Regulation of Neuronal Lipid Homeostasis By Thioesterases

硫酯酶对神经元脂质稳态的调节

• 批准号: 8417333
• 负责人: Michael J. Wolfgang
• 金额: $ 1.37万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8417333
• 关键词: Acyl Coenzyme A; Acylation; Affect; Alzheimer' s Disease; Behavior; Behavioral Assay; Biochemical; Biological Assay; Brain; Cells; Characteristics; Coenzyme A; Defect; Development; Diet; Enzyme Kinetics; Enzymes; Fatty Acids; Fatty acid glycerol esters; Fibroblasts; Functional disorder; Goals; Homeostasis; Human Development; In Vitro; Knock-out; Knockout Mice; Length; Lipids; Membrane; Metabolic; Molecular; Motor Neurons; Nervous System Physiology; Nervous system structure; Neurodegenerative Disorders; Neurologic; Neurologic Dysfunctions; Neurons; Nonesterified Fatty Acids; Oxidative Stress; Parkinson Disease; Pathway interactions; Pattern; Phospholipids; Physiological; Play; Positioning Attribute; Protein Biosynthesis; Proteins; Reaction; Recombinants; Regulation; Role; Specificity; Stimulus; Structure; System; Testing; Work; Zebrafish; base; cell type; enzyme activity; fatty acid metabolism; fatty acid oxidation; feeding; in vivo; insight; lipid metabolism; long chain fatty acid; mouse model; mutant; nervous system disorder; neuron development; neuron loss; neurophysiology; neuroprotection; oxidative damage; palmitoylation; relating to nervous system; selective expression

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.

描述（由申请人提供）：细胞内长链脂肪酰辅酶A为膜磷脂生物合成、蛋白棕榈酰化和细胞氧化能等酰化反应提供底物。神经元对脂质具有独特的作用，与其他细胞类型不同，并且配备有用于调节细胞内脂质的专门机制。虽然人们广泛认识到神经元的脂质组成对人类发育至关重要，并且脂质代谢缺陷会导致严重和衰弱的神经系统疾病，但对神经元如何在基本水平上调节细胞内脂质代谢缺乏了解。我们已经发现，神经元特异性酰基辅酶A硫酯酶对神经元发育和功能至关重要。我们假设酰基辅酶A硫酯酶7（ACOT7）在神经元中脂肪酸利用的重要调节步骤中起作用，并且ACOT7的失调导致神经功能障碍。为了验证这一假设，我们提出了三个具体的目标：1）确定ACOT7在调节细胞脂质代谢中的作用。2)确定ACOT7在脂质代谢中的神经元特异性作用和3）确定ACOT7在神经病理生理学中的作用。