? 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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM064619-01A2
Application #
6678250
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
2003-08-01
Project End
2006-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
1
Fiscal Year
2003
Total Cost
$607,077
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Wong, Hector R; Cvijanovich, Natalie Z; Anas, Nick et al. (2016) Pediatric Sepsis Biomarker Risk Model-II: Redefining the Pediatric Sepsis Biomarker Risk Model With Septic Shock Phenotype. Crit Care Med 44:2010-2017
Wong, Hector R; Walley, Keith R; Pettilä, Ville et al. (2015) Comparing the prognostic performance of ASSIST to interleukin-6 and procalcitonin in patients with severe sepsis or septic shock. Biomarkers 20:132-5
Wong, Hector R; Cvijanovich, Natalie Z; Anas, Nick et al. (2015) Prospective Testing and Redesign of a Temporal Biomarker Based Risk Model for Patients With Septic Shock: Implications for Septic Shock Biology. EBioMedicine 2:2087-93
Shibata, Audrey R Ogawa; Troster, Eduardo J; Wong, Hector R (2015) Glucocorticoid Receptor Expression in Peripheral WBCs of Critically Ill Children. Pediatr Crit Care Med 16:e132-40
Wong, Hector R; Cvijanovich, Natalie Z; Anas, Nick et al. (2015) A Multibiomarker-Based Model for Estimating the Risk of Septic Acute Kidney Injury. Crit Care Med 43:1646-53
Wong, Hector R; Cvijanovich, Natalie Z; Anas, Nick et al. (2015) Developing a clinically feasible personalized medicine approach to pediatric septic shock. Am J Respir Crit Care Med 191:309-15
Weiss, Scott L; Cvijanovich, Natalie Z; Allen, Geoffrey L et al. (2014) Differential expression of the nuclear-encoded mitochondrial transcriptome in pediatric septic shock. Crit Care 18:623
Sandquist, Mary; Wong, Hector R (2014) Biomarkers of sepsis and their potential value in diagnosis, prognosis and treatment. Expert Rev Clin Immunol 10:1349-56
Atkinson, Sarah J; Cvijanovich, Natalie Z; Thomas, Neal J et al. (2014) Corticosteroids and pediatric septic shock outcomes: a risk stratified analysis. PLoS One 9:e112702
Basu, Rajit K; Zappitelli, Michael; Brunner, Lori et al. (2014) Derivation and validation of the renal angina index to improve the prediction of acute kidney injury in critically ill children. Kidney Int 85:659-67

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