BRAIN METABOLISM AND FUNCTION IN HYPOXIA

缺氧时的脑代谢和功能

• 批准号: 6410494
• 负责人: KEVIN L BEHAR
• 金额: $ 18.52万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-12-01 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6410494
• 关键词: age difference; brain metabolism; cellular pathology; cellular respiration; cerebral ischemia /hypoxia; developmental neurobiology; electrophysiology; glucose metabolism; glutamates; glutamine; hexokinase; laboratory rat; neurotransmitter transport; nuclear magnetic resonance spectroscopy

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.

维持大脑的磷酸化状态，这是必不可少的 对于细胞活力和正常的大脑功能，需要不受阻碍 葡萄糖和氧气的供应。 在氧气不足的情况下 某些调节剂的变化（例如ATP，G-6-P，G-1,6-DP）可能会增强 葡萄糖利用速率通过其对关键酶的作用 各自的代谢途径。 此外，随着早期的发展 生命，氧化为二氧化碳和水中的葡萄糖的比例 柠檬酸循环为丙酮酸代谢和乳酸 糖酵解和六磷酸磷酸盐途径发生巨大变化。 这 该项目的主要目的是研究缺氧的影响如何 关于调节脑葡萄糖代谢的机制 发展。 该项目将以酶促控制为中心 通过己糖激酶，葡萄糖-6-磷酸脱氢酶的各自通量， 和新皮层中的α-酮戊二酸脱氢酶复合物 未成熟和成熟的大鼠暴露于缺氧的急性和慢性时期。 这些酶位于其重要的磁通控制点 各自的代谢途径，即糖酵解途径 （己糖酶），六磷酸途径（葡萄糖-6-磷酸盐 脱氢酶）和柠檬酸循环（α-酮戊二酸酯 脱氢酶复合物）。 我们的总体假设是 对特定代谢途径的调节 维持磷酸化状态是钥匙变化的结果 酶促活动或其调节剂。 使用Vivo和Vitro NMR 光谱，磁共振成像和酶促测定=体外， 我们将不仅检查葡萄糖通量的成熟，即机理 参与以及缺氧对这些的影响，也是如此的重要性和 这种通量在神经细胞功能和生存中起的作用 在不成熟和成熟的主题中的潜力。 这个独特性 项目源于1）在体内和体外组合的方法 技术，2）调查人员在解决方面的记录 使用NMR的问题，以及3）该项目补充的事实 该计划中有关中介代谢和 低氧应激期间生存的机制。