Mechanisms of Temperature Regulation

温度调节机制

• 批准号: 9227288
• 负责人: BRUNO CONTI
• 金额: $ 5.58万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9227288
• 关键词: 2-arachidonylglycerol; Adverse effects; Animals; Arachidonic Acids; Biochemical; Brain; CNR1 gene; CNR2 gene; Complex; Cyclooxygenase Inhibitors; Development; Dinoprostone; Dose; Drops; Eicosanoids; Endocannabinoids; Enzymes; Fever; Health; Homeostasis; Human; Hydrolysis; Infection; Inflammation; Inflammatory; Interleukin-1 beta; Knockout Mice; Life; Ligation; Lipopolysaccharides; Measures; Mediating; Mediator of activation protein; Monoacylglycerol Lipases; Mus; Pathway interactions; Peripheral; Pharmacological Treatment; Phospholipase; Phospholipase A2; Play; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Published Comment; Puncture procedure; Pyrogens; Regulation; Resistance; Role; Sepsis; Signal Transduction; Specificity; Systemic infection; Temperature; Testing; Time; Tissues; Transgenic Organisms; anandamide; antipyretic; cyclooxygenase 1; design; fatty acid amide hydrolase; gastrointestinal; inhibitor/antagonist; metabolomics; mouse model; natural hypothermia; neuroinflammation; novel; receptor; research study; response; tool

 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.

 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）合成脑前列腺素（PG）的新途径。简而言之，内源性大麻素2-花生四烯酰甘油（2-AG）通过以下途径转化为花生四烯酸（AA）。单酰基甘油脂肪酶 (MAGL) 的作用为环氧合酶提供独立于磷脂酶 (PLA2) 的 AA 库(COX) 启动前列腺素 (PG) 的合成，内源性大麻素 anandamide（花生四烯酰 N-乙醇酰胺，AEA）也可以通过 FAAH 转化为 AA。 MAGL 拮抗剂 JZ184 显着降低了 IL-1β 或 LPS 诱导的发热程度，因此，在本申请中，我们提出实验来检验这一新途径调节温度稳态的假设。通过使用缺乏 eCB-PG 途径关键酶的小鼠并对其活性进行药理学操作，我们将测量 MAGL 和 FAAH 在介导发烧反应中的作用。我们还发现，MAGL（一种负责水解 2-AG 的酶）缺失的小鼠能够抵抗厌食症，这是脓毒症期间常见的一种危及生命的体温过低的现象。因此，我们将测试 eCB-PG 途径也通过 2-AG 的合成在厌食症中发挥作用的假设，这将通过药理学、转基因和代谢组学方法的组合进行测试。并且不发生在肠道中，表明它的抑制可能代表 新型退热策略不存在通常与目前使用的 COX 抑制剂相关的胃肠道副作用，调节 2-AG 水平的酶可能代表了厌食症的新靶点。