Noninvasive Study of Cerebral ATP Metabolism, Bioenergetics and Brain Function

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）神经成像方法已经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，这些方法依赖于由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。在过去的几年里，我们进行了一系列的研究，这表明在体内的能力，和可行性的31 P磁共振波谱结合磁化传递（MT）技术在磁场直接测量在大脑中的氧化磷酸化率。这些引人注目的发展导致了我们的核心假设：体内31 P MT方法适用于测量和定量成像由Pi和ADP合成ATP的净脑代谢速率（CMRATP），并且该MR测量速率由氧化磷酸化速率主导，氧化磷酸化速率直接反映电子传递链与F1 F0-F1 F1的偶联效率之间的乘积。线粒体ATP酶反应和脑耗氧率（CMRO 2）;这种体内方法的验证和建立，它与CMRO 2的直接测定结合使用，将为非侵入性研究氧化ATP代谢在调节与以下相关的神经能量学中的中心作用提供宝贵的神经成像方式：脑功能和功能障碍。为了验证这一假设，我们提出：1）进一步改进在体31 P MT测量和定量方法，以准确地测定动物脑中的CMRATP; 2）使用高-在静息脑中的现场体内17 O MRS成像方法，以检查31 P MT测量的CMRATP是否与从相应的CMRATP中估计的净氧化磷酸化速率匹配。CMRO 2和P：O比值，以及在较宽的生理范围内它是否对脑活动水平敏感; 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结果相关联，以提供对神经-ATP-代谢耦合关系的新见解。本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：一个基本的和直接的测量大脑ATP能量;并了解可能的作用，ATP氧化代谢的神经能量学和神经生理学支持正常的大脑功能。公共卫生相关性：线粒体中的氧化磷酸化缺陷与许多脑疾病有关，特别是神经退行性疾病和衰老问题。虽然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。

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.