Investigating Individual Susceptibility and Host Response in Acute Respiratory Distress Syndrome

研究急性呼吸窘迫综合征的个体易感性和宿主反应

• 批准号: 10353311
• 负责人: Nuala Jennings Meyer
• 金额: $ 97.5万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-19 至 2029-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10353311
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Acute Respiratory Distress Syndrome; Address; Admission activity; American; Area; Bacteremia; COVID-19 pandemic; COVID-19/ARDS; Cessation of life; Clinical; Cognitive; Cohort Studies; Critical Illness; DNA; Data; Delirium; Fostering; Functional disorder; Funding; Genetic; Genomics; Goals; Health; Human; Immune; Immune response; Individual; Inherited; Injury; Intensive Care; Intensive Care Units; Investigation; Investments; Knowledge; Medicine; Mentorship; Molecular; National Heart, Lung, and Blood Institute; Organ failure; Outcome; Pathway interactions; Patients; Pattern; Pharmacological Treatment; Phenotype; Plasma; Predisposition; Prevention; Proteins; Proteomics; Quantitative Trait Loci; RNA; Recovery; Research; Research Personnel; Resolution; Risk; Sepsis; Shock; Sterility; Syndrome; T-Lymphocyte; Techniques; Testing; Time; Training; Translational Research; Viremia; biomedical informatics; body system; career development; cohort; genomic tools; human subject; improved; individualized medicine; lung health; metabolomics; mortality; organ injury; patient oriented; personalized medicine; predicting response; programs; response; sepsis induced ARDS; trait; transcriptomics; translational research program; whole genome

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.

该 R35 提案旨在支持一项强有力的转化研究计划，重点关注脓毒症相关急性疾病 呼吸窘迫综合征 (ARDS)，解释个体风险并描述 ARDS 宿主免疫特征 反应，以确定可能对特定治疗有不同反应的分子特征。 2020年 SARS-CoV-2 大流行使全球关注脓毒症相关 ARDS 及其缺乏 药物治疗，导致超过 40 万美国人死亡。然而，即使在非大流行年份，ARDS 约 10% 的重症监护病房入院患者因此变得复杂，并影响了近 20 万美国人。 ARDS 的死亡率一直超过 30%。我利用我的转化科学培训来扩展我们的 了解影响 ARDS 风险和解决方案的个体因素和途径，使用基因组工具 推断哪些 ARDS 相关血浆标志物可能是 ARDS 风险和死亡率的因果因素，以及 深入描述宿主对 COVID-19 ARDS 的反应。我制定了一个研究计划，其中包括 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 多个时间点促进基因组和分子发现，同时为职业生涯做出贡献 培养多名 NHLBI 资助的以患者为中心的研究人员。在 R35 的支持下，Meyer 研究计划将重点关注 5 个补充主题，以改善患有该疾病和有风险的患者的健康 败血症相关的ARDS。主题领域 1 侧重于了解 ARDS 的个人风险和 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 分析和遗传因果推理框架来评估遗传风险并确定哪些 RNA 和 血浆特征可能是 ARDS 的因果中间体。区域 2 使用深度解决主机对 ARDS 的响应 免疫分析和综合分析来表征和对比对细菌和病毒的反应 败血症相关的ARDS。在以后的几年中，无菌性ARDS将与传染性ARDS进行比较，并且 将检查激活的 T 细胞的贡献。区域 3 检查 ARDS 和非肺疾病之间的相互作用 败血症期间的器官损伤，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、血浆和细胞计数特征 失败并跨多个器官系统共享。 R35 计划还将促进两个新领域的发展： 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 – 确定协调的反应模式及其与 ARDS 结果的关联。我们还将检查 恢复期间宿主对 ARDS 的纵向反应，测试预测或预防后遗症的反应 重症监护综合症。对我们研究计划的投资将促进预防和个性化 治疗 ARDS，同时促进肺部健康研究的培训和指导。