IGF I THERAPY IN NEONATAL HYPOXIC ISCHEMIC BRAIN INJURY

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Cerebral hypoxia-ischemia remains a leading cause of severe brain damage in newborns. The molecular mechanisms of the neuronal injury and subsequent repair processes are not well understood but may involve persistent disruption of cellular energy homeostasis, as evidenced by alterations in oxidative phosphorylation, nutrient uptake and utilization. Insulin-like growth factor I (IGF-I) is an anabolic pleiotrophic factor required by all cell types in the developing brain for optimal proliferation, differentiation, and survival. Soon after hypoxic-ischemic insult to newborn rat brain, IGF-I gene expression is decreased in vulnerable neurons and is activated in reactive astrocytes only after 2-3 days. Intraventricular infusion of IGF-I two hours following the hypoxic- ischemic insult reduces the neuronal loss in both the adult rat and the late gestation fetal lamb. The mechanism of this IGF-I mediated neuroprotection, however, is not understood. We hypothesize that IGF-I prevents impending neuronal injury during the early post-ischemic phase by regulating cellular energy metabolism. The specific aims of this proposal are: 1) to examine both the expression and the cellular specificity of an exogenous IGF-I gene delivered by virus vectors; 2) to determine the extent to which IGF-I can regulate certain aspects of normal rat brain cellular metabolism, such as substrate uptake, protein synthesis and neuronal activity; and 3) to determine whether hypoxia-ischemia-induced neuronal damage can be ~meliorated as a result of enhanced IGF-I gene expression. Hence, we will first study the functional role of IGF-I at the molecular and cellular levels by directly transferring the IGF-I gene into neonatal rat brain using virus vectors. Overexpressing IGF-I in vivo would make it more available to the type I IGF receptor residing on all brain cells and limits receptor inhibition by IGF binding proteins and protease degradation. We will verify the transduction of the exogenous IGF-I gene with in situ hybridization and immunocytochemistry. Functionally, the alterations in cellular metabolic levels resulting from IGF-I overexpression will be investigated in the brains of both the normal rat and in rat during and after hypoxia-ischemia-induced injury. Should these studies produce encouraging results, we will have provided strong evidence in establishing IGF-I as one important intervention in hypoxia-ischemia- induced brain damage in neonates.