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.

项目二的研究解决了这一假设，即它是至关重要的