BIOSYNTHESIS OF ANANDAMIDE--A NOVEL EICOSANOID

新型二十烷酸阿南达胺的生物合成

• 批准号: 2122673
• 负责人: SUMNER HOWARD BURSTEIN
• 金额: $ 16.13万
• 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/2122673
• 关键词: G protein; amidases; antisense nucleic acid; arachidonate; biological signal transduction; cannabinoids; cell type; diacylglycerols; dimethylsulfoxide; drug receptors; 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表征所涉及的过程 在激动剂刺激的合成中，在 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蛛网膜化的剂 酸似乎也促进了配胺合成。 这个观察结果 提供了我们希望在此测试的假设的基础 提案，即，对拿兰酰胺合成的生理控制 驻留在细胞磷脂酶活性的调节中。 这是 eicosanoid家族的其他成员的情况 阿南达米德是一个新成员。 已经建议anandamide是一种推定的内源性大麻 但是，物质的意义可能会超出该区域 药物滥用。 确实，已经推测它可能代表 新型神经调节剂的分布和 生物学效应。 也已经观察到结合anandamide的受体 在与免疫系统相关的外围细胞中 可能在中枢神经系统之外具有功能。 因此，一个 了解如何控制其组织水平成为一个问题 有些重要。 本提案中要解决的具体问题是； （a）什么是 能够刺激肛门合成的激动剂？ （b）是细胞 在培养适合此类研究的适当实验模型中； （c）是 完整细胞中合成所需的受体？ （d）哪个酶 介体负责anandamide合成？ （e）什么是 细胞肛门合成的重要前体？ 基于对Anandamide属性的了解，其重要性可能 它参与了控制CNS的新型神经调节过程 情绪，运动协调，认知能力，时态等功能 和自我感知。 另外，外围影响对 心血管，免疫，内分泌和呼吸系统也可能是一部分 Anandamides的活动范围。 拟议的研究可能会提供 用于开发疾病治疗方法的有用模型 例如多发性硬化症，亨廷顿的等等。 已经探索了大麻素。 控制内源性的方法 体内的anandamide合成可以证明是有益的 这些类型的疾病的症状。 最后，有可能 Anandamide只是一个监管代理人家族的成员， 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”。