ENDOGENOUS CANNABINOIDS AND BRAIN/IMMUNE FUNCTION

描述(由申请人提供)：现在有令人信服的证据表明 内源性大麻素系统存在于大脑和外周。这个 内源性大麻素的分离和鉴定，如阿南达胺， 2-花生四烯基甘油和诺拉丁醚，已加紧努力 了解内源性大麻素的功能意义。这就是 导致洋流形成的内源性大麻素的发现 计划项目。我们的主要目标仍然是建立这个角色 在正常生理过程中的内源性大麻素系统 疾病状态。这一认识与本病的病因尤其相关。 大麻滥用以及确定大麻素的治疗用途。 近年来，大麻素的研究取得了巨大的进步；然而， 就像通常的情况一样，知识的增加揭示了一个 生物系统。我们现在确信，内源性大麻素会产生一些 它们通过已知的大麻素受体发挥作用，但它们也能够 在尚未确定的地点采取行动。目前尚不清楚内源性大麻素和 植物来源的四氢大麻素(THC)激活内源性大麻素。 一模一样的时尚。合成、细胞摄取和代谢降解是 所有这些都对内源性大麻素的作用至关重要，但这些过程 还没有完全理解。有很多建议说内源性大麻素 参与神经退行性/神经性疾病，但其机制 对这些推定行为的责任仍有待阐明。目的 这项建议是为了解决上述问题，使用这一多学科 该计划由五个研究项目和一个行政核心组成。 每一位私家侦探都是一位经验丰富的研究员，他们将做出独特的贡献。 Mechoulam教授建议分离和识别其他内源 物质，进行合成计划，并评估大麻类物质为 神经保护剂和抗炎药。拉兹丹博士将继续 为该计划的其他成员提供新颖和创新的探索 项目。马丁博士和佩特威博士领导的研究小组将协调他们的 内源性配体及其类似物的药理学评价 进一步研究了激动剂和拮抗剂的构效关系。 CB1受体，建立非CB1的构效关系 大麻素受体，研究大麻素在香草素VR1上的作用 脂肪酸氨基水解酶受体和选择性抑制剂的开发 阿南达胺膜转运蛋白。杜威博士将确定哪种信号 信号转导通路对内型和外型大麻素至关重要 行为。这个高度整合的研究团队将继续密切合作 共同朝着确定内源性大麻素的生物学作用的目标前进。

DESCRIPTION (provided by applicant): There is now convincing evidence that an endogenous cannabinoid system exists in both the brain and periphery. The isolation and identification of endogenous cannabinoids, such as anandamide, 2-arachidonyl glycerol and noladin ether, have intensified efforts to understand the functional significance of endogenous cannabinoids. It was the discovery of the endocannabinoids that led to the formation of the current program project. Our major goal continues to be the establishment of the role of the endocannabinoid system in normal physiological processes as well as in disease states. This understanding is particularly relevant to the etiology of cannabis abuse as well as identification of therapeutic uses of cannabinoids. Cannabinoid research has produced tremendous advances in recent years; however, as is often the case, increased knowledge reveals the complexity of a biological system. We are now assured that endocannabinoids produce some of their effects through known cannabinoid receptors, yet they are also capable of acting at as-yet-unidentified sites. It is unclear whether endocannabinoids and the plant-derived tetrahydrocannabinoid (THC) activate endocannabinoids in an identical fashion. The synthesis, cellular uptake and metabolic degradation are all crucial for the actions of the endocannabinoids, but these processes are not yet fully understood. There are numerous suggestions that endocannabinoids are involved in neurodegenerative/neurological disorders, yet the mechanism responsible for these putative actions remain to be elucidated. The purpose of this proposal is to address the above questions using this multidisciplinary program that consists of five research projects and an administrative core. Each P.I. is an experienced researcher who will make a unique contribution. Professor Mechoulam proposes to isolate and identify other endogenous substances, conduct a synthetic program, and assess cannabinoids as neuroprotective and anti-inflammatory agents. Dr. Razdan will continue to provide novel and innovative probes to the other members of the program project. Research teams led by Drs. Martin and Pertwee will coordinate their pharmacological evaluations of endogenous ligands and their analogs in order to further the structure-activity relationships of agonists and antagonist at the CB1 receptor, establish the structure-activity relationships for non-CB1 cannabinoid receptors, investigate cannabinoid actions at vanilloid VR1 receptors and develop selective inhibitors for fatty acid amidohydrolase and the anandamide membrane transporter. Dr. Dewey will determine which signal transduction pathways are critical for endocannabinoid and exocannabinoid actions. This highly integrated research team will continue to work closely together toward the goal of defining the biological roles of endocannabinoids.