CREATINE KINASE AND BRAIN ENERGETICS

描述(调查人员摘要)：这是一个长远的目标 研究计划是了解ATP代谢的生理学或 在成熟和发育中的大脑中能量的产生和利用。 第二个目标是了解适应在ATP新陈代谢中的作用。 在能量缺乏(缺氧)状态下维持脑细胞活性 和高能量需求(癫痫发作)。关于这一点的主要假设 建议是肌酸激酶(CK)的活性，它催化 磷脂酰胆碱与三磷酸腺苷之间的磷酰化转移也密切相关。 将ATP合成与能源需求的大而快速变化相结合 具有成熟大脑的特点。第二个假设是，活动 CK亚型，特别是线粒体CK，对 在能量降低的情况下维持细胞能量 可用性。因此，对CK催化反应减少的适应 预计在癫痫发作期间，Rate将保持对ATP的密切调控 但不是缺氧。 本方案结合了体内31P-核磁共振 酶和代谢物的体外测量光谱学 在ATP新陈代谢中。脑CK活性在20-30之间的三种情况 正常成人皮质活动的百分比被利用；未成熟的， 喂食肌酸和大脑白质的类似物。这些研究 灰质和白质使用体积定位核磁共振波谱的比较 技巧。在其他活体核磁共振研究中，非定域光谱与 将经常获得高信噪比以提供接近 比较细胞能量、pH、EEG和EKG。 我们的预期是CK催化的反应的条件 心率低会导致低氧时的能量损失较大 比在成熟的大脑中看到的更多，在那里磷酸肌酸(PC)损失了30-50 百分比和ATP是稳定的。相比之下，三磷酸腺苷代谢的生理学 在CK快速或缓慢存在的情况下，预期的反应速率 在癫痫发作期间保持稳定的大脑ATP和PC中的小损失。 这些核磁共振研究的结果将提供对IN的理解 脑内ATP的体内调节，而体外研究将提供一种 对这些的分子和细胞基础的初步了解 代谢特性。这一理解将允许更合理地使用 无创临床新陈代谢脑监测的研究结果也将 对脑细胞疾病的发病机制有更清晰的认识 在伤情危急的临床条件下出现缺氧和癫痫。

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.