BIOSYNTHESIS OF ANANDAMIDE--A NOVEL EICOSANOID

新型二十烷酸阿南达胺的生物合成

• 批准号: 2443494
• 负责人: SUMNER HOWARD BURSTEIN
• 金额: $ 17.23万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-15 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2443494
• 关键词: G protein; amidases; antisense nucleic acid; arachidonate; biological signal transduction; cannabinoid receptor; cannabinoids; cell type; diacylglycerols; dimethylsulfoxide; eicosanoid metabolism; enzyme inhibitors; enzyme linked immunosorbent assay; ethanolamines; laboratory mouse; neuropharmacology; phospholipase A2; phospholipase D; phospholipids; radioimmunoassay; radiotracer; receptor binding; receptor coupling; stimulant /agonist; tissue /cell culture

The main goal of this application is to characterize the process involved in agonist-stimulated synthesis of anandamide (arachidonylethanolamine) in intact cells. A preliminary report (8) from this laboratory showed that agents capable of activating phospholipases to release free arachidonic acid appear to also promote anandamide synthesis. This observation has provided the basis for the hypothesis that we wish to test in this proposal, namely, that physiological control of anandamide synthesis resides in the regulation of cellular phospholipase activity. This is the situation for the other members of the eicosanoid family of which anandamide is a novel member. Anandamide has been suggested to be a putative endogenous cannabimimetic substance, however, its significance will probably extend beyond the area of drug abuse. Indeed, it has been speculated that it may represent a class of novel neuroregulatory agents because of its distribution and biological effects. Receptors that bind anandamide have also been observed in peripheral cells associated with the immune system suggesting that it may have functions outside of the central nervous system as well. Thus, an understanding of how its tissue levels are controlled becomes a matter of some importance. Specific questions to be addressed in this proposal are; (a) What are the agonists that are able to stimulate anandamide synthesis? (b) Are cells in culture suitable experimental models for such studies; (c) Are receptors required for synthesis in intact cells? (d) Which enzymic mediators are responsible for anandamide synthesis? (e) What are the important precursors for cellular anandamide synthesis? Based on what is known about anandamide's properties, its significance may be that it is involved in novel neuroregulatory processes that control CNS functions such as mood, motor coordination, cognitive ability, time-sense and self-perception. In addition, peripheral effects on the cardiovascular, immune, endocrine and respiratory systems may also be part of anandamides' spectrum of activities. The proposed studies may provide useful models for the development of therapeutic approaches to diseases such as multiple sclerosis, Huntington's, etc. where the use of cannabinoids has been explored. Methods for controlling endogenous anandamide synthesis in vivo could prove to be beneficial in relieving the symptoms of these types of ailments. Finally, it is possible that anandamide is only one member of a family of regulatory agents and that data resulting from this project will provide evidence for the existence of other more potent or specific "anandamides".

该应用程序的主要目标是描述所涉及的过程的特征 在激动剂刺激的 anandamide（花生四烯乙醇胺）合成中 完整的细胞。 该实验室的初步报告（8）表明 能够激活磷脂酶以释放游离花生四烯酸的试剂 酸似乎也促进花生四烯酸乙醇胺的合成。 这一观察有 为我们希望在此测试的假设提供了基础 建议，即 anandamide 合成的生理控制 存在于细胞磷脂酶活性的调节中。 这是 类二十烷酸家族其他成员的情况 anandamide 是一个新成员。 Anandamide 被认为是一种假定的内源性大麻模拟物 然而，其重要性可能会超出该领域 滥用药物。 事实上，有人推测它可能代表 由于其分布和分布，一类新型神经调节剂 生物效应。 还观察到结合 anandamide 的受体 与免疫系统相关的外周细胞表明 也可能具有中枢神经系统之外的功能。 因此，一个 了解其组织水平是如何控制的成为一个问题 有一定的重要性。 本提案要解决的具体问题是： （一）有哪些 能够刺激 anandamide 合成的激动剂？ (b) 是细胞吗 培养适合此类研究的实验模型； (c) 是 完整细胞中合成所需的受体？ (d) 哪种酶 介体负责 anandamide 的合成？ (e) 什么是 细胞 anandamide 合成的重要前体？ 根据对 anandamide 特性的了解，其重要性可能 它参与了控制中枢神经系统的新型神经调节过程 情绪、运动协调、认知能力、时间感等功能 和自我认知。 此外，外周效应 心血管、免疫、内分泌和呼吸系统也可能是一部分 anandamides 的活性谱。 拟议的研究可能会提供 开发疾病治疗方法的有用模型 例如多发性硬化症、亨廷顿舞蹈症等在哪里使用 大麻素已被探索。 控制内源性的方法 体内合成 anandamide 可能被证明有助于缓解 这些类型的疾病的症状。 最后，有可能是 anandamide 只是调节剂家族中的一个成员，并且 该项目产生的数据将为存在的证据提供证据 其他更有效或特定的“anandamides”。