CREATINE KINASE AND BRAIN ENERGETICS

肌酸激酶和大脑能量

• 批准号: 3412170
• 负责人: DAVID HOLTZMAN
• 金额: $ 21.2万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-05-01 至 1996-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3412170
• 关键词: adenosine triphosphate; bioenergetics; brain metabolism; cerebral cortex; cerebral ischemia /hypoxia; chemical kinetics; creatine; creatine kinase; creatine phosphate; developmental neurobiology; electrocardiography; electroencephalography; enzyme activity; epilepsy; isozymes; laboratory rat; mitochondria; neurophysiology; nuclear magnetic resonance spectroscopy; swine; tegmentum

DESCRIPTION (Investigator's Abstract): The long-range goal of this research program is to understand the physiology of ATP metabolism or energy production and utilization in the mature and the developing brain. A second goal is to understand the role of adaptations in ATP metabolism in maintaining brain cell viability in states of energy deficit (hypoxia) and high energy demand (seizures). The primary hypothesis for this proposal is that the activity of creatine kinase (CK), which catalyzes the phosphoryl transfer between PC and ATP, also is central in closely coupling ATP synthesis to the large and rapid changes in energy demand characteristic of the mature brain. A second hypothesis is that activity of the CK isoforms, specifically the mitochondrial CK, is critical for maintaining cellular energy under conditions of decreased energy availability. Thus, adaptations to a decrease in CK catalyzed reaction rates are expected to maintain close regulation of ATP during seizures but not hypoxia. The present proposal combines in vivo 31P-nuclear magnetic resonance spectroscopy with in vitro measures of enzymes and metabolites involved in ATP metabolism. Three conditions, in which brain CK activity is 20-30 percent of the activity in normal adult cortex, are used; immaturity, feeding an analogue of creatine, and cerebral white matter. The studies comparing gray and white matter use volume localized NMR spectroscopic techniques. In the other in vivo NMR studies, non-localized spectra with high signal-to-noise will be acquired frequently to provide close comparisons of cellular energy, pH, EEG, and EKG. The expectation is that the conditions in which the CK-catalyzed reaction rate is low will be associated with larger energy losses during hypoxia than seen in the mature brain where phosphocreatine (PC) losses are 30-50 percent and ATP is stable. In contrast, the physiology of ATP metabolism in the presence of rapid or slow CK catalyzed reaction rates is expected to maintain stable brain ATP and a small loss in PC during seizures. The results of these NMR studies will provide an understanding of the in vivo regulation of brain ATP while the in vitro studies will provide an initial understanding of the molecular and cellular bases for these metabolic properties. This understanding will allow more rational use of non-invasive clinical metabolic brain monitoring.The results also will provide a clearer understanding of the pathogenesis of brain cellular injury during the critical clinical conditions of hypoxia and seizures.

描述（研究者摘要）：本研究的长期目标 研究计划是了解ATP代谢的生理学或 成熟和发育中的大脑的能量生产和利用。 第二个目标是了解适应在ATP代谢中的作用 在能量缺乏（缺氧）状态下维持脑细胞活力 高能量需求（癫痫发作）。 对此的主要假设是 建议是，肌酸激酶（CK）的活性，催化 PC和ATP之间磷酰基转移也是密切 将ATP合成与能源需求的巨大而快速的变化相结合 成熟大脑的特征。 第二个假设是， CK同工型，特别是线粒体CK，对于 在能量减少的情况下维持细胞能量 空房的 因此，对CK催化反应减少的适应 在癫痫发作期间， 而不是缺氧。 本建议结合体内31 P-核磁共振 光谱学与酶和代谢物的体外测量有关 在ATP代谢中。 三种情况，其中脑CK活性为20-30 正常成人皮质中活性的百分比，使用;未成熟， 喂食肌酸类似物和大脑白色物质。 研究 比较灰色和白色物质使用体积局部NMR光谱 技术.在其他体内NMR研究中，非局域化光谱与 将频繁地获得高信噪比 比较细胞能量、pH值、EEG和EKG。 预期CK催化反应的条件 在缺氧期间，心率较低将与较大的能量损失相关 在成熟的大脑中，磷酸肌酸（PC）的损失为30-50 %，ATP稳定。 相反，ATP代谢的生理学 在快速或缓慢CK催化反应速率的存在下， 维持癫痫发作期间脑ATP稳定和PC少量丢失。 这些核磁共振研究的结果将提供一个了解在 脑ATP的体内调节，而体外研究将提供一个 初步了解分子和细胞基础， 代谢特性 这种理解将允许更合理地使用 非侵入性临床代谢脑监测。结果也将 提供了一个更清楚的了解脑细胞的发病机制， 在缺氧和癫痫发作的关键临床条件下的损伤。