Noninvasive Study of Cerebral ATP Metabolism, Bioenergetics and Brain Function

脑 ATP 代谢、生物能学和脑功能的无创研究

• 批准号: 8526576
• 负责人: Wei Chen
• 金额: $ 54.99万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8526576
• 关键词: ATP phosphohydrolase; Address; Adenosine Triphosphate; Aging; Anesthesia procedures; Animals; Applications Grants; Bioenergetics; Brain; Brain Diseases; Budgets; Cells; Cerebrum; Clinical; Clinical Research; Consumption; Coupling; Data; Development; Electrical Engineering; Electron Transport; Electrophysiology (science); Energy Metabolism; Enzymes; Felis catus; Frequencies; Functional disorder; Glycolysis Pathway; Health; Image; Imaging Device; Isotopes; Kinetics; Life; Link; Magnetic Resonance; Magnetic Resonance Spectroscopy; Measurement; Measures; Metabolic; Metabolism; Methodology; Methods; Mitochondria; Modality; Modeling; Muscle Contraction; Na(+)-K(+)-Exchanging ATPase; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Optics; Oxidative Phosphorylation; Oxidoreductase; Oxygen Consumption; Pathology; Pathway interactions; Phosphoglycerate Kinase; Photic Stimulation; Physiological; Physiological Processes; Physiology; Plague; Process; Production; Protons; Reaction; Research; Research Project Grants; Rest; Role; Series; Specific qualifier value; Stimulus; Techniques; Testing; Time; Validation; Variant; Visual Cortex; base; clinical Diagnosis; dosage; extracellular; imaging modality; improved; in vivo; inorganic phosphate; insight; interest; magnetic field; neuroimaging; neurophysiology; neurotransmission; response; success; tool

DESCRIPTION (provided by applicant): Energy metabolism is a fundamental process of life. Adenosine triphosphate (ATP) provides energy for most cellular activities in resting and activated brain. Recently developed optical and magnetic resonance (MR) Neuroimaging methods have revolutionized our ability to study the brain and renewed our interests in cerebral bioenergetics involving normal brain function and brain disease. However, these methods rely on secondary metabolic and physiologic processes invoked by neuronal activity and do not provide direct measure of the cellular energetics. In last few years, we have carried out a series of studies, which demonstrated the capability, and feasibility of the in vivo 31P MR spectroscopy in combined with magnetization transfer (MT) techniques at ultrahigh field for directly measuring the oxidative phosphorylation rate in the brain. These compelling developments have led to our central hypothesis: In vivo 31P MT approach is suitable for measuring and quantitatively imaging the net cerebral metabolic rate of ATP synthesis from Pi and ADP (CMRATP) and this MR measured rate is dominated by the rate of oxidative phosphorylation which directly reflects the product between the coupling efficiency of the electron transport chain to the F1F0-ATPase reaction in the mitochondria and the rate of cerebral oxygen consumption (CMRO2); the validation and establishment of this in vivo approach, and its use in conjunction with direct determinations of CMRO2 will provide an invaluable Neuroimaging modality for noninvasively studying the central role of oxidative ATP metabolism in regulating neuroenergetics associated with brain function and dysfunction. To test this hypothesis we propose: 1) to further improve in vivo 31P MT measurements and quantification methods for accurately determining CMRATP in animal brain at ultrahigh field; 2) to conduct concurrent measurements of CMRATP and CMRO2 using high-field in vivo 17O MRS imaging approach in resting brain to examine if the 31P MT measured CMRATP matches the net oxidative phosphorylation rate estimated from the corresponding CMRO2 and the P:O ratio, and if it is sensitive to the brain activity level under a wide physiological range; 3) to conduct functional studies using visual stimulation to examine if CMRATP increases in the activated visual cortex for supporting higher energy demand and stimulus-evoked neuronal activity; 4) to conduct extracellular neuron-recording studies in resting and stimulated animal brain, and to correlate electrophysiology results with CMRATP results for providing new insights into the neuro-ATP-metabolic coupling relationships. The significance of this research lies in two layers: to establish a unique Neuroimaging modality for imaging CMRATP: a fundamental and direct measure of brain ATP energy; and to understand the possible roles of oxidative ATP metabolism in neuroenergetics and neurophysiology for supporting normal brain function. PUBLIC HEALTH RELEVANCE: The oxidative phosphorylation deficit in mitochondria has been linked to numerous brain diseases, in particular, the neurodegenerative and aging problems. Although, the main objective of this proposal does not directly address specific clinical questions, the success of this research project would provide a powerful imaging tool for potential clinical research and diagnosis of various brain disorders and neurodegenerative diseases.

描述（由申请人提供）：能量代谢是生命的基本过程。三磷酸腺苷 (ATP) 为静息和激活的大脑中的大多数细胞活动提供能量。最近开发的光学和磁共振 (MR) 神经成像方法彻底改变了我们研究大脑的能力，并重新激发了我们对涉及正常脑功能和脑疾病的脑生物能量学的兴趣。然而，这些方法依赖于神经元活动引起的次级代谢和生理过程，并且不提供细胞能量学的直接测量。过去几年，我们开展了一系列研究，证明了体内31P MR波谱结合超高场磁化转移（MT）技术直接测量大脑氧化磷酸化率的能力和可行性。这些引人注目的发展引出了我们的中心假设：体内 31P MT 方法适合测量和定量成像 Pi 和 ADP 合成 ATP (CMRATP) 的大脑净代谢率，并且该 MR 测量的速率由氧化磷酸化速率主导，氧化磷酸化速率直接反映了电子传递链与 F1F0-ATPase 反应的耦合效率之间的乘积。 线粒体和脑耗氧率（CMRO2）；这种体内方法的验证和建立，及其与 CMRO2 直接测定的结合使用，将为无创研究氧化 ATP 代谢在调节与脑功能和功能障碍相关的神经能量学中的核心作用提供宝贵的神经影像学模式。为了检验这一假设，我们建议：1）进一步改进体内31P MT测量和定量方法，以在超高场下准确测定动物脑中的CMRATP； 2) 在静息脑中使用高场体内 17O MRS 成像方法同时测量 CMRATP 和 CMRO2，以检查 31P MT 测量的 CMRATP 是否与根据相应 CMRO2 和 P:O 比估计的净氧化磷酸化率匹配，以及它是否对宽生理范围下的大脑活动水平敏感； 3) 使用视觉刺激进行功能研究，以检查激活的视觉皮层中的 CMRATP 是否增加，以支持更高的能量需求和刺激诱发的神经元活动； 4）在静息和刺激的动物大脑中进行细胞外神经元记录研究，并将电生理学结果与CMRATP结果关联起来，为神经-ATP-代谢耦合关系提供新的见解。这项研究的意义在于两层：建立一种独特的神经影像模式来成像CMRATP：大脑ATP能量的基本和直接测量；并了解氧化 ATP 代谢在神经能量学和神经生理学中支持正常脑功能的可能作用。公共健康相关性：线粒体氧化磷酸化缺陷与许多脑部疾病有关，特别是神经退行性和衰老问题。尽管该提案的主要目标并不直接解决具体的临床问题，但该研究项目的成功将为各种脑部疾病和神经退行性疾病的潜在临床研究和诊断提供强大的成像工具。