Sepsis from Bedside to Bench to Bedside

总结/摘要 脓毒症仍然是成人和儿童的主要全球公共卫生问题。 多水平异质性是临床脓毒症的一个重要方面。在这方面有许多重大差距， 这种异质性直接导致了场。有必要更好地了解基本主机 脓毒症的反应，宿主衰竭的途径，并确定新的治疗靶点。有必要 了解发育年龄如何影响宿主对败血症的反应。有必要更多地 可靠地诊断脓毒症，包括早期病原体类别鉴定。需要有效预测 结果，并评估不良结果的风险如何变化，以应对当前和新的 治疗需要表征脓毒症的生物学和表型亚类（内型），并且 这些内型是如何对治疗产生不同反应的。简而言之，需要更好地说明 脓毒症的内在异质性，当照顾病人和进行研究时。因此 该提案的操作主题是通过基本的 和转化研究，采用从床边到实验室再到床边的方法。自2004年以来，我们领导了一个多- 中心研究，以创建，维护和发展一个强大的生物样本库， 儿童脓毒症的综合临床数据。使用全基因组的、以发现为导向的、转录组学的 研究作为基础，我们利用这个数据库进行各种发现， 转化潜能到床边。我们还利用这些数据将我们的研究扩展到成年人 与一些成人重症监护医学的研究人员合作。的 实验室积极从事涉及脓毒症的成人和小儿小鼠模型的基础研究，因此， 为我们的临床发现和观察提供了一个强大的测试平台。事实上，我们所有的现有和 基于实验室的计划研究工作是由我们的临床发现驱动的， 脓毒症儿童的生物学数据库。该实验室还支持NIGMS赞助的T32培训 该计划目前已存在24年，PI作为该计划的共同计划 导演我们提出了一个研究计划，包括全方位的翻译，从床边到 长凳到床边我们的临床和生物学数据库将被用来生成关于以下方面的假设： 脓毒症的病理生物学将在鼠模型中进行测试，并随后返回给 床旁，以推进脓毒症的诊断，预后和治疗方法。该框架提供了一个 为合作和培训奠定了坚实的基础，并将继续推动新的调查， 新的调查员一样。

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.