Sepsis from Bedside to Bench to Bedside

摘要/摘要 败血症仍然是成人和儿童的一个主要的世界性公共卫生问题。 多个水平的异质性是临床败血症的一个重要方面。在这方面有许多重大的差距 场直接源于这种非均质性。有必要更好地了解基本主机 对败血症的反应，宿主失败的途径，以及确定新的治疗靶点。有必要 了解发育年龄如何影响宿主对脓毒症的反应。有必要采取更多 可靠地诊断脓毒症，包括早期病原体类别识别。有必要有效地预测 结果并评估不良结果的风险如何变化以应对当前和新的情况 治疗。有必要确定脓毒症的生物学和表型亚类(内型)的特征，以及 这些内型如何对治疗做出不同的反应。简而言之，有必要更好地解释 在护理病人和进行研究时，脓毒症的内在异质性。因此， 这项建议的操作主题是通过基础设施测量和了解脓毒症的异质性 以及使用床边到长凳再到床边的转化性研究。自2004年以来，我们领导了一项多项 中心研究，以创建、维护和发展强大的生物样本库，结合 脓毒症患儿的综合临床资料。使用全基因组的、面向发现的、转录的 以研究为基础，我们利用这个数据库进行了各种直接的发现 到床边的翻译潜力。我们还利用这些数据将我们的研究扩展到成年人 与一些以成人重症监护医学为基础的研究人员合作进行脓毒症治疗。这个 实验室积极参与成人和儿童败血症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试验场。事实上，我们目前和所有的 计划中的基于实验室的研究工作是由我们的临床和 败血症儿童生物数据库。该实验室还支持由NIGMS赞助的T32培训 目前正处于其存在的第24个年头的计划，国际和平倡议是该计划的联合计划 导演。我们提出了一项研究计划，涵盖从床边到 从长椅到床边。我们的临床和生物数据库将被用来生成关于以下方面的假设 败血症的病理生物学，将在小鼠模型中进行测试，然后带回 在床边推进脓毒症的诊断、预后和治疗方法。该框架提供了一种 为协作和培训奠定了坚实的基础，并将继续推动新的调查和 新的调查人员也一样。

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.