Maintenance of the phosphorylation state of the brain, which is essential for cellular viability and normal brain function, requires an unimpeded supply of glucose and oxygen. Under conditions of oxygen insufficiency, changes in certain modulators (such as ATP, G-6-P, G-1,6-DP) may enhance the rate of glucose utilization by their action on key enzyme in the respective metabolic pathways. In addition, with development in early life, the proportion of glucose oxidized to carbon dioxide and water in the citric acid cycle to that metabolized to pyruvate and lactate in the glycolytic and hexosemonophosphate pathways changes dramatically. The primary objective of this project is to investigate how hypoxia impacts upon the mechanisms which regulate brain glucose metabolism during development. This project will center on the enzymatic control of the respective fluxes through hexokinase, glucose-6-phosphate dehydrogenase, and alpha-ketoglutarate dehydrogenase complex in the neocortex of immature and mature rats exposed to acute and chronic periods of hypoxia. These enzymes are situated at important flux-controlling points in their respective metabolic pathways, namely, the glycolytic pathway (hexokinase), the hexosemonophosphate pathway (glucose-6-phosphate dehydrogenase), and the citric acid cycle (alpha-ketoglutarate dehydrogenase complex). Our general hypothesis is that differences in the regulation of specific metabolic pathways contributing to the maintenance of the phosphorylation state are the result of changes in key enzymatic activities or their modulators. Using in-vivo and in-vitro NMR Spectroscopy, Magnetic Resonance Imaging and enzymatic assays in=vitro, we will examine not only the maturation of glucose flux, the mechanisms involved and the effect of hypoxia on these but also the importance and the role that such fluxes play in nerve cell function and survival potential in the immature and mature subject. The uniqueness of this project derives from 1) the approach of combining in vivo and in-vitro techniques, 2) the track record of the investigators in addressing questions using NMR, and 3) the fact that this project complements others within the Program regarding issues on intermediary metabolism and mechanisms of survival during hypoxic stress.

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