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: 10686805
• 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/10686805
• 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-Cell Activation; Techniques; Testing; Time; Training; Translational Research; Viremia; Visualization; 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的建议是支持一项针对败血症相关的急性的强大翻译研究计划 呼吸窘迫综合征（ARDS），解释个人风险并表征ARDS宿主免疫 为了确定可能对特定疗法反应不同的分子特征的反应。 2020年 SARS-COV-2大流行使全球焦点置于与败血症相关的ARDS上及其缺乏 药物治疗，有超过40万名美国死亡。然而，即使在非大流行的几年中， 在所有重症监护病房的入院术中，大约有10％的人复杂化，并影响近20万美国人。 ARDS的死亡率固执超过30％。我已经使用了翻译科学培训来扩展我们的 了解影响ARDS风险和解决方案的个人因素和途径，使用基因组工具来 推断哪些与ARDS相关的血浆标记可能是导致ARDS风险和死亡率的因果关系，以及 深层表征了对Covid-19 Ards的宿主响应。我已经成长了一个研究计划，其中包括 仔细的表型人群与败血症患有3500多名人类受试者，并在策划的生物样本处 多个时间点促进基因组和分子发现，同时促进职业 开发多个由NHLBI资助的以患者为导向的研究人员。在R35的支持下 研究计划将重点介绍5个完整主题，以改善患有和有风险的患者的健康 败血症相关的弧。主题区域1集中于了解个人ARD的风险和 ARDS死亡率，它将利用整个基因组关联，表达和蛋白质定量特质基因座 分析和遗传因果推理框架，以评估遗传的风险并确定哪种RNA和哪个RNA 血浆特征可能是ARDS中的因果中间体。区域2使用深度解决主机对ARD的反应 免疫分析和综合分析以表征和对比细菌的反应和病毒 败血症相关的弧。在后来的几年中，将将无菌弧度与感染性弧度进行比较， 将检查活化的T细胞的贡献。区域3考试ARDS与非肺部之间的相互作用 败血症期间的器官损伤，尤其是急性肾脏损伤，del妄和认知损伤，以及冲击和 循环功能障碍。我们将识别DNA，RNA，等离子体和细胞仪特征特定于单个器官 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，蛋白质组学，代谢组学和细胞学仪 - 确定响应的协调模式及其与ARDS结果的关联。我们还将检查 恢复过程中对ARDS的纵向宿主反应，测试预测或保护后的反应 重症监护综合征。对我们的研究计划的投资将提高预防和个性化 在培养肺部健康研究中培养训练和心态的同时，对ARDS进行治疗。