Noninvasive Study of Cerebral ATP Metabolism, Bioenergetics and Brain Function

描述（申请人提供）：能量代谢是生命的基本过程。三磷酸腺苷（ATP）在休息和激活的大脑中为大多数细胞活动提供能量。最近发展的光学和磁共振（MR）神经成像方法已经彻底改变了我们研究大脑的能力，并重新引起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生代谢和生理过程，不能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，证明了体内31P磁共振光谱结合磁化转移（MT）技术在超高场下直接测量大脑氧化磷酸化速率的能力和可行性。这些令人信服的发展导致了我们的中心假设：体内31P MT方法适用于测量和定量成像Pi和ADP合成ATP的净脑代谢率（CMRATP），并且该MR测量率主要由氧化磷酸化率决定，氧化磷酸化率直接反映了线粒体中f1f0 -ATP酶反应的电子传递链耦合效率与脑耗氧量（cro2）之间的乘积；这种体内方法的验证和建立，以及将其与cmor2的直接测定相结合，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一种宝贵的神经成像方式。为了验证这一假设，我们提出：1)进一步改进体内31P MT测量和定量方法，以准确测定超高场下动物脑内CMRATP；2)在静息脑内采用高场体内17O MRS成像方法同时测量CMRATP和cmr2，检验测得的31P MT CMRATP是否与相应cmr2和P:O比值估算的净氧化磷酸化率相符，是否对大生理范围内的脑活动水平敏感；3)利用视觉刺激进行功能研究，以检测CMRATP是否在激活的视觉皮层中增加，以支持更高的能量需求和刺激诱发的神经元活动；4)在静息和受刺激的动物大脑中进行细胞外神经元记录研究，并将电生理结果与CMRATP结果相关联，为神经- atp -代谢耦合关系提供新的见解。本研究的意义在于两个层面：建立了一种独特的CMRATP成像的神经成像模式：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。公共卫生相关性：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。虽然，这项提议的主要目的不是直接解决具体的临床问题，但这项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.