MODELING COMPARTMENTATION IN THE BRAIN

大脑分区建模

• 批准号: 7600864
• 负责人: Pierre-Gilles Henry
• 金额: $ 1.51万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7600864
• 关键词: Acetates; Amino Acids; Aspartate; Astrocytes; Back; Brain; Carbon; Citric Acid Cycle; Collaborations; Complex; Computer Retrieval of Information on Scientific Projects Database; Data; Detection; Ensure; Funding; Glucose; Glutamates; Glutamine; Goals; Grant; Heart; Human; Individual; Infusion procedures; Institution; Invasive; Label; Lead; Measurement; Measures; Mental disorders; Metabolic; Metabolism; Methods; Modeling; NMR Spectroscopy; Neurologic; Neurons; Positioning Attribute; Procedures; Rate; Rattus; Research; Research Design; Research Personnel; Resources; Source; Study models; Time; Uncertainty; United States National Institutes of Health; Work; base; brain metabolism; cell type; concept; gamma-Aminobutyric Acid; glucose metabolism; improved; in vivo; metabolic abnormality assessment; multiplet; neurotransmission; presynaptic; programs; simulation; time use; tool

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In vivo 13C NMR spectroscopy has emerged as a unique tool to study compartmentalized brain metabolism. For example, measurements of 13C label incorporation into brain amino acids during infusion of a 13C labeled-substrate (e.g. [1-13C]glucose or [2-13C]acetate and subsequent analysis of 13C NMR time courses with a metabolic model has permitted non-invasive measurements of the TCA cycle rate and the rate of glutamate-glutamine cycle in the brain. Metabolic modeling is particularly challenging in the brain due to compartmentation of metabolism between different cell types such as neurons and astrocytes. This compartmentation has been demonstrated over 30 years ago using 14C labeled substrates and has led to the now widely accepted concept of glutamate-glutamine cycle, whereby glutamate released by presynaptic neurons is taken up by astrocytes, converted to glutamine, and sent back to neurons to resynthesize glutamate. Much progress has been done in the past ten years to develop metabolic models of compartmentalized metabolism. However, these complex models require sufficient experimental data to ensure the stability of the fitting procedure, e.g. including time courses of 13C label incorporation not only into the C4 position of glutamate and glutamine, but also the C3 and C2 positions. This additional data helps stabilize the fitting procedure and reduce uncertainty on fitted parameters. Although resolved detection of multiplets corresponding to individual isotopomers is now feasible in vivo, metabolic modeling has been traditionally performed using time courses of total 13C label at each carbon position, ignoring the additional information from multiply labeled molecules. These individual isotopomers, detected as distinct multiplets in 13C spectra, provide valuable information that could be used to improve the robustness of metabolic modeling studies. This has been demonstrated in the heart, but has not been exploited for brain studies. The goal of this collaboration is to take full advantage of the information from multiply labeled isotopomers by developing a model that can use this information. We expect that