Mechanisms of Temperature Regulation

 描述（由申请人提供）：我们最近发现了一种从内源性大麻素（eCB）合成脑内大麻素（PG）的新途径。简而言之，内源性大麻素2-花生四烯酸酰甘油（2-AG）通过单酰基甘油脂肪酶（MAGL）的作用转化为花生四烯酸（AA），为环氧合酶（考克斯）提供磷脂酶（PLA 2）非依赖性的AA库，以启动花生四烯酸（PG）的合成。内源性大麻素anandamide（花生四烯酸N-乙醇酰胺，AEA）也可以通过FAAH转化为AA。我们先前证明了该途径可以促进神经炎症，并且在初步研究中，我们还发现MAGL拮抗剂JZ 184显著降低了由IL-1β或LPS诱导的发热程度。因此，在本申请中，我们提出了实验来测试这一新的途径调节中枢或外周炎症信号的温度稳态的假设。通过使用缺乏eCB-PG途径关键酶的小鼠和对其活性的药理学操作，我们将测量MAGL和FAAH在介导发热反应中的作用。我们还将研究热原对MAGL和FAAH调节的影响。我们还发现，MAGL（负责水解2-AG的酶之一）无效的小鼠对发热性贫血具有抗性，发热性贫血是在脓毒症和严重全身感染期间经常观察到的危及生命的体温过低。因此，我们将检验eCB-PG途径也通过合成2-AG在发热失调中发挥作用的假设。这将与药理学和转基因和代谢组学方法的组合进行测试。eCB-PG途径是组织特异性的，并且不发生在肠道中，这表明其抑制可能代表了一种免疫抑制剂。 新的解热策略，其没有通常与当前使用的考克斯抑制剂相关的胃肠道副作用。调节2-AG水平的酶可能是治疗发热失调的新靶点。

 DESCRIPTION (provided by applicant): We recently identified a novel pathway for the synthesis of brain prostaglandins (PG) from endocannabinoids (eCB). Briefly, the endocannabinoid 2-arachidonoylglycerol (2-AG) is converted to arachidonic acid (AA) by the action of monoacylglycerol lipase (MAGL) providing a phospholipase (PLA2)-independent pool of AA for cyclooxygenase (COX) to initiate synthesis of prostaglandins (PG). The endocannabinoid anandamide (arachidonoyl N-ethanolamide, AEA) can also be converted to AA by FAAH. We previously demonstrated that this pathway can promote neuroinflammation and in preliminary studies we also found that the MAGL antagonist JZ184 dramatically reduced the extent of fever induced by IL-1β or LPS. Thus, in this application we propose experiments to test the hypothesis that this novel pathway regulates temperature homeostasis to central or peripheral inflammatory signals. By using mice deficient in key enzyme of the eCB-PG pathway and pharmacological manipulation of their activity, we will measure the role of MAGL and FAAH in mediating fever response. We will also investigate the effect of pyrogens on the regulation of MAGL and FAAH. We also found that mice null for MAGL, one of the enzymes responsible for the hydrolysis of 2-AG, are resistant to anapyrexia, a life threatening hypothermia often observed during sepsis and severe systemic infection. Thus, we will test the hypothesis that the eCB-PG pathway also plays a role in anapyrexia via synthesis of 2-AG. This will be tested with a combination of pharmacological and transgenic and metabolomics approaches. The eCB-PG pathway is tissue specific and does not occur in the gut, indicating its inhibition may represent a novel antipyretic strategy devoid of the gastrointestinal side effects typically associated with th current use of COX inhibitors. Enzyme regulating the level of 2-AG may represent novel targets for anapyrexia.