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 该提案的目标是确定是否减少脂肪酸结合蛋白 7 (FABP7) FABP 的表达可改善肌萎缩侧索硬化症 (ALS) 模型中的运动神经元变性。 属于小 (~15kDa) 且广泛表达的细胞内蛋白家族。所有 FABP 均表现出高亲和力。 饱和和不饱和长链脂肪酸以及其他脂质的可逆结合。 FABP 被认为是脂肪酸的生物学上沉默的伴侣，但现在已经清楚 FABP 是核心 脂质代谢、能量稳态和炎症的调节因子参与脂肪酸。 新陈代谢调节它们的摄取和运输，但也可以通过分布调节信号传导过程 和/或核受体的螯合配体，例如过氧化物酶体增殖物激活受体 (PPAR) FABP7（也称为脑脂质结合蛋白，BLBP）在神经干细胞中表达。 在整个发育过程中，其表达减少并仅限于星形胶质细胞和放射状胶质细胞 成人中枢神经系统中的神经胶质细胞上调多种 FABP7 表达。 为了有效地运输和捐赠结合的配体，FABP 在相同的情况下表现出亲和力。 然而，FABP 表达的上调可以影响 PPAR 的范围或稍弱。 产生“下沉效应”，负面调节 PPAR 内源配体的可用性（即增加 FABP 的细胞内水平将导致 PPAR 激活减少）。 参与协调细胞内代谢和炎症途径的基因因此降低了 PPAR。 活性可能有助于改变脂质介导的信号传导和 NF-kB 激活，这是 ALS 的两个显着特征 我们的数据首次表明 FABP7 上调可能是导致这种减少的原因。 使用细胞培养物和小鼠观察 ALS 星形胶质细胞中 PPAR 活性和伴随的 NF-kB 活性增加。 在模型中，我们将评估减少 FABP7 表达应恢复正常活性的假设 这两个相互关联的网络可以潜在地提供针对星形胶质细胞介导的运动的保护 ALS 模型中的神经元死亡。