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AMPK, metabolism and ALS

AMPK、新陈代谢和 ALS

基本信息

批准号：
9244083
负责人：
Robert G Kalb
金额：
$ 38.69万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-15 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9244083
关键词：
5&apos -AMP-activated protein kinase Adopted Adverse effects Alpha Cell 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 Intuition 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 Pharmacology Phenotype Population Positioning Attribute Prevalence Process Production Protein Isoforms Protein Kinase Proteins RNA Splicing Reactive Oxygen Species Reporter Ribosomes Subgroup Surveys Testing Therapeutic Intervention Toxic effect Translating Variant base cell type cholinergic neuron combat experience experimental study genetic manipulation juvenile animal knock-down mature animal metabolic phenotype mitochondrial dysfunction mutant neuronal metabolism neuronal survival new therapeutic target novel therapeutics older patient patient population precision medicine public health relevance response tool

项目摘要

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，这可通过降低细胞AMP/ATP比率或通过产生活性氧导致AMP活化蛋白激酶（AMPK）活化。活性AMPK通过抑制分解代谢和刺激合成代谢过程重新连接细胞代谢。虽然直观地激活AMPK应该对神经元有益，但在几种NDG模型中，AMPK激活已被证明对神经元有害。本研究的目的是探讨在肌萎缩侧索硬化症（ALS）的细胞模型中，神经元中激活的AMPK的损伤机制。表达突变SOD或TDP 43（模拟ALS）的神经元具有增强的糖酵解作为AMPK活化的函数。特定目标#1中的实验测试了以下假设：通过将糖酵解底物从己糖胺生物合成和戊糖磷酸途径（用于维持健康氧化还原状态和抑制未折叠蛋白质反应的关键途径）转移，激活的AMPK对神经元有害。为了将这些观察结果转化为ALS患者的潜在治疗方法，我们需要能够特异性地操纵神经元中的糖酵解-因为抑制胶质细胞中的糖酵解可能会产生不良影响。在具体目标#2中，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，并询问相关的mRNA以获得糖酵解酶的细胞类型特异性变体。在毒性蛋白质的环境中重新布线代谢可能是ALS患者亚组的报告者，该亚组可能对代谢靶向干预有反应。在具体目标#3中，我们将确定ALS患者和对照组中重新编程为神经元的成纤维细胞中代谢重新布线的患病率。了解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靶点。