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: 7454155
• 负责人: BENJAMIN F CRAVATT
• 金额: $ 30.26万
• 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/7454155
• 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，其中涉及广泛的生理过程，包括疼痛，炎症和药物成瘾。 FAA原型Anandamide是中央大麻素（CB1）受体的内源配体。尽管Anandamide在体外结合并激活CB1受体，但由于快速分解代谢，该FAA仅诱导体内大麻素行为效应。该提案的目的是识别和表征调节体内anandamide和其他生物活性FAA功能的酶。一种负责在体内终止FAA信号的候选酶是脂肪酸酰胺水解酶（FAAH），它在体外水解了Anandamide和相关的FAAS。为了测试FAAH在体内调节FAA功能中所扮演的角色，我们创建了faah-knockout [faah（ - / - ）小鼠。 FAAH（ - / - ）小鼠的内源性anandamide（和其他FAA）的内源性大脑水平大大提高，并且表现出降低的疼痛感，而疼痛感被CB1拮抗剂逆转。这些数据表明FAAH是体内FAA信号传导的关键调节剂，设置了调节疼痛感知的内源性大麻素（EC）音调。最近，我们设计了一种转基因方法来限制FAAH对特定组织的表达，从而使我们能够确定外围FAA通过与CB受体无关的机制调节炎症。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性疼痛中发挥的作用。此外，基于我们最近发现的与药物使用问题有关的人类FAAH基因突变的基础，我们将比较FAAH（+/+）和（ - / - ）小鼠的药物依赖性和戒断反应。最后，我们将创建和分析缺乏候选FAA生物合成酶的基因敲除小鼠。这些研究将阐明调节体内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标。