MONOCARBOXYLIC ACIDS AND AMINO ACIDS IN BRAIN METABOLISM AND TRAFFICKING

脑代谢和贩运中的单羧酸和氨基酸

• 批准号: 6301882
• 负责人: MARY C MCKENNA
• 金额: $ 17.82万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6301882
• 关键词: Krebs' cycle; aminoacid biosynthesis; aspartate; astrocytes; brain metabolism; developmental neurobiology; disease /disorder model; enzyme activity; fatty acid biosynthesis; gamma aminobutyrate; glucose metabolism; glutamate dehydrogenase; glutamine; granule cell; human tissue; intracellular transport; laboratory mouse; lactate dehydrogenases; lactates; malates; mature animal; neurotransmitter biosynthesis; newborn animals; nuclear magnetic resonance spectroscopy; phenylketonurias

Studies in Project II address the hypothesis that it is crucial for the brain to maintain the proper balance of production and utilization of lactate since this monocarboxylic acid is a key substrate in both developing brain and mature brain. Impairment in transport of lactate or ketone bodies into brain may limit the use of these key substrates for energy and neurotransmitter biosynthesis in developing brain in Phenylketonuria (PKU) and Maple Syrup Urine Disease. Conversely, an elevated concentration of lactate in cerebrospinal fluid and/or brain tissue is a prominent feature in Leigh's disease, a condition associated with mental retardation. There is evidence that amino acid and monocarboxylic acid metabolism are intimately and dynamically interconnected. A substantial portion of lactate, particularly in the cerebellum, is formed from glutamate and glutamine metabolized via the TCA cycle an converted to pyruvate via malic enzyme. Specifically, labeled precursors and 13/C-NMR will be used to determine the relative importance of the amino acids glutamate and glutamine as precursors for lactate production in astrocytes and neurons. The relative contribution of lactate and ketone bodies to neurotransmitter biosynthesis in cortical neurons, cerebellar granule cells, and in the PAHenu2 mouse (which has the same mutation of humans with PKU) will be determine. Glial/neuronal trafficking of substrates in the PKU mouse brain will be evaluated using [1- 13C]glucose and [2-/13C]acetate. Inhibition of TCA cycle activity with fluorocitrate will be used as a model for Leigh's disease. If a significant portion of the lactate in conditions with cerebral lactic acidosis is synthesize from amino acids, modulating lactate production by this biosynthetic pathway would require different therapeutic strategies than if it was produced via glycolysis.

项目 II 的研究提出了这样一个假设：它对于 大脑维持生产和利用的适当平衡 乳酸，因为这种一元羧酸是两者的关键底物 发育中的大脑和成熟的大脑。乳酸运输受损或 酮体进入大脑可能会限制这些关键底物的使用 大脑发育过程中的能量和神经递质生物合成 苯丙酮尿症 (PKU) 和枫糖浆尿病。相反，一个 脑脊液和/或大脑中乳酸浓度升高 组织是利氏病的一个突出特征，利氏病是一种与 患有智力障碍。有证据表明氨基酸和 一元羧酸代谢是密切且动态的 互联。乳酸盐的很大一部分，特别是在 小脑由谷氨酸和谷氨酰胺通过 TCA 代谢形成 循环并通过苹果酸酶转化为丙酮酸。具体来说，标记为 前体和 13/C-NMR 将用于确定相对重要性 氨基酸谷氨酸和谷氨酰胺作为乳酸的前体 星形胶质细胞和神经元的产生。乳酸的相对贡献 和酮体在皮质神经元中进行神经递质生物合成， 小脑颗粒细胞，以及 PAHenu2 小鼠（具有相同的 人类 PKU 突变）将被确定。胶质细胞/神经元贩运 PKU 小鼠大脑中的底物将使用 [1- 13C]葡萄糖和[2-/13C]乙酸盐。抑制 TCA 循环活性 氟柠檬酸盐将被用作利氏病的模型。如果一个 在患有脑乳酸的情况下，乳酸的很大一部分 酸中毒是由氨基酸合成的，通过调节乳酸的产生 这种生物合成途径需要不同的治疗策略 与通过糖酵解产生的情况相比。