BRAIN METABOLISM AND FUNCTION IN HYPOXIA

缺氧时的脑代谢和功能

• 批准号: 6272334
• 负责人: KEVIN L BEHAR
• 金额: $ 20.25万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-01 至 1998-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6272334
• 关键词: age difference; alpha ketoglutarate; brain metabolism; cellular pathology; cerebral ischemia /hypoxia; confocal scanning microscopy; developmental neurobiology; electron microscopy; electrophysiology; enzyme activity; enzyme complex; glucose 6 phosphate; glucose 6 phosphate dehydrogenase; glucose metabolism; hexokinase; in situ hybridization; laboratory rat; magnetic resonance imaging; mathematical model; neurons; nuclear magnetic resonance spectroscopy; phosphorylation

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 为了细胞的存活和正常的大脑功能，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 通过它们对体内关键酶的作用，葡萄糖的利用率 各自的代谢途径。此外，随着早期的发展， 生命中葡萄糖被氧化成二氧化碳和水的比例 柠檬酸循环到代谢成丙酮酸和乳酸 糖酵解和己糖单磷酸途径发生了巨大的变化。这个 该项目的主要目标是调查低氧对 脑葡萄糖代谢调控机制的研究进展 发展。这个项目将集中在酶的控制上。 通过己糖激酶，葡萄糖-6-磷酸脱氢酶， 和新皮质中的α-酮戊二酸脱氢酶复合体 未成熟和成熟的大鼠暴露在急性和慢性缺氧期。 这些酶位于其体内重要的流量控制点 各自的代谢途径，即糖酵解途径 己糖磷酸途径(葡萄糖-6-磷酸) 脱氢酶)和柠檬酸循环(α-酮戊二酸 脱氢酶复合体)。我们的总体假设是， 对特定代谢途径的调节有助于 磷酸化状态的维持是KEY变化的结果 酶活性或其调节剂。利用体内和体外核磁共振技术 光谱学、核磁共振成像和体外酶分析， 我们不仅要研究葡萄糖流量的成熟度，还要研究其机制 以及低氧对这些的影响，但也包括重要性和 这些通量在神经细胞功能和存活中所起的作用 在不成熟和成熟的学科中的潜力。这是独一无二的 项目源于1)体内和体外相结合的方法 技术，2)调查人员在处理 使用核磁共振的问题，以及3)这个项目补充了 计划内的其他有关中间代谢问题和 低氧应激下的生存机制。