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

生物化学对生物化学机制的研究，通过调节底物的使用， 发育中的大脑和个别类型的脑细胞 这是该实验室在过去19年中的主要重点。 代谢 关键化合物（包括乳酸、丙氨酸和苹果酸）的运输 在星形胶质细胞和突触末梢和/或神经元之间， 在脑能量代谢和神经递质调节中的作用 由于大脑中酶的区室化而导致生物合成。最近 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）的两个分区 星形胶质细胞和突触末梢，并证明乳酸和丙氨酸 是星形胶质细胞和突触之间运输的主要成分。 大脑中的终端在下一个融资周期，我们将确定 调节乳酸和丙氨酸的合成和释放的机制 星形胶质细胞和调节这些化合物的摄取突触 终端和神经元。因为我们的研究也表明不同的乳酸 与星形胶质细胞相比，我们将 进一步描述这些系统的特征， 效应物，特别是因为这种运输明显减弱， 苯丙酮酸和α-酮异己酸在PKU病例中蓄积 和枫树糖浆尿病。其他研究将侧重于 苹果酸酶作用，因为这种酶可能在 星形胶质细胞和突触末梢提供丙酮酸维持TCA 葡萄糖低时的循环活动。苹果酸酶也可能在 星形胶质细胞产生乳酸盐运输到神经元。这些 研究将提供关于综合的重要信息， 乳酸、丙氨酸和苹果酸在星形胶质细胞和神经元之间的运输 和/或突触末梢。生产的不平衡， 所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，关于乳酸合成的调节和 利用应导致新的治疗策略，以防止 与几种形式的智力迟钝有关的乳酸酸中毒。

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.