Cerebral Metabolic Flux Mapping Using Oxygen 17 NMR

使用氧 17 NMR 绘制脑代谢通量图

• 批准号: 7826822
• 负责人: ROBIN A DE GRAAF
• 金额: $ 42.97万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2011-10-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7826822
• 关键词: ATP Synthesis Pathway; Acetates; Affect; Algae; Anesthesia procedures; Animals; Area; Attention; Be++ element; Beryllium; Bicarbonates; Blood - brain barrier anatomy; Blood specimen; Brain; Breathing; Cerebrovascular Circulation; Cerebrum; Characteristics; Chemicals; Chloralose; Citric Acid Cycle; Data; Deoxyglucose; Detection; Development; Diffusion; Evaluation; Functional Imaging; Functional Magnetic Resonance Imaging; Gases; Glucose; Glycolysis; Human; In Vitro; Infusion procedures; Intervention; Intravenous; Isotopes; Knowledge; Label; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Maps; Measurement; Measures; Metabolic; Metabolic Pathway; Metabolism; Methods; Modeling; NMR Spectroscopy; Nature; Neurons; Organ; Oxygen; Pathway interactions; Perfusion; Phase; Photosynthesis; Physiologic pulse; Plants; Positioning Attribute; Process; Property; Protocols documentation; Publishing; Pyruvate Carboxylase; RF coil; Rattus; Relaxation; Resolution; Route; Sampling; Signal Transduction; Steam; System; Techniques; Temperature; Testing; Time; Transmembrane Transport; Treatment Efficacy; Validation; Water; base; brain disorder diagnosis; brain metabolism; data acquisition; hemodynamics; improved; in vivo; interest; magnetic field; pyruvate dehydrogenase; research study; tool

Oxygen is one of the most abundant elements and is present in almost all biologically relevant molecules. In the past the NMR active isotope 17O has received little attention, due to short relaxation times and low sensitivity. However, with the availability of higher magnetic field strengths, the use of 17O-enriched substrates and the favorable T2 */T1 ratio, any sensitivity concerns are quickly overcome, allowing the acquisition of 3D MRSI data in the span of seconds. Furthermore, the wide chemical shift dispersion allows the detection of a wide range of metabolites. Here we propose to develop 17O NMR in combination with 17O-enriched substrate infusion into a fast, sensitive and robust method to spatially map metabolic fluxes in the rat brain in vivo. Metabolism of 17O-glucose enriched in the 1, 2 or 3 positions gives information on glycolytic, tricarboxylic acid cycle or pyruvate dehydrogenase activity, respectively. Astroglial metabolism and pyruvate carboxylase activity can be assessed with 17O-enriched acetate and bicarbonate. The 17O turnover characteristics of each substrate can be described by a metabolic model, some of which require additional inputs such as recirculated 17O-labeled water from other organs. Here we will develop the methods to measure all required inputs in order to reliably obtain the desired metabolic fluxes. Following the optimization of 17O substrate synthesis, the characteristics of 17O NMR and 17O label dynamics will be studied in vitro. The established 1H-[13C]-NMR technique in combination with 13C-labeled glucose and 2-deoxyglucose infusions will be used to validate the 17O-based cerebral metabolic fluxes through the tricarboxylic acid cycle and glycolysis, respectively, in the rat brain in vivo at 11.7 T.

氧是最丰富的元素之一，几乎存在于所有与生物学相关的分子中。在 过去的NMR活性同位素17o由于松弛时间较短而没有引起关注 灵敏度。但是，随着较高磁场强度的可用性，使用17o富集的底物 和有利的T2 */t1比率，任何敏感性问题都会很快克服，允许获得3D MRSI数据在几秒钟内。此外，宽的化学位移色散允许检测 多种代谢物。在这里，我们建议开发17o NMR与17o富含的底物结合 输注一种快速，敏感和健壮的方法，用于在体内绘制大鼠脑中的代谢通量。 在1、2或3位的17o-葡萄糖的代谢提供了有关糖酵解的三羧酸的信息 循环或丙酮酸脱氢酶活性。星形胶质细胞代谢和丙酮酸羧化酶活性 可以用富含17o的醋酸盐和碳酸氢盐评估。每个人的17o失误特征 底物可以通过代谢模型来描述，其中一些需要其他输入，例如再循环 来自其他器官的17O标记水。在这里，我们将开发方法以按顺序测量所有必需的输入 可靠地获得所需的代谢通量。在优化17O底物合成之后， 将在体外研究17o NMR和17O标签动力学的特征。已建立的1H- [13C] -nmr 将使用13C标记的葡萄糖和2-脱氧葡萄糖输注的技术来验证 在大鼠中分别通过三羧酸周期和糖酵解的17o基脑代谢通量分别 大脑在体内为11.7 T.