Hypoxic-ischemic brain injury to fetuses results in stillbirths, neonatal death, cerebral palsy, mental retardation or learning disabilities. Hypoxia-ischemia in the fetus results in one of the highest indexes of burden of disease, if one considers mortality, lost years of life, loss of years of healthy life or the lifetime burden of caretakers. The long-term goal of our research group is to understand the mechanisms of brain injury and develop interventions that will ameliorate hypoxia-ischemic fetal brain injury. We have developed a clinically relevant model of acute placental insufficiency that results in a cerebral palsy phenotype in the newborn animals. Magnetic resonance imaging during the acute insult and the early reperfusion period predicts which animals will develop the cerebral palsy phenotype. This timing implicates oxidative stress and mitochondrial dysfunction as candidates for deciding cellular fate. One of the primary enzymes that removes superoxide one of the major sources of oxidative stress, is manganese superoxide dismutase which is found in the mitochondria The hypothesis is the level of mitochondrial dysfunction and superoxide accumulation are the initiators of brain cell injury. The level of manganese superoxide dismutase is crucial to for the ability of the mitochondrion to remove the superoxide before is causes damage. This proposal uses the predictive value of MRI and our animal model of cerebral palsy to look at mitochondrial dysfunction and superoxide at 30 minutes, 2 hours and 6 hours of reperfusion. It utilizes a unique approach to look directly at the brain cells in vitro after the insult before repair or ongoing injury cascades occur. It uses the unique tools of flow cytometry and cell sorting combined with molecular biology techniques. It will test antioxidant therapies in the clinical relevant animal model and if these are successful could lead to treatments that could decrease brain injury to newborn babies and decrease cerebral palsy, mental retardation or learning disabilities. Public Health Relevance: Lack of oxygen to the brain either before or just after a baby is born can result in severe brain damage or death of the baby. If the child survives one of the results can be cerebral palsy. This proposal aims to understand how lack of oxygen causes brain damage and will test potential treatments that could decrease the severity of brain damage and prevent the child from developing cerebral palsy. ? ? ?
