Enzymes that Regulate Fatty Acid Amide Function in Vivo

体内调节脂肪酸酰胺功能的酶

• 批准号: 7258908
• 负责人: BENJAMIN F CRAVATT
• 金额: $ 30.5万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7258908
• 关键词: Absence of pain sensation; Acute; Acute inflammatory pain; Addictive Behavior; Address; Adrenergic Agents; Amides; Anabolism; Analgesics; Anatomy; Animal Model; Animals; Behavior; Behavioral; Binding; Brain; Brain region; CNR1 gene; Cannabinoids; Catabolism; Catalepsy; Chronic inflammatory pain; Data; Dependence; Disruption; Drug Addiction; Drug abuse; Drug usage; Elevation; Endocannabinoids; Enzymes; Esthesia; Exhibits; Family; Fatty Acids; Genetic; Goals; Human; Hydrolase Gene; Hydrolysis; In Vitro; Inflammation; Knock-out; Knockout Mice; Lead; Learning; Ligands; Link; Lipids; Mediating; Memory; Methods; Modeling; Molecular; Mus; Mutation; Nervous system structure; Nociception; Opioid; Pain; Perception; Peripheral; Phenotype; Physiological; Physiological Processes; Physiology; Play; Prosencephalon; Proteins; Range; Regulation; Research; Research Design; Research Personnel; Role; SR141716; Signal Transduction; Stimulus; System; Testing; Tissues; Transgenic Animals; Transgenic Organisms; Withdrawal; addiction; adrenergic; anandamide; drug of abuse; fatty acid amide hydrolase; in vivo; inflammatory pain; inhibitor/antagonist; member; mouse model; natural hypothermia; nervous system disorder; programs; prototype; psychostimulant; receptor; response

DESCRIPTION (provided by applicant): Fatty acid amides (FAAs) are an emerging family of endogenous signaling lipids implicated in a broad range of physiological processes, including pain, inflammation, and drug addiction. A prototype FAA anandamide serves as an endogenous ligand for the central cannabinoid (CB1) receptor. Although anandamide binds and activates the CB1 receptor in vitro, this FAA induces only weak cannabinoid behavioral effects in vivo due to rapid catabolism. The objective of this proposal is to identify and characterize enzymes that regulate the function of anandamide and other bioactive FAAs in vivo. One candidate enzyme responsible for terminating FAA signals in vivo is fatty acid amide hydrolase (FAAH), which hydrolyzes anandamide and related FAAs in vitro. To test the role that FAAH plays in regulating FAA function in vivo, we have created FAAH-knockout [FAAH(-/-)] mice. FAAH(-/-) mice possess greatly increased endogenous brain levels of anandamide (and other FAAs) and display reduced pain sensation that is reversed by CB1 antagonists. These data indicate that FAAH is a key regulator of FAA signaling in vivo, setting an endocannabinoid (EC) tone that modulates pain perception. More recently, we have devised a transgenic method to restrict the expression of FAAH to specific tissues, allowing us to determine that peripheral FAAs regulate inflammation through a CB receptor-independent mechanism. In this application, we propose to extend our analysis of transgenic FAAH mouse models to examine the role that the EC/FAA system play in multiple forms of acute and chronic inflammatory pain. Additionally, building on our recent discovery of a mutation in the human FAAH gene linked to problem drug use, we will compare the drug dependence and withdrawal responses of FAAH(+/+) and (-/-) mice. Finally, we will create and analyze knockout mice lacking candidate FAA biosynthetic enzymes. These studies will elucidate the functions of key enzymes that regulate FAA signaling in vivo. These proteins may represent new targets for the treatment of pain, addiction, and other neurological disorders.

描述（由申请人提供）：脂肪酸酰胺（FAA）是一个新兴的内源信号脂质家族，涉及广泛的生理过程，包括疼痛、炎症和药物成瘾。原型 FAA anandamide 作为中枢大麻素 (CB1) 受体的内源性配体。尽管 anandamide 在体外结合并激活 CB1 受体，但由于快速分解代谢，这种 FAA 在体内仅诱导微弱的大麻素行为效应。该提案的目的是鉴定和表征体内调节 anandamide 和其他生物活性 FAA 功能的酶。负责体内终止 FAA 信号的一种候选酶是脂肪酸酰胺水解酶 (FAAH)，它在体外水解 anandamide 和相关的 FAA。为了测试FAAH在体内调节FAA功能中所起的作用，我们创建了FAAH基因敲除的[FAAH(-/-)]小鼠。 FAAH(-/-) 小鼠脑内内源性 anandamide（和其他 FAA）水平大大增加，并表现出疼痛感减弱，CB1 拮抗剂可逆转这种情况。这些数据表明，FAAH 是体内 FAA 信号传导的关键调节因子，设定调节疼痛感知的内源性大麻素 (EC) 基调。最近，我们设计了一种转基因方法，将 FAAH 的表达限制在特定组织，使我们能够确定外周 FAA 通过 CB 受体独立机制调节炎症。在此应用中，我们建议扩展对转基因 FAAH 小鼠模型的分析，以检查 EC/FAA 系统在多种形式的急性和慢性炎症疼痛中发挥的作用。此外，基于我们最近发现的与问题药物使用相关的人类 FAAH 基因突变，我们将比较 FAAH(+/+) 和 (-/-) 小鼠的药物依赖性和戒断反应。最后，我们将创建并分析缺乏候选 FAA 生物合成酶的基因敲除小鼠。这些研究将阐明体内调节 FAA 信号传导的关键酶的功能。这些蛋白质可能代表治疗疼痛、成瘾和其他神经系统疾病的新靶点。