? The systemic inflammatory response syndrome (SIRS) is a clinical concept describing a generic host response to various disease processes. The incidence of SIRS is very high in critically ill children and most clinicians have experienced the disheartening scenario wherein some children with SIRS progress to septic shock, multiple organ dysfunction syndrome (MODS), and death, despite seemingly optimal treatment. One biologically plausible explanation to account for the development of septic shock/MODS/death in some children with SIRS, but not in others, may lie in the genetic background of the individual host. That is, differences in the host's genetic background can lead to a dysregulated proinflammatory and/or antiinflammatory response, in the setting of SIRS, which can subsequently lead to septic shock/MODS/death. The central hypothesis of this proposal is based on the premise that a true understanding of the individual host's response to SIRS is dependent on genome-level investigations and that microarray technology affords an effective means to test this hypothesis. Our preliminary data indicate that RNA derived from whole blood can be used for microarray analyses to effectively study the genomic response of children with SIRS and septic shock. An additional premise of this proposal is that significant developmental differences exist in the host response to SIRS to warrant this type of investigation in an exclusively pre-pubertal population. Accordingly, the central hypothesis of this proposal is that in children with SIRS, the progression to septic shock, MODS, and/or death is, in large part, dependent on the discoverable expression patterns and interactions of a defined set of multiple gene products. To test this hypothesis we will generate a national-level, ethnically diverse, genomic database of children with SIRS, septic shock, and/or MODS (Specific Aim I). This database will be used for studies designed to elucidate the host genomic response during SIRS, septic shock, and MODS using microarray technology (Specific Aim II). Data derived from Specific Aim II studies will be partially confirmed at the level of protein expression (Specific Aim III). These data will provide the fundamental foundation for a more comprehensive understanding of these important clinical problems and thereby potentially open up new areas of investigation that will allow for the development of more specific and effective therapeutic interventions. ? ?
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