AMPK, metabolism and ALS

AMPK、新陈代谢和 ALS

• 批准号: 9114785
• 负责人: Robert G Kalb
• 金额: $ 49.29万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-15 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9114785
• 关键词: 5' -AMP-activated protein kinase; AMP-activated protein kinase kinase; Adopted; Adverse effects; Amyotrophic Lateral Sclerosis; Animals; Astrocytes; Automobile Driving; Biochemical Reaction; Biosensor; C9ORF72; Cell model; Cells; Degenerative Disorder; Disease; Disease model; Enzymes; Fibroblasts; Frequencies; Genetic; Glycolysis; Glycolysis Inhibition; Grant; Health; Hexosamines; Human; Indolent; Intervention; Knowledge; Lead; Mediating; Messenger RNA; Metabolic; Metabolic Pathway; Metabolic stress; Metabolism; Modeling; Monitor; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Oligodendroglia; Oxidation-Reduction; Pathway interactions; Patients; Pentosephosphate Pathway; Pentoses; Phenotype; Population; Positioning Attribute; Prevalence; Process; Production; Protein Isoforms; Proteins; RNA Splicing; Reactive Oxygen Species; Reporter; Ribosomes; Subgroup; Surveys; Testing; Therapeutic Intervention; Toxic effect; Translating; Variant; base; cell type; cholinergic neuron; combat; experience; genetic manipulation; juvenile animal; knock-down; mature animal; metabolic phenotype; mitochondrial dysfunction; mutant; neuronal metabolism; neuronal survival; novel therapeutics; older patient; patient population; precision medicine; programs; public health relevance; research study; response; tool

 DESCRIPTION (provided by applicant): All neurodegenerative diseases (NDG) display mitochondrial dysfunction and this can lead to activation of AMP activated protein kinase (AMPK) either through a reduced cellular AMP/ATP ratio or via the production of reactive oxygen species. Active AMPK re-wires cellular metabolism by inhibiting catabolic and stimulating anabolic processes. While intuitively activated AMPK ought to be healthful for neurons, in several NDG models AMPK activation has been shown to be noxious to neurons. This proposal aims to identify the mechanism by which activated AMPK in neurons is injurious in cellular models of Amyotrophic Lateral Sclerosis (ALS). Neurons expressing mutant SOD or TDP43 (to model ALS) have enhanced glycolysis as a function of AMPK activation. Experiments in Specific Aim #1 test the hypothesis that by diverting glycolytic substrates away from the hexosamine biosynthetic and the pentose phosphate pathways - key pathways for maintaining healthy redox state and suppressing the unfolded protein response - activated AMPK is noxious to neurons. To translate these observations into a potential therapy for ALS patients we need to be able to manipulate glycolysis in neurons specifically - since inhibition of glycolysis in glial cells could have adverse effects. In Specific Aim #2, we will use genetically modified mice to isolate ribosomes from neurons and glial cells separately and interrogate the associated mRNA for cell type specific variants of glycolytic enzymes. Rewiring metabolism in the setting of toxic proteins may be reporter for a subgroup of ALS patients that could respond to metabolism-targeted intervention. In Specific Aim #3, we will determine the prevalence of metabolic re-wiring in fibroblasts re-programmed into neurons from ALS patients and controls. Understanding the neuron-specific adaptation to metabolic stress in NDG has the potential to uncover new targets for therapeutic intervention.

 描述（由申请人提供）：所有神经退行性疾病 (NDG) 均表现出线粒体功能障碍，这可能会通过降低细胞 AMP/ATP 比率或通过产生活性氧来激活 AMP 激活蛋白激酶 (AMPK)。通过抑制分解代谢和刺激合成代谢过程来重新连接细胞代谢虽然直观地激活 AMPK 对神经元来说应该是健康的，但在一些 NDG 模型中，AMPK 激活已被证明对神经元有害。该提案旨在确定神经元中激活的 AMPK 在肌萎缩性脊髓侧索硬化症 (ALS) 细胞模型中的损伤机制，表达突变型 SOD 或 TDP43（用于模型 ALS）的神经元通过 AMPK 激活增强糖酵解。在具体目标#1中测试了以下假设：通过将糖酵解底物从己糖胺生物合成和磷酸戊糖途径中转移出来——这是健康维持氧化还原状态的关键途径抑制未折叠的蛋白质反应——激活的 AMPK 对神经元有害。为了将这些观察结果转化为针对 ALS 患者的潜在疗法，我们需要能够操纵神经元中的糖酵解——因为抑制神经胶质细胞中的糖酵解可能会产生不利影响。具体目标#2，我们将使用转基因小鼠分别从神经元和神经胶质细胞中分离核糖体，并在有毒环境下重新连接代谢的细胞类型特异性糖酵解酶变异的相关 mRNA。蛋白质可能是 ALS 患者亚组的报告者，可以对代谢靶向干预做出反应。在特定目标#3中，我们将确定 ALS 患者和对照组的成纤维细胞中代谢重新连接的发生率。 NDG 中神经元对代谢应激的特异性适应有可能发现治疗干预的新目标。