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.