IMAGING METABOLIC FLUX WITH HYPERPOLARIZED NUCLEI

使用超极化核对代谢流进行成像

• 批准号: 8363885
• 负责人: MATTHEW E MERRITT
• 金额: $ 27.34万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8363885
• 关键词: Acetyl Coenzyme A; Alanine; Attention; Automobile Driving; Biochemical Pathway; Blood; Cell Nucleus; Chemical Shift Imaging; Clinic; Coupled; Data; Detection; Development; Funding; Gluconolactone; Glucose; Glutamates; Goals; Grant; Heart; Image; Imaging technology; In Vitro; Kinetics; Label; Liver; Measurement; Measures; Metabolic; Metabolism; Methods; Mind; Modality; Modeling; Mus; National Center for Research Resources; Organ; Oxygen Consumption; Pattern; Pentosephosphate Pathway; Physiologic pulse; Physiological; Principal Investigator; Protocols documentation; Protons; Rattus; Relative (related person); Research; Research Infrastructure; Resources; Scheme; Signal Transduction; Source; Spectrum Analysis; System; Techniques; Technology; Time; Tissue Extracts; Tissues; Tracer; United States National Institutes of Health; Weight; clinically relevant; cost; glucose analog; glucose metabolism; in vivo; indexing; mathematical model; multiplet; research study; stable isotope; tool

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The ability to measure 13C enrichments and isotopomer patterns in certain target molecules such as glutamate can be paired with mathematical modeling to estimate flux in intact systems. MR provides a unique tool for making these measurements since it can easily measure the presence of a variety of isotopomers by observing the j-coupled multiplets present in 13C spectra. Progress has been made with both in vivo and ex vivo spectroscopy methods, as well as in vitro analysis of extracts from organs or blood. With this in mind, it seems appropriate that the Resource turn its attention to the new field of hyperpolarization for MR sensitivity enhancement. Hyperpolarization of 13C is one of the most promising new modalities for metabolic imaging. The combination of 13C isotopomer analysis with this new physical technique is both logical and pertinent, and serves the goals of multiple driving projects. We believe that the increased sensitivity available through hyperpolarization will allow the in vivo use of isotopically labeled compounds for assessing metabolism in clinically reasonable time periods. Extending this technology to the clinic depends upon development of new experimental MR methods as well as adaptation of the metabolic models already produced by the Resource to the unique constraints imposed by the HP technology itself. The goal of in vivo measurement of flux using hyperpolarized stable isotopes demands the advancement of 5 aims: Aim 1 is to develop a new set of tracer molecules for assessing glucose metabolism. Within this Aim, the pentose phosphate pathway will be probed with a gluconolactone glucose analogue and the utility of other glucose agents, synthesized in TR&D 1, will be assessed. Aim 2 is to develop new methods for measuring absolute flux using hyperpolarization. We will take advantage of our expertise with 13C NMR isotopomer analysis and prelabel tissues that will allow us to simultaneously measure relative fluxes from tissue extracts and index this information to results from hyperpolarization experiments. By judicious selection of the labeling pattern of available substrates, molecules that produce [1-13C] and [1,2-13C]acetyl-CoA can be generated. Mathematical models for analysis of observed kinetics will be developed and validated against standard physiological measurements such as oxygen consumption. Finally, we will integrate pre-labeling and kinetic analysis from hyperpolarization studies to obtain complete pictures of metabolic networks from 13C data exclusively. Aim 3 presents a major challenge: detect hyperpolarized 13C signals through protons. INEPT parameters will be optimized to detect [1-13C] lactate and alanine in isolated tissues and the detection threshold will be determined in the perfused rat heart and mouse liver. Aim 4 is to adapt current chemical shift imaging (CSI) technologies to the detection of hyperpolarized nuclei at 4.7 T. In this Aim, CSI protocols will be implemented and schemes that explore polarization transfer imaging will be evaluated. Aim 5 is to transfer hyperpolarized BC technology to a 3 T scanner. This will require a number of steps and milestones including: 1) Implement acquisition-weighted double spin-echo EPSI for rapid 13C CSI, 2) Implement FLOPSY-EPSI for transferring polarization from glutamate C5 to C4 and C3. 3) Develop low-SAR adiabatic decoupling with WURST RF pulses 4) Develop SENSE-EPSI, keyhole-EPSI, and compressed EPSI. This TR&D project interacts extensively with the other TR&D projects as well as with multiple Driving Biomedical Projects. The intent is to develop in the Research Resource a suite of technologies for assessing in vivo metabolism in periods that are clinically relevant.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 测量某些目标分子（例如谷氨酸）中 13C 富集度和同位素异构体模式的能力可以与数学模型相结合，以估计完整系统中的通量。 MR 为进行这些测量提供了一种独特的工具，因为它可以通过观察 13C 光谱中存在的 j 耦合多重峰轻松测量各种同位素异构体的存在。体内和离体光谱方法以及器官或血液提取物的体外分析都取得了进展。 考虑到这一点，该资源将注意力转向用于增强 MR 灵敏度的超极化新领域似乎是合适的。 13C 超极化是代谢成像最有前途的新模式之一。 13C 同位素异构体分析与这种新的物理技术的结合既符合逻辑又具有针对性，并且服务于多个驱动项目的目标。 我们相信，通过超极化提高的灵敏度将允许在体内使用同位素标记的化合物来评估临床合理时间段内的代谢。将这项技术扩展到临床取决于新的实验性 MR 方法的开发以及资源已经产生的代谢模型对 HP 技术本身施加的独特限制的适应。使用超极化稳定同位素体内通量测量的目标需要实现 5 个目标： 目标 1 是开发一套新的示踪分子来评估葡萄糖代谢。在此目标中，将用葡萄糖酸内酯葡萄糖类似物探测戊糖磷酸途径，并评估 TR&D 1 中合成的其他葡萄糖制剂的效用。 目标 2 是开发使用超极化测量绝对通量的新方法。 我们将利用我们在 13C NMR 同位素异构体分析和预标记组织方面的专业知识，这将使我们能够同时测量组织提取物的相对通量，并将这些信息索引到超极化实验的结果。 通过明智地选择可用底物的标记模式，可以生成产生 [1-13C] 和 [1,2-13C] 乙酰辅酶 A 的分子。 将开发用于分析观察到的动力学的数学模型，并根据标准生理测量（例如耗氧量）进行验证。 最后，我们将整合超极化研究中的预标记和动力学分析，专门从 13C 数据中获得代谢网络的完整图片。 目标 3 提出了一个重大挑战：通过质子检测超极化 13C 信号。 将优化 INEPT 参数以检测分离组织中的 [1-13C] 乳酸和丙氨酸，并将在灌注的大鼠心脏和小鼠肝脏中确定检测阈值。 目标 4 是使当前的化学位移成像 (CSI) 技术适应 4.7 T 超极化核的检测。在此目标中，将实施 CSI 协议，并对探索偏振转移成像的方案进行评估。 目标 5 是将超极化 BC 技术转移到 3 T 扫描仪上。这将需要许多步骤和里程碑，包括：1）实施采集加权双自旋回波 EPSI 以实现快速 13C CSI，2）实施 FLOPSY-EPSI 以将极化从谷氨酸 C5 转移到 C4 和 C3。 3) 使用 WURST RF 脉冲开发低 SAR 绝热去耦 4) 开发 SENSE-EPSI、锁孔-EPSI 和压缩 EPSI。 该 TR&D 项目与其他 TR&D 项目以及多个驱动生物医学项目广泛互动。目的是在研究资源中开发一套技术，用于评估临床相关时期的体内代谢。