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AMPK, metabolism and ALS

AMPK、新陈代谢和 ALS

基本信息

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
项目类别：
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&apos -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

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.