response in Acute Respiratory Distress Syndrome

本R35提案旨在支持一项专注于脓毒症相关急性呼吸窘迫综合征的强有力的翻译研究计划 呼吸窘迫综合征(ARDS)，解释个体风险并表征ARDS宿主免疫 以确定对特定治疗可能有不同反应的分子特征。2020年 SARS-CoV-2大流行使全球关注与脓毒症相关的ARDS及其缺乏 药物治疗，有超过40万美国人死亡。然而，即使在非大流行年份，ARDS 使所有重症监护病房入院人数的约10%复杂化，并影响了近20万美国人。 ARDS的死亡率一直顽固地超过30%。我利用我的翻译科学培训延长了我们的 了解影响ARDS风险和解决的个别因素和途径，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风险和死亡率的因素，以及 深刻描述东道主对新冠肺炎急性呼吸窘迫综合征的反应。我已经制定了一个研究计划，其中包括 对3500多名患有严重脓毒症的人类受试者进行了仔细的表型分析，并在 多个时间点，促进基因组和分子发现，同时为职业生涯做出贡献 发展多个NHLBI资助的以患者为导向的研究人员。在R35的支持下，Meyer 研究计划将集中在5个相辅相成的主题上，以改善患有和面临糖尿病风险的患者的健康 败血症相关性急性呼吸窘迫综合征。专题领域1集中于了解急性呼吸窘迫综合征和 ARDS死亡率，将利用全基因组关联、表达和蛋白质数量性状基因座 分析和遗传因果推断框架，以评估遗传风险并确定哪些RNA和 血浆性状可能是ARDS的致病中间产物。区域2使用深度来处理主机对ARDS的响应 免疫图谱和综合分析，以表征和对比对细菌和病毒的反应 败血症相关性急性呼吸窘迫综合征。在以后的几年里，无菌ARDS将被比作传染性ARDS，而 将检查激活的T细胞的贡献。区域3检查ARDS和非肺源性疾病之间的相互作用 脓毒症时的器官损伤，特别是急性肾损伤、精神错乱和认知损伤，以及休克和 循环功能障碍。我们将识别特定于单个器官的DNA、RNA、血浆和细胞学特征 出现故障，并在多个器官系统共享。R35计划还将催化两个新的领域 为迈耶实验室做调查。首先，我们将应用生物医学信息学技术来集成、可视化 并分析多个数据网络--临床、基因组、转录组、蛋白质组、代谢组和细胞学 -确定协调的反应模式及其与急性呼吸窘迫综合征结果的关联。我们还将检查 在恢复期间对ARDS的纵向宿主反应，测试预测或预防后ARDS的反应 重症监护综合征。对我们的研究项目的投资将促进预防和个性化 治疗急性呼吸窘迫综合征，同时促进肺部健康研究的培训和指导。

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.