CREATINE KINASE AND BRAIN ENERGETICS

描述：(申请人摘要)能量耦合过程全部使用ATP 原核细胞和真核细胞。这个项目的长期目标是 对三磷酸腺苷代谢(合成和利用)的生理学认识 发育成熟的大脑。第一个假设是 磷酸肌酸(PCR)/肌酸激酶(CK)/ATP系统，包括 线粒体CK(MICK)，将ATP合成与可变的ATP紧密结合 对成熟大脑的要求。第二个假设是，PCR/CK/ATP 系统是大脑ATP代谢适应改变状态的中心 能量供应(缺氧)或能量需求(癫痫发作)。第三个假设是 大脑中至少存在两个PCR/CK/ATP系统，其生理机制是 白质更喜欢骨骼肌，灰质更喜欢平滑肌肉。 脑内ATP代谢和PCR/CK/ATP系统的体内研究将使用 31)核磁共振波谱及其体外应用 孤立的、白色和灰色的氧气消耗的极谱测量 物质切片。核磁共振研究将测量CK催化的反应速度 以及缺氧和癫痫发作时的反应物浓度。在小鼠中， 信号将来自大脑灰质加白质。在仔猪身上， 信号将主要在灰质和白质中进行比较 切片。 脑内ATP代谢不同于成熟的三种情况 将对大脑皮层进行研究。第一个是在缺乏Mick in的小鼠身上 大脑。第二种情况是在喂食肌酸(Cr)或 一种类似物，可以增加或降低大脑对 缺氧。第三种情况是脑白质和灰质中的ATP代谢。 体外循环中代谢不成熟和成熟的仔猪。这些 研究将集中在缺氧和缺血的区域性影响上。 这些研究为研究区域内的ATP代谢提供了重要的新途径 发育成熟的大脑。这些假说的目的是 建立脑能量调节的生理学原理。这些 原则将是理解能源规则的作用(S)的核心 在正常脑活动和细胞病变等条件下 临床常见情况下的损伤，如中风和癫痫持续状态。 进一步的研究可能会产生直接的临床益处。 铬及其类似物在低氧条件下的神经保护作用第二个临床 对缺乏人类模型Mick的小鼠的研究将带来好处 涉及ATP代谢先天缺陷的疾病。

DESCRIPTION: (Applicant's Abstract) Energy coupled processes use ATP in all prokaryotic and eukaryotic cells. The long-term goal of this project is the physiologic understanding of ATP metabolism (synthesis and utilization) in developing and mature brain. The first hypothesis is that the phosphocreatine (PCr)/creatine kinase (CK)/ATP system, including the mitochondrial CK (MiCK), closely couples ATP synthesis to the variable ATP requirements in mature brain. A second hypothesis is that the PCr/CK/ATP system is central in adaptation of brain ATP metabolism to altered states of energy supply (hypoxia) or energy demand (seizures). A third hypothesis is that at least two PCr/CK/ATP systems exist in brain with the physiology of white matter liked skeletal muscle and gray matter more like smooth muscle. Brain ATP metabolism and PCr/CK/ATP systems will be studied in vivo using 31) nuclear magnetic resonance (NMR) spectroscopy and in vitro using polarographic measures of oxygen consumption in isolated and white and gray matter slices. The NMR studies will measure the CK catalyzed reaction rates and reactant concentrations during hypoxia and seizures. In mice the signals will come from cerebral gray plus white matter. In piglets, the signals will be compared in predominantly gray matter and white matter slices. Three conditions in which brain ATP metabolism is different from mature cerebral cortex will be studied. The first is in mice lacking MiCK in brain. The second condition is in mice which have been fed creatine (Cr) or an analog which either increases or decreases the brain sensitivity to hypoxia. The third condition is ATP metabolism in white and gray matter in metabolically immature and mature piglets on cardiopulmonary bypass. These studies will concentrate on regional effects of hypoxia and ischemia. These studies provide important new approaches to ATP metabolism in regions of the developing and mature brain. The hypotheses are designed to establish physiological principles of brain energy regulation. These principles will be central in understanding the role(s) of energy regualtion in conditions such as normal brain activation and pathogenesis of cellular injury in common clinical conditions such as stroke and status epilepticus. An immediate clinical benefit may arise from further studies of the neuroprotective effects of Cr and Cr analogs in hypoxia. A second clinical benefit will come from studies of mice lacking MiCK, a model for human diseases involving inborn errors of ATP metabolism.