Endocannabinoid Metabolic Enzymes: Structure, Function, In Vivo Inhibition

内源性大麻素代谢酶：结构、功能、体内抑制

• 批准号: 8279262
• 负责人: BENJAMIN F CRAVATT
• 金额: $ 117.64万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8279262
• 关键词: 2-arachidonylglycerol; Active Sites; Address; Anxiety; Behavior; Behavioral; Biochemical; Biochemical Pathway; CNR1 gene; Chemicals; Cognition; Communities; Complex; Degradation Pathway; Disease; Emotional; Endocannabinoids; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Esthesia; Ethanolamines; Genetic; Goals; Health; Human; Hydrolase; Inflammation; Instruction; Interdisciplinary Study; Knowledge; Lead; Lipids; Mental Depression; Metabolic; Metabolic Diseases; Metabolism; Methods; Nervous system structure; Pain; Pathway interactions; Peripheral; Physiological; Physiological Processes; Process; Proteomics; Research; Scientist; Signal Transduction; Structure; Therapeutic Agents; anandamide; behavioral pharmacology; chemical genetics; chronic pain; design; endogenous cannabinoid system; enzyme structure; experience; feeding; human disease; in vivo; inhibitor/antagonist; mutant; neurochemistry; neurophysiology; new therapeutic target; programs; three dimensional structure; tool

The endocannabinoids (ECs) A/-arachidonoyl ethanolamine (anandamide, AEA) and 2-arachidonoylglycerol (2-AG) are lipid transmitters that activate the central and peripheral cannabinoid receptors (CB1 and CB2, respectively) to regulate a broad range of physiological processes, including pain sensation, inflammation, cognition, emotional state, and feeding. The magnitude and duration of EC signaling are tightly regulated by hydrolytic enzymes. However, our understanding of the distinct biochemical pathways that terminate AEA and 2-AG signaling in vivo remains incomplete. Key outstanding questions include: 1) what are the mechanisms and three-dimensional structures of EC hydrolases? 2) what are the neurochemical and physiological consequences of perturbing the function of EC hydrolases in vivo? 3) do multiple hydrolases coordinately control 2-AG metabolism in vivo? and 4) do AEA- and 2-AG-dependent EC pathways regulate distinct mammalian behaviors? In this Program Project, we have assembled a multidisciplinary research team that aims to address these questions by developing and implementing cutting-edge chemical, enzymological, genetic, proteomic, structural, and behavioral pharmacology methods. Specifically, we plan to: 1) characterize the biochemical and cellular mechanisms for terminating EC signaling the nervous system (Project 1), 2) determine the crystal structures of key EC hydrolases, including apo-enzymes, inhibitor complexes, and active-site mutants (Project 2), and 3) evaluate the neurochemical and behavioral effects of disrupting EC hydrolases in vivo (Projects 3 and 4). The knowledge gained from these studies will be further applied towards the design of increasingly potent and selective inhibitors of EC hydrolases (Core), which should prove of great value as both research tools and potential therapeutic agents for the treatment of a range of human diseases, including chronic pain, depression, anxiety, and metabolic disorders..

内源性大麻素（ECS）A/-Arachidonoyl乙醇胺（Anandamide，AEA）和2-芳基烯丙基甘油 （2-ag）是激活中心和外周大麻素受体（CB1和CB2， 分别）调节广泛的生理过程，包括疼痛感觉，炎症， 认知，情绪状态和喂养。 EC信号的大小和持续时间受到严格调节 水解酶。但是，我们对终止AEA的独特生化途径的理解 体内的2-ag信号传导仍然不完整。关键问题包括：1） EC水解酶的机理和三维结构？ 2）什么是神经化学和 扰动体内EC水解酶功能的生理后果？ 3）做多个水解酶 在体内协调控制2-AG代谢？和4）进行AEA-和2-AG依赖性EC途径调节 独特的哺乳动物行为？在这个计划项目中，我们组装了一项多学科研究 旨在通过开发和实施尖端化学物质来解决这些问题的团队 酶，遗传学，蛋白质组学，结构和行为药理学方法。具体来说，我们计划 TO：1）表征生化和细胞机制，用于终止EC信号神经 系统（项目1），2）确定关键EC水解酶的晶体结构，包括apo-酶，， 抑制剂复合物和活动位点突变体（项目2），3）评估神经化学和行为 破坏体内EC水解酶的影响（项目3和4）。从这些研究中获得的知识将 进一步应用于越来越有效和选择性抑制剂的EC水解酶（Core）， 这应该证明具有研究工具和潜在治疗剂的巨大价值 一系列人类疾病，包括慢性疼痛，抑郁，焦虑和代谢疾病。