Recent studies suggest that the capacity for the brain to use multiple substrates such as 3-hydroxybutyrate, acetoacetate and glutamine, in addition to glucose, for energy and lipid synthesis is critical for normal development of mammalian nervous tissue. As a result, new hypothses and research strategies related to studies of neurobiological mechanisms have been developed which form the basis of this program project grant. These approaches offer novel perspectives for neurobiology and guide out attempts to understand and ameliorate the multiple causes of mental retardation. The present group of studies represents a multi-disciplinary program directed toward identifying the factors that regulate the utilization of different substrates by nervous under a variety of conditions. Several models will be used to determine whether alterations in the utilization of these substrates is correlated with aberrant development of neural tissue. Incorporated into these new approaches is the consideration that the synthesis and regulation of neurotransmitters, as well as structural components, are directly related to the regulation of intermediary metabolism of the various cells. One project will investigate characteristics of the metabolism of ketone bodies (acetoacetate and 3-hydroxybutyrate) and glutamine in the brain and the factors which determine their preferential use for lipid synthesis and/or oxidation by specific cell types. A second project examines the metabolic fate of glycerol and its possible role as an antagonist of catecholamine metabolism. A third project determines the metabolic events associated with the growth and regeneration of adrenergic neurons using the superior cervical ganglion as a model. The fourth project will establish methods for obtaining homogenous cell populations from a single animal species and delineate the unique biochemical characteristics of each cell type. We anticipate that the comprehensive approach taken in these studies will shed light on the complex metabolic alteration underlying mental retardation.
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