Supplement for MIRA award_Wong_2021

摘要(原始应用程序) 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。异构性在 多水平是临床脓毒症的一个重要方面。这一领域直接存在许多重大空白。 源于这种异质性。有必要更好地了解宿主对 败血症，宿主衰竭的途径，并确定新的治疗靶点。有必要理解 发育年龄如何影响宿主对败血症的反应。需要更可靠地诊断 脓毒症，包括早期病原体分类鉴定。有必要有效地预测结果和 评估不良结果的风险如何在当前和新的治疗方法下发生变化。有一个 需要确定脓毒症的生物学和表型亚类(内型)，以及这些内型是如何 对治疗有不同的反应。简而言之，有必要更好地解释 在护理病人和进行研究时出现败血症。因此，这一行动的主题是 建议通过基础研究和翻译研究测量和了解脓毒症的异质性 使用床边到长凳再到床边的方法。自2004年以来，我们领导了一项多中心研究， 维护和发展强大的生物样本库，并结合全面的临床数据 患有败血症的儿童。以全基因组、以发现为导向的转录组研究为基础，我们 利用这个数据库进行了各种发现，这些发现对床边有直接的翻译潜力。我们 我还利用这些数据，与许多 以成人重症监护医学为基础的研究人员。该实验室积极从事基础研究。 包括成人和儿童败血症的小鼠模型，从而为我们的临床提供了一个强有力的试验场 发现和观察。事实上，我们目前和计划的所有基于实验室的研究工作都是 由我们的败血症儿童临床和生物学数据库产生的发现推动。这个 实验室还支持NIGMS赞助的T32培训计划，该计划目前已进入存在的第24个年头， 并且PI担任该项目的联合项目总监。我们提出了一项研究计划，包括 全方位的翻译，从床边到长凳再到床边。我们的临床和生物数据库将是 用来产生关于脓毒症的病理生物学假说，这些假说将在小鼠模型和 随后被带回床边，以改进诊断、预后和治疗方法 败血症。这一框架为协作和培训提供了坚实的基础，并将继续成为 对于新的调查和新的调查人员来说都是催化剂。

ABSTRACT (original application) 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.