MONOCARBOXYLIC ACIDS AND AMINO ACIDS IN BRAIN METABOLISM AND TRAFFICKING

项目II中的研究解决了这样的假设，即它对 大脑要保持生产和利用的适当平衡 乳酸，因为这种单羧酸是这两种物质的关键底物 发育中的大脑和成熟的大脑。乳酸盐运输障碍或 酮体进入大脑可能限制这些关键底物的使用 脑发育过程中能量和神经递质的生物合成 苯丙酮尿症(PKU)与枫糖尿症相反，一个 脑脊液和/或脑中乳酸浓度升高 组织是Leigh病的一个显著特征，这种情况与 精神发育迟滞。有证据表明，氨基酸和 一元羧酸代谢密切而动态 互联互通。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三氯乙酸代谢而成 通过苹果酸酶转化为丙酮酸。具体地说，被标记为 将使用前体和13/C-核磁共振来确定其相对重要性 谷氨酸和谷氨酰胺作为乳酸前体的氨基酸 在星形胶质细胞和神经元中产生。乳酸的相对贡献 和酮小体对皮质神经元中神经递质的生物合成， 小脑颗粒细胞，在PAHenu2小鼠中(具有相同的 人类与PKU的突变)将被确定。神经胶质细胞/神经元运输 将使用[1-]来评估PKU小鼠大脑中底物的数量 13C]葡萄糖和[2-/13C]醋酸酯。对TCA循环活性的抑制作用 氟柠檬酸盐将被用作Leigh‘s病的模型。如果一个 脑乳酸症患者体内的大量乳酸 酸中毒是由氨基酸合成，通过以下方式调节乳酸的产生 这种生物合成途径需要不同的治疗策略。 如果它是通过糖酵解产生的。

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.