Imaging Brain Metabolism Using MRS of Hyperpolarized 13C-Pyruvate

使用超极化 13C-丙酮酸 MRS 成像脑代谢

• 批准号: 9269573
• 负责人: Daniel M Spielman
• 金额: $ 50.4万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9269573
• 关键词: Acetyl Coenzyme A; Acute; Alanine; Bicarbonates; Biochemical; Biomass; Brain; Brain Diseases; Brain Neoplasms; Brain imaging; Carbon Dioxide; Citric Acid Cycle; Clinic; Clinical; Complex; Cytosol; Data; Detection; Development; Dichloroacetate; Disease; Energy Metabolism; Future; Glioblastoma; Glioma; Glucose; Glycolysis; Goals; Grant; Heart; Heart Diseases; Heart Research; Image; Imaging Device; Label; Lactate Dehydrogenase; Link; Magnetic Resonance Spectroscopy; Malignant Neoplasms; Measurement; Measures; Metabolic; Metabolism; Methods; Mitochondria; Modeling; Neoplasms; Nerve Degeneration; Neuroglia; Neurons; Neurotransmitters; Nodal; Noise; Organ; Oxaloacetates; Oxidative Phosphorylation; Patients; Performance; Physiologic pulse; Play; Production; Pyruvate; Pyruvate Metabolism Pathway; Rattus; Reaction; Regulation; Reporting; Resolution; Role; Signal Transduction; Source; Speed; System; Techniques; Testing; Translating; Translations; aerobic glycolysis; amidation; bevacizumab; brain metabolism; brain research; carbon skeleton; glutamatergic signaling; human imaging; human subject; imaging modality; imaging study; improved; in vivo; in vivo magnetic resonance spectroscopy; inhaled nitric oxide; insight; interest; magnetic resonance spectroscopic imaging; metabolic imaging; mitochondrial metabolism; novel; public health relevance; pyruvate dehydrogenase; temporal measurement; tool; treatment response; tumor; tumor metabolism; validation studies

 DESCRIPTION (provided by applicant): Magnetic resonance spectroscopy (MRS) of hyperpolarized 13C-labeled substrates provides unique noninvasive measurements of critical dynamic metabolic processes, with hyperpolarized [1-13C]pyruvate (Pyr) being the first (and currently only) 13C-compound to reach the clinic. Occupying a key nodal point in energy metabolism, among the fates of Pyr are reduction to lactate (Lac) as the end product of glycolysis (GLY), amidation to produce alanine (Ala), or conversion in mitochondria to form acetyl CoA and CO2 (measured with 13C-MRS as a 13C-bicarbonate [Bic] peak) as the first step towards oxidative phosphorylation (OXPHOS) via the tricarboxylic acid (TCA) cycle. To date, the most prominent applications of hyperpolarized 13C-Pyr metabolic imaging are studies of cancer and heart disease. With a growing interest into cancer metabolic reprogramming fueling new studies into Warburg's 1965 observation that less energy-efficient aerobic GLY is favored in neoplasms over more efficient OXPHOS, MRS of hyperpolarized 13C-Pyr and the subsequent labeling of 13C-Lac provides an unprecedented noninvasive measurement of GLY. While 13C-Lac changes have now been well documented in multiple brain tumors and other neoplasms, these cancer studies have been largely silent on other downstream Pyr metabolic products, which can provide important information beyond glycolytic capacity. A more complete understanding of cancer metabolism requires measurements reflecting the complex interplay between both GLY and OXPHOS, and our preliminary findings with a glioblastoma multiforme model demonstrate that imaging Pyr products beyond Lac can provide this information. Energy regulation and mitochondrial function are also critically important for understanding brain function, and current data suggest a complex relationship involving the exchange of metabolic intermediates between glia and neurons. Conventional 13C MRS is well established as the primary noninvasive tool to study neuroenergetics and linked neurotransmitter cycling, but hyperpolarized 13C-MRS, with its high spatial and temporal resolution, has the potential to provide new insights. Although hyperpolarized [1-13C]Pyr provides little information on the TCA cycle, in vivo measurements downstream metabolic products of [2-13C]Pyr, for which the 13C-label is retained with the conversion of Pyr to acetyl-CoA, potentially add significant insights ino both OXPHOS and mitochondrial function. However, outside of the heart, few results concerning [2-13C]Pyr products beyond Lac (and Ala) have been reported. We believe the dearth of brain research on downstream Pyr products beyond Lac is due to the low signal- to-noise ratio (SNR) and other imaging difficulties associated with these resonances, rather than a lack of biochemical significance. The overall goal of this 4-year technical development grant is to develop optimized methods for imaging brain energy metabolism using hyperpolarized 13C-pyruvate in order to assess GLY, OXPHOS, and mitochondrial function. Many of to-be-developed methods will also be applicable to other organs and diseases. The Specific Aims are to develop improved acquisition and quantification methods for use with [1-13C]Pyr (Aim 1) and [2-13C]Pyr (Aim 2), assess Pyr metabolism and anti-VEGF treatment response in a rat C6-glioma model (Aim 3), and optimize sequences and hardware for future clinical hyperpolarized 13C- Pyr studies (Aim 4).

