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

基本信息

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
项目类别：
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&apos -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

项目摘要

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 激活蛋白激酶（AMPK）正在成为大脑能量平衡的关键传感器。在外周，AMPK 敏锐地调节细胞代谢并长期调节基因表达，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 在大脑中高度表达，并且在缺血等能量匮乏状态下迅速激活。然而，AMPK 激活在中风中的后果可能很复杂，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 生成途径。此外，神经元不能有效地氧化脂肪酸，并且没有糖原储备。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。相反，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毒性、减少钙流入和减少小胶质细胞介导的炎症来保护神经元。星形细胞 AMPK 的激活可能会减少脑缺血损伤。这凸显了检查效果的重要性中风后星形胶质细胞或神经元选择性丧失 AMPK。我们培育出了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，星形胶质细胞中缺乏 AMPK 的小鼠中风后的功能恢复较差；有趣的是，我们还观察到这些星形细胞敲除小鼠中风后出血转化增加。该提案的总体目标是首先表征细胞特异性 AMPK 操作的中风结果，其次确定对此类操作的代谢反应。选择性地靶向 AMPK 信号传导（一种基本代谢途径）不仅可以让我们对基本神经元和星形细胞能量动力学有更好的科学理解，而且还使我们能够确定未来临床开发的细胞特异性靶标。公共卫生相关性：中风是美国第三大死亡原因，也是最常见的残疾原因。 AMPK 是一种关键的能量代谢传感器，但其在神经元和星形胶质细胞中的作用可能不同，并对中风结果产生显着且独特的影响。在本申请中，我们将针对细胞选择性 AMPK 缺失的后果开展重点研究，试图开发新的、特异性的中风治疗方法。