AMP Activated Kinase in Neurons

神经元中的 AMP 激活激酶

基本信息

批准号：
7154742
负责人：
Gabriele V Ronnett
金额：
$ 36.87万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-12-05 至 2008-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7154742
关键词：
5&apos -AMP-activated protein kinase 5-(tetradecyloxy)-2-furancarboxylic acid AICA ribonucleotide Affect Antibodies Apoptotic Biochemical Brain Carnitine O-Palmitoyltransferase Catabolic Process Cell Death Cellular Stress Cessation of life Condition Contralateral Data Development Energy-Generating Resources Enzymes Failure Fatty-acid synthase Gene Expression Goals Hippocampus (Brain)Hypoxia In Vitro Infarction Intervention Investigation Ischemia Knockout Mice Lipids Location Mediating Metabolic Metabolic Pathway Metabolic stress Metabolism Methodology Mitochondria Modeling Molecular Neuronal Injury Neurons Nitric Oxide Synthase Nutrient Oxidative Stress Pathway interactions Perception Peripheral Peroxonitrite Physiological Physiological reperfusion Play Positioning Attribute Process Proteins Reaction Regulation Reperfusion Therapy Research Personnel Role Side Signal Pathway Signal Transduction Slice Starvation Stress Stroke Stroke Volume Therapeutic Intervention Time Western Blotting complement C2a deprivation design energy balance etomoxir fatty acid metabolism in vitro Model in vivo in vivo Model inhibitor/antagonist long chain fatty acid neuronal survival neuroprotection novel oxidation research study response sensor size

项目摘要

DESCRIPTION (provided by applicant): Despite significant advances in our understanding of the consequences of neuronal stress at molecular levels, interventions for neuronal injury, as in stroke, remain elusive. One approach is to identify changes in neuronal metabolism incurred as a consequence of oxidative or metabolic stress that may be neuroprotective, or, alternatively, that may be pro-apoptotic. AMP-activated protein kinase (AMPK) is a known sensor of peripheral energy balance, and is activated when energy sources are low. Peripherally, AMPK acutely regulates cellular metabolism and chronically regulates gene expression. We demonstrated that AMPK in highly expressed in neurons and responds to metabolic challenges by altering neuronal metabolism, suggesting that AMPK may play a physiological role in regulating neuronal energy balance. However, AMPK activation appears to be deleterious in stroke models, in a parallel line of investigation, we have established roles for the fatty acid synthase (FAS) pathway and carnitine palmitoyltransferase (CPT-1) in metabolism and as targets for modulating cellular energy utilization/perception. We have shown that modulation of these pathways by synthetic FAS inhibitors/CPT-1 stimulators that we designed, such as C75, can alter neuronal metabolism. Most recently, we have combined these lines of investigation and shown that C75 inhibits AMPK activation in vitro and in vivo and significantly reduces stroke volume. Our hypothesis is that AMPK plays a role in neuronal energy perception, but its over-activation with metabolic failure is deleterious; furthermore, modulation of the FAS/CPT-1 pathway alters neuronal metabolism to inhibit AMPK and produce neuroprotection under conditions of cellular stress. Aim 1 will use in vitro models to define the regulation of AMPK activity in neurons. Aim 2 will study the role and regulation of AMPK in an ischemia-reperfusion model. Aim 3 will determine the mechanisms by which modulation of the FAS and CPT-1 activities alters AMPK activity and affords neuroprotection.

描述（由申请人提供）：尽管我们在分子水平上对神经元应激后果的理解取得了重大进展，但对神经元损伤（如中风）的干预措施仍然难以捉摸。一种方法是识别由于氧化或代谢应激而引起的神经元代谢变化，这些变化可能是神经保护性的，或者可能是促凋亡的。 AMP 激活蛋白激酶 (AMPK) 是一种已知的外周能量平衡传感器，当能量来源较低时会被激活。在外周，AMPK 敏锐地调节细胞代谢并长期调节基因表达。我们证明 AMPK 在神经元中高表达，并通过改变神经元代谢来应对代谢挑战，这表明 AMPK 可能在调节神经元能量平衡中发挥生理作用。然而，AMPK 激活在中风模型中似乎是有害的，在平行的研究中，我们已经确定了脂肪酸合酶 (FAS) 途径和肉碱棕榈酰转移酶 (CPT-1) 在代谢中的作用以及作为调节细胞能量利用的靶标/洞察力。我们已经证明，通过我们设计的合成 FAS 抑制剂/CPT-1 刺激剂（例如 C75）对这些途径的调节可以改变神经元代谢。最近，我们结合了这些研究，结果表明 C75 在体外和体内抑制 AMPK 激活，并显着减少每搏输出量。我们的假设是 AMPK 在神经元能量感知中发挥作用，但其因代谢衰竭而过度激活是有害的；此外，FAS/CPT-1 通路的调节会改变神经元代谢，从而抑制 AMPK 并在细胞应激条件下产生神经保护作用。目标 1 将使用体外模型来定义神经元中 AMPK 活性的调节。目标 2 将研究 AMPK 在缺血再灌注模型中的作用和调节。目标 3 将确定调节 FAS 和 CPT-1 活性改变 AMPK 活性并提供神经保护的机制。