Brain and brain cell injury in newborn infants

The main objective of the proposed project is to investigate basic mechanisms for regulation of brain injury and brain cell death in newborn infants. Specifically, we propose to study these mechanisms as they relate to two common causes of brain damage in the newborn period, namely asphyxia (hypoxia and reoxygenation) and kernicterus (bilirubin encephalopathy). By applying studies in human neuronal cells and neuroblastoma cells in culture, different animal models, as well as clinical studies, we will app roach our objective from three different angles which together have greater potential for revealing mechanisms of injury. Our long-term goals are to improve the understanding and therapy of these important diseases in children. We are using 1) animal mod els a) a newborn piglet model for studying hypoxia- reoxygenation has been developed b) Newborn transgenic luciferase mice expressing NFkappa B, SOD, HIF, antioxidant capacity, or glutathion level, are studied during hypoxia-reoxygention with d ifferent oxygen concentrations. Inflammatory markers (cytokines, metalloproteinases), oxidative stress markers, gene expression, DNA injury, myocardial function are assessed by different methods. 2. Cell cultures a) Neuroblasomta cells are used to st udy molecular mechanisms for bilirubintoxicity b) Human neurons (NT2-N cells) are studied during energy deprivation (hypoxia-hypoglycemia) with different oxygen concentrations and in hypothermia and normothermia