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.

对调节底物使用的生化机制的研究 发育中的大脑和个体类型的脑细胞一直是 在过去的19年中，该实验室的主要重点。 代谢 贩运关键化合物（包括乳酸，丙氨酸和苹果酸） 在星形胶质细胞和突触终端和/或神经元之间具有关键 在调节脑能量代谢和神经递质的作用 由于脑中酶的分室引起的生物合成。最近的 我们小组和其他人的研究提供了多重的证据 两者中能量代谢的隔室（或TCA循环活性） 星形胶质细胞和突触终端，以及乳酸和丙氨酸的证据 是星形胶质细胞和突触之间贩运的主要组成部分 大脑中的终端。在下一个资金周期中，我们将确定 调节乳酸和丙氨酸的合成和释放的机制 星形胶质细胞和通过突触对这些化合物摄取的调节 末端和神经元。由于我们的研究也显示出不同的乳酸 与星形胶质细胞相比，突触终端中的运输系统，我们将 进一步描述了这些系统的反应 效应子，特别是因为这种运输显着衰减 苯基丙酮酸酯和α-酮二铜酸盐，在PKU的情况下积累 和枫糖浆尿液疾病。其他研究将重点 苹果酶的作用，因为该酶在两者中可能具有关键作用 星形胶质细胞和突触终端提供丙酮酸以保持TCA 葡萄糖低时的循环活性。苹果酶也可能在 由星形胶质细胞生产乳酸，用于贩运神经元。这些 研究将提供有关综合和的关键信息 星形胶质细胞和神经元之间乳酸，丙氨酸和苹果酸的贩运 和/或大脑中的突触终端。生产不平衡， 任何正在研究的代谢物的运输或利用都可以 直接导致神经系统发展的危险。 此外，有关乳酸合成调节的信息和 利用应导致新的治疗策略，以防止 乳酸酸中毒与几种形式的智力低下有关。