NEUROPROTECTIVE EFFECTS OF KETONE BODY OXIDATION IN CEREBRAL ISCHEMIA

酮体氧化对脑缺血的神经保护作用

基本信息

批准号：
8770382
负责人：
KWEE LIU LIN THIO
金额：
$ 22.88万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-15 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8770382
关键词：
Abbreviations Acetoacetates Acetyl Coenzyme A Acetyl-CoA C-Acetyltransferase Acids Acute Adult Affect Animal Model Apoptotic Astrocytes Behavioral Assay Biochemical Biological Assay Brain Brain Injuries Brain Ischemia Carbohydrates Cause of Death Cell Death Cell membrane Cerebral Ischemia Chloride Ion Chlorides Citrate (si)-Synthase Citric Acid Cycle Coenzyme A Coenzyme A-Transferases Enzymes Equilibrium Event Exhibits Failure Fatty Acids Fatty acid glycerol esters Glutamates Hydroxybutyrates Interruption Intervention Ischemia Ischemic Brain Injury Ischemic Stroke Ketone Bodies Ketoses Ketosis Knockout Mice Lead Liver Measurement Metabolic Metabolism Middle Cerebral Artery Occlusion Mitochondria Modeling Morbidity - disease rate Mus Necrosis Neurons Nicotinamide adenine dinucleotide Nonesterified Fatty Acids Nuclear Magnetic Resonance Oxidoreductase Phospholipids Property Reaction Reactive Oxygen Species Reperfusion Injury Reperfusion Therapy Research Role Source Stroke Testing Thrombectomy Vascular blood supply acetoacetyl CoA brain tissue disability experience fatty acid oxidation high risk ketogenic diet malic enzyme mortality neuroprotection oxidation public health relevance quantum response small molecule succinyl-coenzyme A thrombolysis triphenyltetrazolium

项目摘要

DESCRIPTION (provided by applicant): Stroke is a leading cause of morbidity and mortality in the US despite the availability of therapies such thrombolysis and thrombectomy. Focal ischemic stroke occurs when the blood supply to a portion of the brain is interrupted. The affected brain tissue experiences energy failure that can cause cell death. When the interruption is temporary, the ischemia reperfusion sequence initiates a cascade of events causing necrotic and apoptotic cell death. The metabolic response of the brain to energy failure is not completely understood, though one component of this response is a massive release of free fatty acids from plasma membrane phospholipids. Oxidation of these free fatty acids could produce ketone bodies. This project tests the hypothesis that locally produced ketone bodies within the brain are neuroprotective. This hypothesis extends the observation that ketone bodies administered exogenously or synthesized by the liver while on a ketogenic diet protect the brain from ischemic damage in animal models. Regardless of their source, whether neuroprotection from ischemia depends on ketone body oxidation is unknown. Ketone body oxidation requires the ketolytic enzyme (SCOT), which participates in the conversion of ketone bodies into acetyl CoA for entry into the tricarboxylic acid cycle. SCOT is present in neurons and astrocytes. Notably, astrocytes but not neurons oxidize fatty acids, and the synthesis of ketone bodies by astrocytes likely depends on SCOT. A role for SCOT in ketone body oxidation and synthesis is possible because the reaction it catalyzes is near equilibrium. The hypothesis that locally synthesized ketone bodies are neuroprotective during focal ischemia requires an astrocyte-neuron ketone body shuttle. Accordingly, astrocytes would oxidize fatty acids and need SCOT to synthesize ketone bodies. The astrocytes would then send the ketone bodies to neurons, which then oxidize them in a SCOT dependent manner. This model provides a framework to test the hypothesis that ketone bodies protect the brain from ischemia / reperfusion damage via a mechanism requiring their oxidation. This project will test this hypothesis by examining the effects of transient proximal middle cerebral artery occlusion (tMCAO) in neuron-specific and astrocyte-specific SCOT knockout mice using histological, biochemical, and behavioral assays.

描述（由申请人提供）：尽管有溶栓和血栓切除术等治疗方法，但中风是美国发病和死亡的主要原因。当大脑一部分的血液供应中断时，就会发生局灶性缺血性中风。受影响的脑组织会经历能量衰竭，从而导致细胞死亡。当中断是暂时的时，缺血再灌注序列会引发一系列事件，导致细胞坏死和凋亡。大脑对能量衰竭的代谢反应尚不完全清楚，尽管这种反应的一个组成部分是质膜磷脂中游离脂肪酸的大量释放。这些游离脂肪酸的氧化可以产生酮体。该项目测试了大脑内局部产生的酮体具有神经保护作用的假设。这一假说扩展了这样的观察：在动物模型中，生酮饮食期间外源施用或由肝脏合成的酮体可以保护大脑免受缺血性损伤。无论其来源如何，缺血的神经保护是否依赖于酮体氧化尚不清楚。酮体氧化需要酮解酶（SCOT），它参与酮体转化为乙酰辅酶A进入三羧酸循环。 SCOT 存在于神经元和星形胶质细胞中。值得注意的是，星形胶质细胞而不是神经元氧化脂肪酸，星形胶质细胞合成酮体可能取决于 SCOT。 SCOT 在酮体氧化和合成中发挥作用是可能的，因为它催化的反应接近平衡。局部合成的酮体在局灶性缺血期间具有神经保护作用的假设需要星形胶质细胞-神经元酮体穿梭。因此，星形胶质细胞会氧化脂肪酸并需要SCOT来合成酮体。然后星形胶质细胞将酮体发送到神经元，然后神经元以 SCOT 依赖性方式氧化它们。该模型提供了一个框架来检验酮体通过需要氧化的机制保护大脑免受缺血/再灌注损伤的假设。该项目将通过组织学、生化和行为分析，检查短暂性近端大脑中动脉闭塞（tMCAO）对神经元特异性和星形胶质细胞特异性 SCOT 敲除小鼠的影响，来检验这一假设。