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，这是至关重要的 细胞活力和正常的大脑功能，需要一个畅通无阻的 葡萄糖和氧气的供应。 在氧气不足的情况下， 某些调节剂（如ATP、G-6-P、G-1，6-DP）的变化可能会增强 葡萄糖利用率通过它们对葡萄糖代谢中关键酶的作用来确定。 各自的代谢途径。 此外，随着早期 生命中，葡萄糖氧化成二氧化碳和水的比例 柠檬酸循环到代谢为丙酮酸盐和乳酸盐 糖酵解和己糖磷酸途径发生显著变化。 的 该项目的主要目标是研究缺氧如何影响 调节大脑葡萄糖代谢的机制， 发展 该项目将集中在酶的控制， 通过己糖激酶，葡萄糖-6-磷酸脱氢酶， 和α-酮戊二酸脱氢酶复合物在新皮层的 暴露于急性和慢性缺氧期的未成熟和成熟大鼠。 这些酶位于它们的重要通量控制点， 各自的代谢途径，即糖酵解途径 （己糖激酶），磷酸己糖途径（葡萄糖-6-磷酸 脱氢酶）和柠檬酸循环（α-酮戊二酸 脱氢酶复合物）。 我们的一般假设是， 调节特定的代谢途径， 磷酸化状态的维持是关键变化的结果 酶活性或其调节剂。 使用体内和体外NMR 体外光谱、磁共振成像和酶测定， 我们将不仅研究葡萄糖流量的成熟， 参与和缺氧对这些的影响，但也是重要的， 这些通量在神经细胞功能和存活中所起作用 在未成熟和成熟的主题的潜力。 这件事的独特性 项目来源于1）体内和体外相结合的方法 技术，2）调查人员在解决 问题使用核磁共振，和3）事实上，这个项目补充 该计划中关于中间代谢的其他问题， 缺氧应激时的生存机制。