GLUTAMINE, GLUTAMATE, BRANCHED CHAIN AMINO ACIDS AND OXIDATIVE BRAIN METABOLISM

谷氨酰胺、谷氨酸盐、支链氨基酸和氧化脑代谢

• 批准号: 6240923
• 负责人: H. Ronald Zielke
• 金额: $ 14.02万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 1998-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6240923
• 关键词: aminoacid biosynthesis; aminoacid transport; astrocytes; brain metabolism; branched chain aminoacid; glutamate dehydrogenase; glutamates; glutaminase; glutamine; granule cell; high performance liquid chromatography; intracellular transport; ketoacid; laboratory rat; microdialysis; mixed tissue /cell culture; neurons; tissue /cell culture

The study of biochemical mechanisms that regulate the use of substrates by the developing brain and individual types of brain cells has been the major focus of this laboratory for the past 19 years. Metabolic trafficking of key compounds (including lactate, alanine and malate) between astrocytes and synaptic terminals and/or neurons has a crucial role in the regulation of brain energy metabolism and neurotransmitter biosynthesis due to the compartmentation of enzymes in brain. Recent studies from our group and others provide evidence of multiple compartments of energy metabolism (or TCA cycle activity) in both astrocytes and synaptic terminals, and evidence that lactate and alanine are major components in the trafficking between astrocytes and synaptic terminals in brain. During the next funding cycle we will determine the mechanisms regulating the synthesis and release of lactate and alanine by astrocytes and the regulation of the uptake of these compounds by synaptic terminals and neurons. Since our studies have also shown different lactate transport systems in synaptic terminals as compared to astrocytes, we will further characterize these systems with respect to their response to effectors, especially since this transport is markedly attenuated by phenylpyruvate and alpha-ketoisocaproate which accumulate in cases of PKU and Maple Syrup Urine Disease, respectively. Other studies will focus on the role of malic enzyme since this enzyme may have a key role in both astrocytes and synaptic terminals in providing pyruvate to maintain TCA cycle activity when glucose is low. Malic enzyme may also have a role in production of lactate by astrocytes for trafficking to neurons. These studies will provide crucial information about the synthesis and trafficking of lactate, alanine and malate between astrocytes and neurons and/or synaptic terminals in brain. An imbalance in the production, transport or utilization of any of the metabolites being studies could lead directly to a derangement in the development of the nervous system. Furthermore, information about the regulation of lactate synthesis and utilization should lead to new therapeutic strategies in preventing the lactic acidosis associated with several forms of mental retardation.

调节底物使用的生化机制的研究 发育中的大脑和脑细胞的个体类型一直是 过去 19 年来该实验室的主要研究重点。 代谢 贩运关键化合物（包括乳酸、丙氨酸和苹果酸） 星形胶质细胞和突触末梢和/或神经元之间具有至关重要的 调节大脑能量代谢和神经递质的作用 由于酶在大脑中的划分而进行生物合成。最近的 我们小组和其他人的研究提供了多种证据 能量代谢（或 TCA 循环活动）的区室 星形胶质细胞和突触末梢，以及乳酸和丙氨酸的证据 是星形胶质细胞和突触之间运输的主要组成部分 大脑中的终端。在下一个资助周期中，我们将确定 调节乳酸和丙氨酸合成和释放的机制 星形胶质细胞和突触对这些化合物的摄取的调节 终端和神经元。由于我们的研究还表明不同的乳酸 与星形胶质细胞相比，突触末梢的运输系统 进一步描述这些系统的响应特征 效应器，特别是因为这种运输明显减弱 PKU 病例中会积聚的苯丙酮酸和 α-酮异己酸 和枫糖浆尿病。其他研究将集中于 苹果酸酶的作用，因为这种酶可能在两者中都发挥着关键作用 星形胶质细胞和突触末梢提供丙酮酸以维持 TCA 葡萄糖低时的循环活动。苹果酸酶也可能发挥作用 星形胶质细胞产生乳酸并运输至神经元。这些 研究将提供有关合成和合成的重要信息 星形胶质细胞和神经元之间乳酸、丙氨酸和苹果酸的运输 和/或大脑中的突触末端。生产不平衡， 正在研究的任何代谢物的运输或利用可以 直接导致神经系统发育紊乱。 此外，有关乳酸合成和调节的信息 利用应该导致新的治疗策略来预防 乳酸性酸中毒与多种形式的精神发育迟滞有关。