The distinct roles of AMPK in neurons and astrocytes following stroke

AMPK 在中风后神经元和星形胶质细胞中的独特作用

• 批准号: 8445979
• 负责人: Jun Li
• 金额: $ 18.85万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445979
• 关键词: 5' -AMP-activated protein kinase; Ablation; Acidosis; Area; Astrocytes; Autophagocytosis; Blood - brain barrier anatomy; Blood flow; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Calcium; Catabolic Process; Cause of Death; Cell Survival; Cells; Cellular Stress; Cerebral Ischemia; Cerebrum; Clinical; Complex; Development; Edema; Energy Metabolism; Energy Supply; Enzymes; Exploratory/Developmental Grant; Failure; Fatty Acids; Floods; Functional disorder; Future; Gene Expression; Glucose; Glucose Transporter; Glycogen; Glycolysis; Goals; Hyperglycemia; Hypoxia; Infarction; Inflammation; Injury; Intervention; Investigation; Ischemia; Ketones; Knockout Mice; Lead; Mediating; Metabolic; Metabolic Pathway; Metabolism; Microglia; Middle Cerebral Artery Occlusion; Modeling; Molecular; Mus; Neurons; Outcome; Pathway interactions; Peripheral; Pharmaceutical Preparations; Phase; Production; Protein Isoforms; Recovery of Function; Relative (related person); Reperfusion Therapy; Research; Role; Signal Transduction; Stroke; Technology; Testing; Tissues; Up-Regulation; acute stroke; brain cell; cell type; clinically significant; disability; energy balance; excitotoxicity; fatty acid oxidation; nanoparticle; novel; response; sensor

DESCRIPTION (provided by applicant): AMP-activated protein kinase (AMPK) is emerging as a key sensor of brain energy balance. In the periphery, AMPK acutely regulates cellular metabolism and chronically regulates gene expression, reducing energy storage and increasing energy production (glycolysis, fatty acid oxidation and glycogen utilization). We have demonstrated that AMPK is highly expressed in brain and is rapidly activated in energy deprived states such as ischemia. However, the consequences of AMPK activation in stroke may be complex as the two major types of brain cells, neurons and astrocytes, are metabolically distinct. Unlike peripheral tissues, neurons are lacking the key enzymes to produce ATP via glycolysis, the major ATP-generating pathway activated during ischemia. In addition, neurons do not oxidize fatty acids efficiently, and have no glycogen stores. Therefore it could be predicted that activating catabolic processes by up-regulation of neuronal AMPK during severe ischemia would propagate metabolic failure and acidosis. In contrast, astrocytes can perform glycolysis, oxidize fatty acids to form ketones, and store some glycogen providing an energy supply for ischemic neurons. Compelling evidence additionally demonstrates that through ATP production and release, astrocytes may protect neurons by reducing excitotoxicity, lowering calcium influx and decreasing microglia mediated inflammation. Activation of astrocytic AMPK will likely reduce cerebral ischemic injury. This highlights the importance of examining the effect of loss of AMPK selectively in astrocytes or neurons following stroke. We have developed mice that are deficient in the catalytic isoforms of AMPK in either neurons or astrocytes. We found that mice deficient in AMPK in astrocytes had worse functional recovery after stroke; interestingly we also observed increased hemorrhagic transformation in these astrocytic KO mice after stroke. The overall goal of this proposal is to first characterize stroke outcome on cel specific AMPK manipulation and secondly determine the metabolic response to such manipulation. Selectively targeting AMPK signaling, a fundamental metabolic pathway, will not only provide us with a better scientific understanding of basic neuronal and astrocytic energy dynamics, but will also allow us to identify cellular specific targets for future clinical development. PUBLIC HEALTH RELEVANCE: Stroke is the third leading cause of death in the U.S., and the most common cause of disability. AMPK is a key energy metabolic sensor, but its role in neurons and astrocytes may differ and produce significant and distinct effects on stroke outcome. In this application, we will initiate a focused investigation on the consequences of cell selective AMPK deletion an attempt to develop novel and specific treatments for stroke.

描述（由申请人提供）：AMP活化蛋白激酶（AMPK）正在成为大脑能量平衡的关键传感器。在外周，AMPK急性调节细胞代谢并慢性调节基因表达，减少能量储存并增加能量产生（糖酵解、脂肪酸氧化和糖原利用）。我们已经证明AMPK在脑中高度表达，并且在能量剥夺状态如缺血时被迅速激活。然而，中风中AMPK激活的后果可能是复杂的，因为两种主要类型的脑细胞，神经元和星形胶质细胞，在代谢上是不同的。与外周组织不同，神经元缺乏通过糖酵解产生ATP的关键酶，糖酵解是缺血期间激活的主要ATP产生途径。此外，神经元不能有效地氧化脂肪酸，并且没有糖原储存。因此，可以预测，在严重缺血期间通过上调神经元AMPK来激活分解代谢过程将传播代谢衰竭和酸中毒。相比之下，星形胶质细胞可以进行糖酵解，氧化脂肪酸形成酮，并储存一些糖原为缺血神经元提供能量供应。令人信服的证据还表明，通过ATP的产生和释放，星形胶质细胞可以通过减少兴奋性毒性，降低钙内流和减少小胶质细胞介导的炎症来保护神经元。星形胶质细胞AMPK的激活可能会减轻脑缺血损伤。这突出了检查影响的重要性 AMPK在中风后星形胶质细胞或神经元中的选择性丢失。我们已经开发出在神经元或星形胶质细胞中缺乏AMPK催化亚型的小鼠。我们发现星形胶质细胞中AMPK缺陷的小鼠在中风后功能恢复较差;有趣的是，我们还观察到这些星形胶质细胞KO小鼠中风后出血性转化增加。该提案的总体目标是首先表征细胞特异性AMPK操纵的中风结果，其次确定对这种操纵的代谢反应。选择性靶向AMPK信号传导，一个基本的代谢途径，不仅将为我们提供一个更好的科学理解的基本神经元和星形胶质细胞的能量动力学，但也将使我们能够确定细胞的具体目标，为未来的临床开发。 公共卫生相关性：中风是美国第三大死亡原因，也是导致残疾的最常见原因AMPK是一种关键的能量代谢传感器，但它在神经元和星形胶质细胞中的作用可能不同，并对卒中结局产生显著而独特的影响。在本申请中，我们将启动一个集中调查的后果细胞选择性AMPK删除，试图开发新的和具体的治疗中风。