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脑和外周。的 内源性大麻素，如大麻素， 2-花生四烯酸甘油和诺拉丁醚，已加紧努力， 了解内源性大麻素的功能意义。这是 内源性大麻素的发现导致了电流的形成 程序项目。我们的主要目标仍然是建立一个角色， 内源性大麻素系统在正常的生理过程以及 疾病状态。这种理解特别适用于 大麻滥用以及确定大麻素的治疗用途。 大麻素研究近年来取得了巨大进展;然而， 通常情况下，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 它们的作用通过已知的大麻素受体，但它们也能够 在尚未确认的地点活动目前还不清楚内源性大麻素和 植物衍生四氢大麻素（THC）在 相同的方式。合成、细胞摄取和代谢降解是 都是内源性大麻素发挥作用的关键，但这些过程 尚未完全理解。有很多证据表明内源性大麻素 参与神经退行性/神经系统疾病，但机制 对这些假定行为的责任仍有待阐明。的目的 这一建议是为了解决上述问题，利用这一多学科 该计划由五个研究项目和一个行政核心组成。 每个私家侦探是一位经验丰富的研究人员，他将做出独特的贡献。 Mechoulam教授建议分离和鉴定其他内源性 物质，进行合成计划，并评估大麻素作为 神经保护剂和抗炎剂。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 项目由马丁博士和佩特维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， 进一步研究了受体激动剂和拮抗剂的构效关系， CB 1受体，建立非CB 1的结构-活性关系 大麻素受体，研究大麻素对香草素VR 1的作用 受体，并开发脂肪酸酰胺水解酶的选择性抑制剂， anandamide膜转运蛋白。杜威博士会确定 转导途径对于内源性大麻素和外切大麻素是至关重要的 行动这个高度整合的研究团队将继续密切合作 共同致力于定义内源性大麻素的生物学作用。

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.