Pediatric septic shock continues to be a major public health problem in the United States. The systemic inflammatory response syndrome (SIRS) is biologically linked to septic shock and reflects a generic inflammatory state present in many critically ill children. We are studying this clincial problem by establishing a national-level genomic data bank of children with SIRS and septic shock, and conducting of genome-wide scans through the application of microarray technology. Over the last 2.5 years we have found: a) the existence of clinically distinct subgroups of critically ill children with SIRS or septic shock having distinct gene expression profiles;b) the existence of major relevant gene networks within these subgroups of patients;c) differential expression of these networks between the patient subgroups;d) potential biomarkers for poor outcome (death) in pediatric septic shock;and e) the existence of one major gene network that is largely under expressed in non-survivors of pediatric septic shock. These findings have led to new hypotheses that are currently being taken back to the laboratory and bedside for validation. We now seek to build on the success of this program by continuing to build the data bank and conducting further microarray-based experiments. While we seek to continue discovery-oriented data mining with a larger data set, the main focus of the program will now be to address several prospectively designed questions.
In Specific Aim 1 we will test the hypothesis that subgroups of patients with SIRS and septic shock exist by applying bioinformatic approaches that make use of a trainining data set and a validation data set.
In Specific Aim 2 we will test the hypothesis that development (modeled by groups of children within specific age ranges) and pathogen- associated factors strongly influence the genome level expression profiles of children with SIRS and septic shock.
In Specific Aim 3 we will test the hypothesis that the genome-level expression profiles of children with SIRS and septic shock can be more accurately defined by analyzing RNA from specific white blood cell subpopulations. The data generated through this program will serve to substantially enhance our genome level understaning of SIRS and septic shock and provide the foundation for novel hypotheses, diagnostic approaches, and therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM064619-06
Application #
7681488
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Dunsmore, Sarah
Project Start
2001-12-01
Project End
2011-08-31
Budget Start
2009-09-01
Budget End
2011-08-31
Support Year
6
Fiscal Year
2009
Total Cost
$334,103
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
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
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
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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