Regulation of Neuronal Lipid Homeostasis By Thioesterases

Johns Hopkins University, Baltimore MD

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Abstract

DESCRIPTION (provided by applicant): Intracellular long chain fatty acyl-CoAs provide the substrate for acylation reactions for membrane phospholipid biosynthesis, protein palmitoylation and cellular oxidative energy among others. Neurons have unique roles for lipids that are distinct from other cell types and are equipped with specialized machinery for regulating intracellular lipids. Although it is widely appreciated that the lipid composition of neurons is critical for human development and defects in lipid metabolism result in severe and debilitating neurological disease, there is a dearth of understanding about how neurons regulate intracellular lipid metabolism at a fundamental level. We have found that neuronal-specific acyl-CoA thioesterases are critical for neuronal development and function. We hypothesize that acyl-CoA thioesterase 7 (ACOT7) functions at an essential regulatory step for fatty acid utilization in neurons and that dysregulation of ACOT7 results in neurological dysfunction. To test this hypothesis we propose three specific aims: 1) Determine the role of ACOT7 in regulating cellular lipid metabolism. 2) Determine the neuron-specific role of ACOT7 in lipid metabolism and 3) Determine the role of ACOT7 in neurological pathophysiology.