CREATINE KINASE AND BRAIN ENERGETICS

肌酸激酶和大脑能量

• 批准号: 2750834
• 负责人: DAVID HOLTZMAN
• 金额: $ 25.9万
• 依托单位: BRIGHAM AND WOMEN'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 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2750834
• 关键词: adenosine triphosphate; aminoacid analog; bioenergetics; brain metabolism; cerebral ischemia /hypoxia; creatine kinase; creatine phosphate; creatinine; disease /disorder model; generalized seizures; inborn metabolism disorder; laboratory mouse; mitochondria; nuclear magnetic resonance spectroscopy; polarography; swine

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.

描述：（申请人的摘要）能量耦合过程全部使用ATP。 原核和真核细胞。 该项目的长期目标是 ATP代谢（合成和利用）的生理学理解， 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ATP紧密耦合 成熟大脑的需求。 第二个假设是PCr/CK/ATP 系统是适应大脑ATP代谢的中心，以改变状态， 能量供应（缺氧）或能量需求（癫痫发作）。 第三个假设是 脑内至少存在两个PCr/CK/ATP系统， 白色物质更像骨骼肌，灰质更像平滑肌。 脑ATP代谢和PCr/CK/ATP系统将使用 31)核磁共振（NMR）光谱和体外使用 极谱法测定分离的、白色和灰色的氧消耗量 物质切片。 NMR研究将测量CK催化的反应速率 以及缺氧和癫痫发作期间的反应物浓度。 喂养老鼠 信号将来自大脑灰质和白色物质。 在仔猪中， 将在主要是灰质和白色物质中比较信号 切片 脑ATP代谢不同于成熟的三个条件 大脑皮层将被研究。 第一种是在缺乏MiCK的小鼠中， 个脑袋 第二种情况是在已经喂食肌酸（Cr）或 一种类似物，它可以增加或降低大脑对 缺氧 第三个条件是白色和灰质中的ATP代谢， 代谢不成熟和成熟的小猪进行心肺转流。 这些 研究将集中于缺氧和局部缺血的区域效应。 这些研究为研究区域内ATP代谢提供了重要的新途径 发育和成熟的大脑。 这些假设旨在 建立脑能量调节的生理学原理。 这些 原则将是理解能源调节作用的核心 在诸如正常脑激活和细胞的发病机制的情况下， 在常见的临床条件下，如中风和癫痫持续状态的损伤。 进一步的研究可能会产生直接的临床益处， Cr和Cr类似物在缺氧中的神经保护作用。 第二次临床 对缺乏MiCK的小鼠的研究将带来好处，MiCK是人类的一个模型。 先天性ATP代谢缺陷的疾病。