Oxygen deficiency in babies results in dire consequences of stillbirths, newborn epilepsy, cerebral palsy, mental retardation and learning difficulties later in life. The emotional and monetary costs of these consequences to society are enormous. The long-term objectives are to find new ways of diagnosing and treating brain damage in a baby resulting from oxygen deficiency in the mother's womb. A versatile animal model in pregnant rabbits was developed that allows the study of different ages before birth and manipulation of different types of oxygen deficiency. Initial studies show that certain manipulations can result in baby rabbits behaving similarly to cerebral palsy patients. The proposal aims to study critical causes of baby brain injury from oxygen deficiency, such as production of a certain type of free radicals, called reactive nitrogen species. These are highly reactive chemicals originating from nitric oxide and superoxide. The main question asked in this proposal is whether the enzymes that produce nitric oxide or superoxide, called nitric oxide synthase and xanthine oxidase, are responsible for the injury to one specific brain cell type, neurons, in oxygen deficiency.
The specific aims are: 1) Determine the modality of hypoxia-ischemia and gestational age that causes neurobehavioral changes mimicking cerebral palsy, 2) Determine the role of reactive nitrogen species in fetal neuronal injury following hypoxia-ischemia at different gestational ages, and 3) Determine the role of neuronal nitric oxide synthase and xanthine oxidase in reactive nitrogen species-mediated neuronal injury caused by fetal hypoxia- ischemia. New innovations proposed are the study of brain cell fate using tissue culture techniques and flow cytometry, use of behavior testing in rabbit babies, the study of live brain structures and state of neurons by magnetic resonance imaging, and new treatments for the reactive nitrogen species produced. These studies will result in a better understanding of the mechanisms of brain injury in babies and may result in the development of better diagnostic tools and treatments for babies at risk for brain injury from oxygen deficiency.
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