MOLECULAR MECHANISMS--ISCHEMIA/REPERFUSION BRAIN INJURY

描述：（改编自研究者摘要）自由基- 介导的脂质和蛋白质损伤，改变线粒体电子 运输链活动和异常的组织代谢模式 与神经系统疾病的病理生理学密切相关 全脑缺血再灌注引起的。 整体 本项目的目标是描述 这些因素，并将其与观察到的神经功能障碍 对动物进行临床相关场景，包括 心脏骤停后30分钟至24小时恢复 自发循环 这些研究的具体目的是检验以下假设： (1)短暂的全身缺血会导致 线粒体呼吸和Ca 2+摄取活动的改变， 与延迟的再灌注诱导的改变不同。 （二） 脑缺血/再灌注所致的自由基损伤 影响蛋白质以及脂质存在于线粒体和其他 细胞隔室和膜。 (3)线粒体膜损伤 和酶失活导致的即时和延迟的改变， 心脏骤停后的脑能量代谢和ROSC。 （四） 临床上可行的灵感和大脑操作02 浓度改变分子、亚细胞和代谢的程度， 损伤，对应于神经损伤程度的差异 在这些不同的复苏方案下观察到的。 接近这些目标的方法将包括测量O2 离体脑的消耗、过氧化物形成和Ca 2+摄取 线粒体和毛地黄皂苷透化的突触神经体和PC 12 嗜铬细胞瘤细胞;脂质和蛋白质氧化的测定， 磷脂和游离脂肪酸部分的测量， 测定与糖酵解相关的代谢活动， TCA循环。 对具体参与的额外支持 亚细胞和代谢改变的发病机制 缺血/再灌注脑损伤将从结果的比较 用不同的动物治疗方案以及用 神经化学测量和组织学测试。 体外建模 细胞和亚细胞损伤也将有助于阐明 因果关系。 这些研究的意义 他们将提供独特的分子洞察力， 改变的生物能量学和自由基代谢在脑损伤中的作用 与心脏骤停和复苏以及其他形式的 包括中风和外伤的脑缺血。

DESCRIPTION: (Adapted from investigator's abstract) Free radical- mediated damage to lipids and proteins, altered mitochondrial electron transport chain activities and abnormal patterns of tissue metabolism are strongly implicated in the pathophysiology of neurological morbidity caused by global cerebral ischemia and reperfusion. The overall objective of this project is to characterize the relationships between these factors and to relate them to the neurological impairment observed with animals subjected to a clinically relevant scenario consisting of cardiac arrest followed by 30 minutes to 24 hours of restoration of spontaneous circulation. The specific aims of these studies are to test the following hypotheses: (1) A short period of global ischemia causes immediate and reversible alterations in mitochondrial respiratory and Ca2+ uptake activities that are distinguishable from delayed, reperfusion-induced alterations. (2) Free radical damage due to cerebral ischemia/reperfusion adversely affects proteins as well as lipids present within mitochondria and other cellular compartments and membranes. (3) Mitochondrial membrane damage and enzyme inactivation result in immediate and delayed alterations in cerebral energy metabolism following cardiac arrest and ROSC. (4) Clinically-feasible manipulations of inspired and brain 02 concentrations alter the degree of molecular, subcellular, and metabolic injury, corresponding to differences in the extent of neurological injury observed following these different resuscitation protocols. Methods of approach to these aims will include measurements of 02 consumption, peroxide formation and Ca2+ uptake by isolated brain mitochondria and digitonin-permeabilized synaptoneurosomes and PC12 pheochromocytoma cells; determinations of lipid and protein oxidation, measurements of phospholipid and free fatty acid moieties and determinations of metabolic activities associated with glycolysis and the TCA cycle. Additional support for involvement of specific subcellular and metabolic alterations in the pathogenesis of ischemia/reperfusion brain injury will come from comparison of results obtained with different animal treatment protocols as well as with neurochemical measurements and histological testes. In vitro modeling of cellular and subcellular injury will also assist in the elucidation of cause and effect relationships. The significance of these studies is that they will provide unique molecular insight into the roles that altered bioenergetics and free-radical-metabolism play in brain injury associated with cardiac arrest and resuscitation as well as other forms of cerebral ischemia including stroke and trauma.