Sepsis from Bedside to Bench to Bedside

摘要/文摘

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.