Sepsis from Bedside to Bench to Bedside

脓毒症从床边到长凳到床边

• 批准号: 9898384
• 负责人: HECTOR R. WONG
• 金额: $ 50.59万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898384
• 关键词: Adolescent; Adult; Age; Back; Basic Science; Biological; Biological databases; Child; Childhood; Clinical; Clinical Data; Clinical Research; Collaborations; Critical Care; Data; Databases; Development; Diagnosis; Diagnostic; Failure; Foundations; Heterogeneity; Immune response; Investigation; Laboratories; Measures; Medicine; Multicenter Studies; National Institute of General Medical Sciences; Outcome; Pathway interactions; Patient Care; Phenotype; Public Health; Research; Research Personnel; Risk; Sampling; Sepsis; Testing; Training; Training Programs; Translational Research; Translations; base; bench to bedside; catalyst; clinical database; clinically relevant; data warehouse; genome-wide; mouse model; new therapeutic target; novel therapeutics; outcome prediction; pathogen; prognostic; programs; repository; response; stem; transcriptomics; translational study; validation studies

SUMMARY/ABSTRACT Sepsis continues to be a major, worldwide public health problem in both adults and children. Heterogeneity at multiple levels is an important aspect of clinical sepsis. There are many major gaps in the field directly stemming from this heterogeneity. There is a need to better understand the fundamental host responses to sepsis, the pathways to host failure, and to identify novel therapeutic targets. There is a need to understand how developmental age influences the host response to sepsis. There is a need to more reliably diagnose sepsis, including earlier pathogen class identification. There is a need to effectively predict outcomes and assess how the risks for bad outcomes change in response to both current and novel therapies. There is a need to characterize biological and phenotypic subclasses (endotypes) of sepsis, and how those endotypes differentially respond to therapies. In short, there is a need to better account for the intrinsic heterogeneity of sepsis when caring for patients and when conducting research. Accordingly, the operational themes of this proposal are measuring and understanding sepsis heterogeneity through basic and translational research using a bedside to bench to bedside approach. Since 2004, we have led a multi- center study to create, maintain, and grow a robust repository of biological samples combined with comprehensive clinical data for children with sepsis. Using genome-wide, discovery-oriented, transcriptomic studies as the foundation, we have leveraged this database for various discoveries having direct translational potential to the bedside. We have also leveraged these data to expand our studies to adults with sepsis in collaboration with a number of investigators based in adult critical care medicine. The laboratory is actively engaged in basic research involving adult and pediatric murine models of sepsis, thus providing a robust testing ground for our clinical discoveries and observations. In fact, all of our current and planned laboratory-based research efforts are driven by discoveries generated from our clinical and biological database of children with sepsis. The laboratory also supports a NIGMS-sponsored T32 training program that is currently in its 24th year of existence, and for which the PI serves as the Co-Program Director. We propose a program of research that encompasses the full range of translation, from bedside to bench to bedside. Our clinical and biological data repository will be leveraged to generate hypotheses about the pathobiology of sepsis that will be tested in murine models and subsequently brought back to the bedside to advance diagnostic, prognostic, and treatment approaches in sepsis. This framework provides a strong foundation for collaboration and training, and will continue to be a catalyst for new investigations and new investigators alike.

摘要/摘要 在成人和儿童中，败血症仍然是全球的主要公共卫生问题。 多级别的异质性是临床败血症的重要方面。有很多主要差距 场直接源于这种异质性。有必要更好地了解基本主持人 对败血症的反应，宿主失败的途径以及确定新颖的治疗靶标。有需要 了解发育年龄如何影响宿主对败血症的反应。需要更多 可靠地诊断败血症，包括早期的病原体类识别。有必要有效预测 结果并评估不良结果的风险如何响应当前和新颖 疗法。有必要表征败血症的生物学和表型亚类（内型），以及 这些内型如何差异地对疗法做出反应。简而言之，有必要更好地说明 照顾患者和进行研究时，败血症的固有异质性。因此， 该提案的操作主题是通过基本来衡量和理解败血症异质性 以及使用床边进行床头的翻译研究。自2004年以来，我们领导了 中心研究以创建，维护和种植强大的生物样品存储库 败血症儿童的综合临床数据。使用全基因组，面向发现的转录组 作为基础的研究，我们利用该数据库进行了各种直接发现 床边的翻译潜力。我们还利用这些数据将研究扩展到成年人 与败血症与许多成人重症监护医学的研究人员合作。这 实验室积极从事涉及败血症的成人和儿科鼠模型的基础研究，因此 为我们的临床发现和观察提供了强大的测试场。实际上，我们所有的当前和 计划的基于实验室的研究工作是由我们的临床和 败血症儿童的生物数据库。该实验室还支持NIGMS赞助的T32培训 目前处于生存的24年的计划，PI作为共同计划 导演。我们提出了一项研究计划，涵盖了从床头到 长凳到床边。我们的临床和生物数据存储库将被利用，以产生有关的假设 败血症的病理生物学将在鼠模型中进行测试，然后带回 在脓毒症中推进诊断，预后和治疗方法的床边。这个框架提供了 协作和培训的强大基础，并将继续成为新调查的催化剂， 新的调查人员。