? ? This submission describes a comprehensive 3 year training program in molecular biology and molecular genetics designed to provide Dr. Mark W. Hall with the tools to become an outstanding, independent physician-scientist. This training, combined with his K12 support to date, will give him the necessary skills to investigate the regulation of inflammation in pediatric sepsis. Dr. Hall completed his medical training in Pediatrics and Pediatric Critical Care Medicine at Children's Hospital of Pittsburgh and is now Assistant Professor at The Ohio State University / Columbus Children's Hospital. Dr. Mark D. Wewers, a leader in the field of innate immunobiology, will serve as Dr. Hall's sponsor and mentor. Dr. Hall has generated, with the help of Dr. Wewers and his laboratory staff, preliminary data from a cohort of 28 children with sepsis-induced organ failure. These data show that monocytes in survivors demonstrate a marked downregulation of mRNA for the protein pyrin compared to nonsurvivors. Pyrin is an important regulatory protein which is associated with inflammation in the disease familial Mediterranean fever. Pyrin and its gene MEFV have not been described in this context before. In the course of the award period we expect to: 1) understand the associations between monocyte MEFV mRNA expression, monocyte pyrin protein expression, and mortality in the setting of pediatric severe sepsis/septic shock, 2) understand the role of mRNA production versus mRNA degradation in determining MEFV mRNA levels in survivors versus nonsurvivors of pediatric severe sepsis/septic shock, and 3) test the hypothesis that reduction in monocyte MEFV mRNA expression in the setting of pediatric severe sepsis/septic shock is associated with the presence of a cis-acting polymorphism in the MEFV gene. In order to accomplish this final goal, and to provide Dr.Hall with a robust foundation in molecular genetics, he will spend time in training and experimentation in the laboratory of Dr. Wolfgang Sadee, a world expert in the area of regulatory genetic polymorphisms. The combined facilities of Columbus Children's Research Institute, the Davis Heart and Lung Research Institute, and The Ohio State University offer an unparalleled array of scientific resources and provide an ideal setting for Dr. Hall's academic and scientific development. ? ? (End of Abstract) ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL085525-03
Application #
7436321
Study Section
Special Emphasis Panel (ZHL1-CSR-O (M1))
Program Officer
Sarkar, Rita
Project Start
2006-07-24
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2010-06-30
Support Year
3
Fiscal Year
2008
Total Cost
$132,300
Indirect Cost
Name
Nationwide Children's Hospital
Department
Type
DUNS #
147212963
City
Columbus
State
OH
Country
United States
Zip Code
43205
Muszynski, Jennifer A; Nofziger, Ryan; Greathouse, Kristin et al. (2014) Innate immune function predicts the development of nosocomial infection in critically injured children. Shock 42:313-21
Muszynski, Jennifer A; Nofziger, Ryan; Greathouse, Kristin et al. (2014) Early adaptive immune suppression in children with septic shock: a prospective observational study. Crit Care 18:R145
Muszynski, Jennifer; Nateri, Jyotsna; Nicol, Kathleen et al. (2012) Immunosuppressive effects of red blood cells on monocytes are related to both storage time and storage solution. Transfusion 52:794-802
Marquardt, David J; Knatz, Nina L; Wetterau, Lawrence A et al. (2010) Failure to recover somatotropic axis function is associated with mortality from pediatric sepsis-induced multiple organ dysfunction syndrome. Pediatr Crit Care Med 11:18-25
Frazier, W Joshua; Hall, Mark W (2008) Immunoparalysis and adverse outcomes from critical illness. Pediatr Clin North Am 55:647-68, xi
Hall, Mark W; Gavrilin, Mikhail A; Knatz, Nina L et al. (2007) Monocyte mRNA phenotype and adverse outcomes from pediatric multiple organ dysfunction syndrome. Pediatr Res 62:597-603
Stoner, Michael J; Goodman, Deborah G; Cohen, Daniel M et al. (2007) Rapid fluid resuscitation in pediatrics: testing the American College of Critical Care Medicine guideline. Ann Emerg Med 50:601-7