Role of FABP7 in ALS models

摘要 这项提案的目标是确定是否减少脂肪酸结合蛋白7（FABP 7） 表达改善肌萎缩侧索硬化（ALS）模型中的运动神经元变性。FABPs 属于一个小的（~ 15 kDa）和广泛表达的细胞内蛋白质家族。所有的FABP都表现出高亲和力 饱和和不饱和长链脂肪酸以及其他脂质的可逆结合。FABPs已经 被认为是生物学上沉默的脂肪酸伴侣，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剂。FABPs参与脂肪酸合成 代谢调节其摄取和运输，但也可以通过分布调节信号传导过程。 和/或核受体如过氧化物酶体增殖物激活受体的螯合配体 （PPARs）。FABP 7（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，其表达减少并局限于星形胶质细胞和放射状胶质细胞。 成年人中枢神经系统中的神经胶质细胞。反应性星形胶质细胞上调FABP 7在多种肿瘤中的表达 病理条件。为了有效地转运和提供结合的配体，FABPs在相同的配体中显示出亲和力。 范围或略弱于PPARs所表现出的。然而，FABPs表达的上调可以 产生“汇效应”，负调节PPARs的内源性配体的可用性（即，增加 FABPs的细胞内水平将导致PPARs活化降低）。PPAR控制着 参与协调细胞中代谢和炎症途径的基因。因此，降低的PPAR 活动可以导致改变脂质介导的信号传导和NF-κ B激活，这是ALS的两个突出特征。 星形胶质细胞我们的数据首次表明，FABP 7上调可能是导致细胞凋亡减少的原因。 ALS-星形胶质细胞中的PPAR活性和伴随的NF-κ B活性增加。使用细胞培养和小鼠 我们将评估降低FABP 7表达应该恢复正常活性的假设。 这两个相互连接的网络，可以潜在地提供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。

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.