Role of FABP7 in ALS models

FABP7 在 ALS 模型中的作用

• 批准号: 10415000
• 负责人: Marcelo R Vargas
• 金额: $ 38.21万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10415000
• 关键词: ALS pathology; ALS patients; Adult; Affect; Affinity; Amyotrophic Lateral Sclerosis; Astrocytes; Autopsy; Binding; Binding Proteins; Biology; Brain; Brain Stem; Cause of Death; Cell Culture Techniques; Cell physiology; Cells; Cellular Metabolic Process; Cessation of life; Coculture Techniques; Cytoplasmic Granules; DNA Sequence Alteration; Data; Defect; Development; Disease; Disease Progression; Down-Regulation; Energy Metabolism; Energy-Generating Resources; Environmental Exposure; Exhibits; Family; Fatty Acids; Functional disorder; Gene Expression; Genetic Transcription; Goals; Growth; Health; Homeostasis; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Knock-out; Lead; Ligands; Link; Lipid Binding; Lipids; Mediating; Metabolic; Metabolism; Mitochondria; Modeling; Molecular; Molecular Chaperones; Motor Cortex; Motor Neurons; Movement; Mus; Muscle; Muscle Weakness; Mutation; NF-kappa B; Nerve Degeneration; Neuraxis; Neuroglia; Neurons; Nuclear Receptors; Oxidative Stress; Paralysed; Pathogenicity; Pathologic; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Phenotype; Play; Process; Proteins; Publishing; Radial; Receptor Activation; Recording of previous events; Rest; Riluzole; Role; Shapes; Signal Transduction; Signaling Molecule; Spinal Cord; Symptoms; Therapeutic; Time; Transcription Factor 3; United States; Up-Regulation; effective therapy; experimental study; familial amyotrophic lateral sclerosis; fatty acid metabolism; fatty acid-binding proteins; in vivo; in vivo Model; induced pluripotent stem cell; insight; lipid metabolism; long chain fatty acid; mitochondrial dysfunction; motor neuron degeneration; mouse model; nerve stem cell; neuroinflammation; neuron loss; neurotoxic; novel therapeutic intervention; phenylmethylpyrazolone; prevent; response; sporadic amyotrophic lateral sclerosis; therapeutic target; uptake

Abstract The goal of this proposal is to establish whether decreasing fatty acid-binding protein 7 (FABP7) expression ameliorates motor neuron degeneration in amyotrophic lateral sclerosis (ALS) models. The FABPs belong to a family of small (~15kDa) and widely expressed intracellular proteins. All FABPs exhibit high affinity reversible binding of saturated and unsaturated long-chain fatty acids as well as other lipids. FABPs have been considered biologically silent chaperones of fatty acids, but it has now become clear that the FABPs are central regulators of lipid metabolism, energy homeostasis and inflammation. FABPs participate in fatty acid metabolism regulating their uptake and transport but can also regulate signaling processes by distributing and/or sequestering ligands for nuclear receptors such as peroxisome proliferator activated receptors (PPARs). FABP7 (also known as brain lipid binding protein, BLBP) is expressed in neural stem cells throughout development and its expression decreases and becomes restricted to astrocytes and radial-like glial cells in the adult central nervous system. Reactive astrocytes up-regulate FABP7 expression in multiple pathological conditions. To effectively transport and donate bound ligands, FABPs display affinities in the same range or slightly weaker than those exhibited by PPARs. However, up-regulation of FABPs expression can create a “sink effect”, negatively regulating the availability of endogenous ligands for PPARs (i.e., increased intracellular levels of FABPs will result in decreased PPARs activation). PPARs govern the expression of genes involved in coordinating metabolic and inflammatory pathways in the cell. Thus, decreased PPAR activity can contribute to altered lipid-mediated signaling and NF-kB activation, two prominent features of ALS- astrocytes. Our data show for the first time that FABP7 up-regulation may be responsible for the decreased PPAR activity and concomitant increase in NF-kB activity in ALS-astrocytes. Using cell culture and mouse models we will evaluate the hypothesis that decreasing FABP7 expression should restore normal activity of these two interconnected networks and can potentially provide protection against astrocyte-mediated motor neuron death in ALS models.

抽象的 该建议的目的是确定脂肪酸结合蛋白7（FabP7）是否减少 表达可以改善肌萎缩性侧索硬化症（ALS）模型中运动神经元变性。 Fabps 属于一个小（约15kDa）的家族，并属于广泛表达的细胞内蛋白质。所有Fabps都暴露了高亲和力 饱和和不饱和的长链脂肪酸以及其他脂质的可逆结合。 Fabps曾经 被认为是脂肪酸的生物静音伴侣，但现在已经很清楚的是Fabps是中心的 脂质代谢，能量稳态和炎症的调节剂。 Fabps参与脂肪酸 代谢调节其摄取和运输，但也可以通过分发来调节信号过程 和/或用于核接收器的隔离配体，例如过氧化物组增殖物激活受体 （PPARS）。 FABP7（也称为脑脂质结合蛋白BLBP）在神经干细胞中表达 在整个开发中及其表达下降，并局限于星形胶质细胞和径向样 成人中枢神经系统中的神经胶细胞。反应性星形胶质细胞上调了多个的FABP7表达 病理状况。为了有效地运输和捐赠结合的配体，Fabps在同一中显示亲和力 范围或比PPAR暴露的范围稍弱。但是，Fabps表达的上调可以 创建“下沉效应”，负面评估内源配体的可用性（即增加） 细胞内FABPS的水平将导致PPARS激活降低）。 PPAR控制的表达 涉及细胞中的代谢和炎症途径的基因。那减少了PPAR 活性可以导致脂质介导的信号传导和NF-KB激活改变，这是ALS-的两个突出特征 我们的数据显示FabP7上调可能是拒绝的 PPAR活性和ALS-核细胞中NF-KB活性的同时增加。使用细胞培养和小鼠 模型我们将评估以下假设：降低FabP7表达应恢复 这两个相互联系的网络，并有可能提供防止星形胶质细胞介导的电动机的保护 ALS模型中的神经元死亡。