? ? 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) ? ? ?
