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

基本信息

批准号：
7756555
负责人：
Wei Chen
金额：
$ 51.73万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-15 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7756555
关键词：
ATP Synthesis Pathway ATP phosphohydrolase Address Adenosine Triphosphate Age Aging Anesthesia procedures Animals Applications Grants Bioenergetics Brain Brain Diseases Budgets Cells Cerebrum Clinical Clinical Research Consumption Coupling Data Development Diagnosis Electrical Engineering Electron Transport Electrophysiology (science)Energy Metabolism Enzymes Felis catus Frequencies Functional disorder Glycolysis Pathway 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 dosage extracellular imaging modality improved in vivo inorganic phosphate insight interest magnetic field neuroimaging neurophysiology neurotransmission public health relevance response success tool

项目摘要

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）为静息和活化大脑中的大多数细胞活性提供了能量。最近开发的光学和磁共振（MR）神经影像学方法彻底改变了我们研究大脑的能力，并更新了我们对涉及正常脑功能和脑部疾病的脑生物能学的兴趣。但是，这些方法依赖于神经元活性引用的二级代谢和生理过程，并且不提供对细胞能量学的直接度量。在过去的几年中，我们进行了一系列研究，这些研究证明了体内31p MR光谱与超高场的磁化转移（MT）技术的能力和可行性，以直接测量大脑中氧化磷酸化的速率。这些引人入胜的发展导致了我们的中心假设：体内31p MT方法适用于从PI和ADP（CMRATP）中测量和定量成像ATP合成的净大脑代谢速率（CMRATP），并且该MR测量速率由氧化磷酸化速率主导，这是直接反映了氧化磷酸化的速率，该速率在氧化磷酸化速率上反映了coupplory off coupploration of coupl效率 - 线粒体和脑氧的消耗率（CMRO2）；这种体内方法的验证和建立及其与CMRO2的直接确定结合使用，将为非侵入性研究与脑功能和功能障碍相关的神经发电学在调节神经发电机中的氧化ATP代谢在调节神经发电机中的核心作用。为了检验这一假设，我们提出：1）进一步改善体内31p MT测量和定量方法，以准确确定超高田中动物脑中的CMRATP； 2）在静止大脑时使用高场In Vivo进行CMRATP和CMRO2进行同时测量，以检查31p MT是否测量CMRATP是否与相应的CMRO2和P：O比相应的氧化磷酸化速率以及在大脑范围内均与大脑相关的范围匹配，并符合相应的氧化磷酸化率。 3）使用视觉刺激进行功能研究，以检查激活视觉皮层中CMRATP是否增加，以支持更高的能量需求和刺激引起的神经元活性； 4）在静息和刺激动物大脑中进行细胞外神经元录制研究，并将电生理学结果与CMRATP结果相关联，以提供对神经-ATP-ATP-象代谢偶联关系的新见解。这项研究的意义在于两层：建立用于成像CMRATP的独特神经影像的方式：脑ATP能量的基本和直接测量；并了解氧化性ATP代谢在神经生成术和神经生理学中的可能作用在支持正常脑功能方面。公共卫生相关性：线粒体中的氧化磷酸化不足与众多脑部疾病有关，尤其是神经退行性和衰老问题。尽管该提案的主要目的不是直接解决特定的临床问题，但该研究项目的成功将为潜在的临床研究和诊断各种脑部疾病和神经退行性疾病提供强大的成像工具。