Endogenous Cannabinoids and Brain Function

描述（由申请人提供）：本项目的主要目标是建立内源性大麻素系统在正常生理过程和异常或疾病状态下的功能作用，并确定其作为外源性大麻素作用的中介的程度。我们的前提是，了解内源性大麻素系统将使我们能够解决有关药物滥用的公共卫生问题，以及包括认知障碍、强迫行为、疼痛、运动功能障碍和许多外周疾病在内的合并症。在过去的十年中，令人难以置信的进展已经坚定地确立了内源性大麻素系统及其关键成分（受体亚型、内源性配体、合成和代谢途径、信号通路等）的存在和稳态重要性。与大多数生物系统一样，随着知识的积累，复杂性的水平也在提高。我们已经组建了一个由化学家（Mechoulam， Razdan和Mahadevan），生物化学家和分子生物学家（Cravatt和Di Marzo）以及药理学家（Martin, Wiley, Lichtman， Pertwee和Ross）组成的团队，他们将解决与区分anandamide （AEA）和2-花生四烯醇甘油（2- ag）的生理功能相关的基本问题，调查是否存在其他内源性大麻素。并确定内源性大麻素在神经过程（如疼痛、奖励、神经保护）和外周过程（如骨形成、炎症）中的作用之间的关系。我们的方法包括合成假定的内源性大麻素，稳定和有效的类似物，代谢和合成酶抑制剂以及CB1受体变构调节剂。此外，我们将操纵被认为负责AEA和2-AG合成和降解的酶，并使用液相色谱、离子阱、飞行时间质谱建立最终的脂质谱，以确定与内源性大麻素系统相关的新脂质实体。Cravatt博士将系统地删除小鼠体内现有的以及拟议的AEA和2-AG合成和代谢酶。这些转基因动物，以及合成探针和新发现的内源性大麻素，将用于进一步阐明内源性大麻素系统在神经性和炎症性疼痛、神经创伤、奖励和依赖相关事件中的功能。最终，从这项基础研究中获得的知识将产生新的治疗靶点，可以利用这里开发的药理学药物。

DESCRIPTION (provided by applicant): The primary objectives of this Program Project are to establish the functional roles of the endocannabinoid system in normal physiological processes and in abnormal or disease states and to determine the extent to which it serves as a mediator in the effects of exogenous cannabinoids. It is our premise that understanding the endogenous cannabinoid system will allow us to address public health issues regarding drugs of abuse as well as co-morbidities that include cognitive disorders, compulsive behavior, pain, motor dysfunction and numerous peripheral disorders. Incredible progress in the past decade has firmly established the existence and homeostatic importance of the endocannabinoid system and its key components (receptor subtypes, endogenous ligands, synthetic and metabolic pathways, signaling pathways, etc.) As with most biological systems, as knowledge accumulates so does the level of complexity. We have assembled a team of chemists (Mechoulam, Razdan and Mahadevan), biochemists and molecular biologists (Cravatt and Di Marzo), and pharmacologists (Martin, Wiley, Lichtman, Pertwee, and Ross) who will address fundamental questions related to distinguishing between the physiological functions of anandamide (AEA) and 2- arachidonoylglycerol (2-AG), investigating whether other endocannabinoids exist, and determining the relationship between the roles of endocannabinoids in neural processes (e.g., pain, reward, neuroprotection) and peripheral processes (e.g., bone formation, inflammation). Our approach involves synthesis of putative endocannabinoids, stable and potent analogs, metabolic and synthetic enzyme inhibitors and CB1 receptor allosteric modulators. Furthermore, we will manipulate enzymes that are putatively responsible for AEA and 2-AG synthesis and degradation as well as establish the resulting lipid profiles using liquid chromatography, ion trap, time-of-flight mass spectrometry to identify new lipid entities associated with the endocannabinoid system. Dr. Cravatt will systematically delete existing as well as proposed synthetic and metabolic enzymes for AEA and 2-AG in mice. These genetically modified animals, along with the synthetic probes and newly discovered endocannabinoids, will be used to further elucidate the function of the endocannabinoid system in neuropathic and inflammatory pain, neurotrauma, reward, and dependence-related events. Ultimately, the knowledge gained from this basic research will yield novel therapeutic targets that can be exploited with the pharmacological agents developed here. PROGRAM CHARACTERISTICS