NONINVASIVE STUDY OF CEREBRAL ATP METABOLISM, BIOENERGETICS AND BRAIN FUNCTION

脑 ATP 代谢、生物能量学和脑功能的非侵入性研究

• 批准号: 7954980
• 负责人: WEI CHEN
• 金额: $ 2.57万
• 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: 2009-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7954980
• 关键词: ATP phosphohydrolase; Adenosine Triphosphate; Animal Model; Animals; Automobile Driving; Bioenergetics; Brain; Cerebrum; Computer Retrieval of Information on Scientific Projects Database; Coupled; Coupling; Disease; Electrophysiology (science); Functional disorder; Funding; Grant; Heart; Human; Image; In Situ; Institution; Magnetic Resonance Imaging; Measurement; Measures; Metabolic; Metabolism; Methods; Mitochondria; Modality; Neurons; Oxidative Phosphorylation; Oxygen; Photic Stimulation; Physiological; Play; Reaction; Research; Research Personnel; Resources; Rest; Role; Source; Spectrum Analysis; Stimulus; Testing; United States National Institutes of Health; Visual Cortex; Work; extracellular; imaging modality; improved; in vivo; insight; neuroimaging; neurophysiology

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. Adenosine triphosphate (ATP), which mainly formed in mitochondria through oxidative phosphorylation and F1F0-ATPase, provides energy for driving most cellular activities in the brain. This oxidative ATP metabolism plays essential roles in brain bioenergetics, function and disease. The sole approach possible for directly assessing the metabolic rate of ATPase reaction in situ is the use of in vivo 31P MRS combined with magnetization transfer (MT). However, previous work of perfused heart suggested that the apparent ATP synthesis rate measured by in vivo 31P MT approach was not coupled with the net rate of oxidative phosphorylation and its change. In contrast, our recent work has shown that the measured cerebral metabolic rate of ATP (CMRATP) via ATPase reaction is closely matched with the net oxidative phosphorylation rate in anesthetized animals and awaked human, and it is also sensitive to the change of brain activity induced by varied baseline activity and/or brain stimulation. These compelling findings have led to our central hypothesis: In vivo 31P MT approach should be suitable for measuring and imaging CMRATP, which directly reflects the net rate of oxidative phosphorylation of ADP for producing the majority of brain ATP molecules; and establishment of this in vivo approach can provide an invaluable, completely noninvasive neuroimaging modality for studying the central roles of oxidative ATP metabolism in regulating neuroenergetics associated with brain function and dysfunction. This hypothesis will be tested by four specific aims: 1) to further optimize and improve in vivo 31P MT measurements and quantification methods for accurately determining CMRATP using an animal model at high field; 2) to conduct concurrent noninvasive measurements of CMRATP and the cerebral metabolic rate of oxygen (CMRO2) using our newly developed high-field in vivo 17O MRS imaging approach in resting brains with varied baseline activity levels, and to examine if CMRATP is sensitive to brain activity change, and if CMRATP correlates to the rate of oxidative phosphorylation under a wide physiological range of brain activity; 3) to conduct functional activation 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 under resting and activated conditions, and to correlate electrophysiology results with CMRATP results for providing new insights into the neuro-ATP-metabolic coupling relationships in the resting and activated brain. The significance of this research lies in two layers: to establish a unique neuroimaging modality for imaging CMRATP: a most fundamental and direct measure of brain energy; and to understand the possible roles of oxidative ATP metabolism in neuroenergetics and neurophysiology for supporting brain function and work.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 三磷酸腺苷（ATP）主要通过氧化磷酸化和F1 F0-ATP酶在线粒体中形成，为大脑中大多数细胞活动提供能量。这种氧化ATP代谢在大脑生物能量学、功能和疾病中起着重要作用。直接评价ATP酶反应代谢率的唯一方法是结合磁化转移（MT）使用体内31 P MRS。然而，以前的工作灌注心脏表明，在体内31 P MT方法测量的表观ATP合成速率与氧化磷酸化的净速率及其变化不耦合。与此相反，我们最近的工作表明，通过ATP酶反应测定的脑ATP代谢率（CMRATP）与麻醉动物和清醒人的净氧化磷酸化率密切匹配，并且对不同基线活动和/或脑刺激引起的脑活动变化敏感。这些令人信服的发现导致了我们的中心假设：在体内31 P MT方法应该适合于测量和成像CMRATP，它直接反映了ADP产生大部分脑ATP分子的氧化磷酸化净速率;这种体内方法的建立可以提供一种非常宝贵的，完全非侵入性的神经影像学模式，用于研究氧化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中心作用。本研究将从以下四个方面对这一假说进行验证：1）进一步优化和改进体内31 P MT测量和定量方法，以在高场下使用动物模型准确测定CMRATP; 2）使用我们新开发的高-在不同基线活动水平的静息脑中进行现场活体17 O MRS成像，并检查CMRATP是否对脑活动变化敏感，以及在广泛的生理脑活动范围内CMRATP是否与氧化磷酸化速率相关; 3）使用视觉刺激进行功能激活研究，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）在静息和激活条件下进行细胞外神经元记录研究，并将电生理学结果与CMRATP结果相关联，以提供对神经ATP的新见解，在休息和激活的大脑代谢耦合关系。这项研究的意义在于两个层面：建立一个独特的神经成像模式成像CMRATP：一个最基本和最直接的测量大脑能量;并了解可能的作用，氧化ATP代谢在神经能量学和神经生理学支持大脑功能和工作。