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Regulation of Brain Neurotransmitter Synthesis

脑神经递质合成的调节

基本信息

批准号：
7259420
负责人：
SUSAN M HUTSON
金额：
$ 24.43万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-06-05 至 2008-07-07
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7259420
关键词：
Activity Cycles Affect Alanine Amino Acids Antisense Technology Area Aspartate Astrocytes Attention Back Beta Catenin Staining Method Biochemical Brain Branched-Chain Amino Acids Carbon Cells Citric Acid Cycle Complex Data Decarboxylation Diet Drug Metabolic Detoxication Effectiveness Energy Metabolism Enzymes Epilepsy Equilibrium Funding Glucose Glutamate Metabolism Pathway Glutamates Glutaminase Glutamine Glycolysis Goals Hippocampus (Brain)In Vitro Inborn Errors of Metabolism Infusion procedures Intractable Epilepsy Isoenzymes Keto Acids Lead Left Leucine Link Malate-Aspartate Shuttle Pathway Malates Maple Syrup Urine Disease Maps Measures Metabolic Metabolism Methods Mitochondria Modeling Molecular Muller&apos s cell NADH NMR Spectroscopy Nerve Degeneration Neuraxis Neuroglia Neurologic Neurons Neurotransmitters Nitrogen Operative Surgical Procedures Oxalacetic Acid Oxidation-Reduction Pathway interactions Peripheral Peripheral Nerves Pharmaceutical Preparations Physiological Protein Isoforms Pyruvate Pyruvate Carboxylase Pyruvates Rate Rattus Regulation Research Personnel Rest Retina Retinal Role Series Site Slice Source Spatial Distribution Spinal Cord Synapses Testing Tissues Treatment Protocols Upper arm aerobic glycolysis aspartate-glutamate carrier awake base branched-chain-amino-acid transaminase carboxylation defined contribution gabapentin gamma-Aminobutyric Acid in vivo inhibitor/antagonist insight ketogenic diet malate neuroprotection neurotransmission neurotransmitter metabolism oxidation programs sample fixation theories

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this proposal is to understand mechanisms that regulate glutamate metabolism and how it interrelates with glutamate neurotransmission in the central nervous system (CNS). Glutamate and aspartate are the major excitatory neurotransmitters in the mammalian brain. These amino acids are unusual, because they have dual roles, first as neurotransmitters, and second as important intermediates in nitrogen and energy metabolism. Their metabolic roles in peripheral tissues are well recognized, but the relationship between their metabolism and neurotransmitter function in the brain has received much less attention. Release of glutamate during neurotransmission generates a loss of glutamate from the neuron. If left in the synaptic space, the glutamate is excitotoxic. In the proposal we will determine the effect of altering the complex metabolic processes in astroglia and neurons that operate to detoxify and replenish the released glutamate. Our goal is to define the contribution of branched chain amino acid (BCAA) nitrogen and the branched chain aminotransferas.e (SCAT) isozymes to the synthesis of glutamate. We will test the neurological consequences of blocking nitrogen transfer from BCAAs via specific BCAT isozymes in vitro in hippocampal slices and after lowering expression of BCAT isozymes in vivo in rat brain. We will also test the metabolic hypothesis for the mechanism of action of neuroactive drug gabapentin. We will examine neurological consequences of inhibiting the carbon regulatory step of the glutamate/pyruvate cycle catalyzed by pyruvate carboxylase (PC). We will determine the consequences of lowering PC expression on de novo glutamate synthesis and neurotransmission in hippocampus. We will test the hypothesis that the efficacy of the ketogenic diet in treating intractable epilepsy results from lowering pyruvate carboxylation by PC. We will test, in vivo, the metabolic theory underlying current models for calculating flux through PC pathway using nuclear magnetic resonance spectroscopy. Our recent studies reveal the molecular basis for the Magistretti hypothesis and the high rates of aerobic glycolysis in retinal glia. We will determine if this observation provides a mechanism for tying glutamate neurotransmission to the anaplerotic arm of the glutamate pyruvate cycle Results from this study will provide insight into mechanisms underling current dietary treatments for epilepsy and insight into the biochemical basis of the neurological consequences of inborn errors of metabolism that affect these pathways (Maple Syrup Urine Disease and Pyruvate Carboxylase deficiency) that may lead to better treatment regimens.

描述（由申请人提供）：该提案的总体目标是了解调节谷氨酸代谢的机制及其与中枢神经系统（CNS）中谷氨酸神经传递的相互关系。谷氨酸和天冬氨酸是哺乳动物大脑中主要的兴奋性神经递质。这些氨基酸很不寻常，因为它们具有双重作用，首先作为神经递质，其次作为氮和能量代谢的重要中间体。它们在外周组织中的代谢作用已得到充分认识，但它们的代谢与大脑中神经递质功能之间的关系却很少受到关注。神经传递过程中谷氨酸的释放导致神经元谷氨酸的损失。如果留在突触间隙，谷氨酸就会产生兴奋毒性。在该提案中，我们将确定改变星形胶质细胞和神经元中复杂代谢过程的效果，这些代谢过程用于解毒和补充释放的谷氨酸。我们的目标是确定支链氨基酸 (BCAA) 氮和支链转氨酶 (SCAT) 同工酶对谷氨酸合成的贡献。我们将测试体外海马切片中通过特定 BCAT 同工酶阻断 BCAA 氮转移以及降低大鼠脑体内 BCAT 同工酶表达后的神经学后果。我们还将测试神经活性药物加巴喷丁作用机制的代谢假设。我们将研究抑制丙酮酸羧化酶 (PC) 催化的谷氨酸/丙酮酸循环的碳调节步骤的神经学后果。我们将确定降低 PC 表达对海马谷氨酸从头合成和神经传递的影响。我们将检验生酮饮食治疗顽固性癫痫的功效是由于 PC 降低丙酮酸羧化作用的假设。我们将在体内测试当前模型的代谢理论，用于使用核磁共振波谱计算通过 PC 途径的通量。我们最近的研究揭示了马吉斯特雷蒂假说的分子基础和视网膜神经胶质细胞的高有氧糖酵解率。我们将确定这一观察是否提供了一种将谷氨酸神经传递与谷氨酸丙酮酸循环的回补臂联系起来的机制。这项研究的结果将深入了解当前癫痫饮食治疗的机制，并深入了解影响这些途径的先天性代谢错误的神经学后果的生化基础（枫糖浆尿病和丙酮酸羧化酶）缺陷），这可能会导致更好的治疗方案。