this work will lead to new metabolic modeling approaches that make optimal use of the highly specific information that can be obtained with 13C NMR and has recently become available also in vivo, ultimately increasing the robustness and precision of metabolic modeling studies in the brain. This is significant because 13C NMR measurements of brain metabolic fluxes would provide a means to directly and non-invasively measure glucose metabolism and glutamate neurotransmission in the human brain in a variety of neurological and psychiatric disorders. Preliminary data: Research Design- 1. Develop and implement a two-compartment model that includes information from 13C time courses of individual singly and multiply-labeled isotopomers. 2. Validate the new models using in vivo data obtained in the rat brain during infusion of [1,6- 13C2]glucose under different 3. Assess the reliability of the new models using Monte-Carlo simulations and compare it with the exiting model that fits total 13C label at each carbon position. Methods - The new model will be based on the most current two-compartment model for brain metabolic studies and on methods developed at UTSouthwestern to include information from individual isotopomers. This will include information from the following isotopomers that can be detected in vivo at 9.4 Tesla: (Glutamate GluC4S, GluC4D43, GluC3S, GluC3D, GluC3T, GluC2S, GluC2D23, GluC2D21, GluC2DD), Glutamine (GlnC4S, GlnC4D43, GlnC3S, GlnC3D, GlnC3T, GlnC2S, GlnC2D23, GlnC2D21, GlnC2DD). In a second step, information from aspartate and GABA isotopomers could also be included. In vivo spectra will be obtained in the rat brain during infusion of[1,6-13C2]glucose and will be quantified using the program LCModel in order to obtain time courses for multiply-labeled isotopomers.The resulting 13C time courses will be scaled to reflect actual 13C concentration using 13C NMR of brain extracts obtained at the end of the in vivo time course.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 体内13C NMR光谱已成为研究分隔型脑代谢的独特工具。例如，在输注13C标记的靠形成物（例如[1-13c]葡萄糖或[2-13C]乙酸盐的[1-13C]乙酸盐以及随后通过代谢模型对13C NMR时间库进行分析时，测量13C标记掺入脑氨基酸的测量值允许对TCA周期的型号和GlutAmate速率进行分析。由于神经元和星形胶质细胞等不同细胞类型之间的代谢，在大脑中尤其具有挑战性。在过去的十年中，神经元重新培养了谷氨酸。包括掺入谷氨酸和谷氨酰胺的C4位置的13C标签的时间课程，还包括C3和C2位置。这些附加数据有助于稳定拟合程序并减少拟合参数的不确定性。尽管现在可以在体内可行的与单个同位素剂相对应的多重组的分解检测，但是传统上，使用每个碳位置的总13C标签进行代谢建模，而忽略了来自多标记分子的其他信息。这些单独的同位素体在13C光谱中被发现为不同的多重组，提供了有价值的信息，可用于改善代谢建模研究的鲁棒性。这在心脏中已经证明了这一点，但尚未被利用用于大脑研究。这项协作的目的是通过开发可以使用此信息的模型来充分利用倍数标记的同位素的信息。我们预计这项工作将导致新的代谢建模方法，这些方法可以最佳地使用高度特定的信息，这些信息可以通过13C NMR获得，并且最近也可以在体内获得，最终增加了大脑中代谢建模研究的鲁棒性和精度。这很重要，因为脑代谢通量的13C NMR测量将提供一种直接和非侵入性测量葡萄糖代谢和人类大脑中谷氨酸神经传递的方法。 初步数据：研究设计-1。开发和实施一个两室模型，其中包含来自单个单独和多重标记的同位素的13C时间课程的信息。 2。使用蒙特卡洛模拟的新模型评估新模型的可靠性，并将其与拟合每个碳位置的总13C标签进行比较，使用在不同的3下注入[1,6-13C2]葡萄糖在不同3的[1,6-13C2]葡萄糖下验证新模型。评估新模型的可靠性。 方法 - 新模型将基于用于脑代谢研究的最新两室模型，以及在Utsouth -Western开发的方法，以包括来自单个同位素剂的信息。 这将包括以下同位素的信息，可以在9.4 Tesla中在体内检测到：（谷氨酸GLUC4S，GLUC4D43，GLUC3S，GLUC3S，GLUC3D，GLUC3T，GLUC3T，GLUC2S，GLUC2D23，GLUC2D23，GLUC2D21，GLUC2DD），GLUTAMINE（GLUTAMINE）（GLNC4S，GLNC4S，GLNC4D，GLNC4D） GLNC3D，GLNC3T，GLNC2S，GLNC2D23，GLNC2D21，GLNC2DD）。在第二步中，也可以包括来自天冬氨酸和GABA同位素的信息。在输注[1,6-13C2]葡萄糖期间，将在大鼠大脑中获得体内光谱，并将使用程序LCMODEL进行定量，以获取用于多重标记的同位素的时间疗程。结果13C时间课程将使用13C NMR来反映13C NMR，使用13C NMR来反映13C NMR，将其量化为末端。