 描述（由申请人提供）：超极化 13C 标记底物的磁共振波谱 (MRS) 提供了关键动态代谢过程的独特无创测量，超极化 [1-13C]丙酮酸 (Pyr) 是第一个（也是目前唯一）到达临床的 13C 化合物。 Pyr 占据能量代谢的关键节点，其命运包括还原为乳酸 (Lac) 作为糖酵解 (GLY) 的最终产物，酰胺化产生丙氨酸 (Ala)，或在线粒体中转化形成乙酰 CoA 和 CO2（用 13C-MRS 测量为 13C-碳酸氢盐 [Bic] 峰）作为氧化磷酸化的第一步 (OXPHOS) 通过三羧酸 (TCA) 循环。迄今为止，超极化 13C-Pyr 代谢成像最突出的应用是癌症和心脏病的研究。随着人们对癌症代谢重编程的兴趣日益浓厚，推动了对 Warburg 1965 年观察的新研究，即在肿瘤中，能量效率较低的需氧 GLY 比效率更高的 OXPHOS 更受青睐，超极化 13C-Pyr 的 MRS 以及随后的 13C-Lac 标记提供了前所未有的 GLY 无创测量。虽然 13C-Lac 的变化现已在多种脑肿瘤和其他肿瘤中得到充分记录，但这些癌症研究在很大程度上对其他下游 Pyr 代谢产物保持沉默，而这些产物可以提供糖酵解能力之外的重要信息。要更全面地了解癌症代谢，需要进行反映 GLY 和 OXPHOS 之间复杂相互作用的测量，我们对多形性胶质母细胞瘤模型的初步发现表明，对 Lac 以外的 Pyr 产品进行成像可以提供此信息。能量调节和线粒体功能对于理解大脑功能也至关重要，目前的数据表明神经胶质细胞和神经元之间代谢中间体的交换存在复杂的关系。传统的 13C MRS 已成为研究神经能量学和相关神经递质循环的主要非侵入性工具，但超极化 13C-MRS 凭借其高空间和时间分辨率，有可能提供新的见解。尽管超极化的 [1-13C]Pyr 提供的 TCA 循环信息很少，但体内测量 [2-13C]Pyr 的下游代谢产物（随着 Pyr 转化为乙酰辅酶 A 而保留了 13C 标签），可能会增加对 OXPHOS 和线粒体功能的重要见解。然而，在心脏之外，关于 Lac（和 Ala）以外的 [2-13C]Pyr 产品的结果很少有报道。我们认为，缺乏对 Lac 以外的下游 Pyr 产物的大脑研究是由于低信噪比 (SNR) 和与这些共振相关的其他成像困难，而不是缺乏生化意义。这项为期 4 年的技术开发资助的总体目标是开发使用超极化 13C-丙酮酸成像脑能量代谢的优化方法，以评估 GLY、OXPHOS 和线粒体功能。许多即将开发的方法也将适用于其他器官和疾病。具体目标是开发改进的采集和定量方法，用于 [1-13C]Pyr（目标 1）和 [2-13C]Pyr（目标 2），评估大鼠 C6-神经胶质瘤模型中的 Pyr 代谢和抗 VEGF 治疗反应（目标 3），并优化未来临床超极化 13C-Pyr 研究的序列和硬件（目标 4）。