Therapeutic targeting of monoacylglycerol lipase after traumatic brain injury

项目总结 创伤性脑损伤在人类的残疾、医疗费用和损失方面是一个主要的健康问题。 生产力。除了直接的机械性创伤，继发性神经血管功能障碍，包括 脑水肿、脑血流障碍和神经细胞死亡在几个小时内使患者预后恶化。 以及脑外伤后的几天。急性激活髓系细胞上的Toll样受体4(TLR4)可加重炎症和 实验性脑损伤后的水肿与临床脑损伤后的不良预后相关。髓系TLR4的激活 增加幼稚辅助T细胞(TH0)向促炎TH1和TH17细胞的极化，持续数周 脑损伤后的表型。随着TH1和TH17细胞增强T细胞介导的免疫，放大促炎作用 巨噬细胞/小胶质细胞激活，并使神经变性永久化，确定新的治疗策略 减少创伤后炎症可能会显著改善患者的预后。内源性大麻素，如 烷胺(N-花生四烯基乙醇胺，AEA)和2-花生四烯基甘油(2-AG)是以花生四烯酸为基础的 激活大麻素受体CB1R和CB2R的脂类。CB2R激活可恢复免疫平衡， 减少浮肿，改善血管功能，并提高行为结果，提示保护性 脑外伤后内源性大麻素的作用。值得注意的是，内源性大麻素代谢酶的激活 单酰基甘油脂肪酶(MAGL)，选择性地将单酰基甘油(如2-AG)降解为游离脂肪 酸和甘油，会恶化脑损伤后的预后。然而，MAGL的作用仍然定义不清 在TBI之后。我们的长期目标是在以下情况下定义ECS的监管机制和功能影响 脑损伤，可能建立一个机制框架，以促进免疫调节的发展 治疗，以提高患者的预后。我们的中心假设是内源性大麻素代谢 酶，MAGL，是脑创伤后潜在的促炎激活的分子开关。为了检验我们的假设， 我们提出了三个特定目标：特定目标1将检验髓系CB2R激活的假设 通过抑制脑外伤后MAGL改善神经血管功能。《特定目标2》将检验这一假设 髓系特异性TLR4调节脑外伤后MAGL的天然免疫激活。《特定目标3》将测试 假设髓系特异性缺失MAGL限制了髓系和淋巴系的相互作用，从而保护了白人 颅脑损伤后的物质损伤(WMI)和慢性行为障碍。预期结果：我们建议的研究具有 深远的翻译含义，作为髓系MAGL-CB2R-TLR4在 调节炎症和慢性WMI的消退可能会改善脑外伤的长期预后。

PROJECT SUMMARY Traumatic brain injury (TBI) is a major health concern in terms of human disability, medical expenses, and lost productivity. In addition to immediate mechanical trauma, secondary neurovascular dysfunction, including cerebral edema, impaired cerebral blood flow, and neuronal cell death, worsens patient outcome in the hours and days after TBI. Acute activation of toll-like receptor 4 (TLR4) on myeloid cells aggravates inflammation and edema after experimental TBI and correlates with poor outcomes after clinical TBI. Activation of myeloid TLR4 increases the polarization of naïve helper T cells (TH0) into pro-inflammatory TH1 and TH17 cells, for weeks after TBI phenotypes. As TH1 and TH17 cells augment T-cell mediated immunity, amplify pro-inflammatory macrophage/microglia activation, and perpetuate neurodegeneration, the identification of novel strategies to reduce post-traumatic inflammation may substantially improve patient outcomes. Endocannabinoids, such as anandamide (N-arachidonoylethanolamide, AEA) and 2-arachidonoylglycerol (2-AG), are arachidonate based lipids that activate the cannabinoid receptors, CB1R and CB2R. CB2R activation restores immune balance, reduces edema, improves vasculature function, and enhances behavioral outcomes, suggesting a protective effect of endocannabinoids after TBI. Of note, activation of the endocannabinoid metabolizing enzyme monoacylglycerol lipase (MAGL), which selectively degrades monoacylglycerols, such as 2-AG, into free fatty acids and glycerol, worsens outcomes after brain injury. However, the role of MAGL remains poorly defined after TBI. Our long-term goal is to define the regulatory mechanisms and functional implications of eCS after TBI, which may establish a mechanistic framework to advance the development of immunomodulatory therapeutics to enhance patient outcomes. Our central hypothesis is that the endocannabinoid metabolizing enzyme, MAGL, is a molecular switch underlying pro-inflammatory activation after TBI. To test our hypothesis, we propose three Specific Aims: Specific Aim 1 will test the hypothesis that myeloid-CB2R activation improves neurovascular function via suppression of MAGL after TBI. Specific Aim 2 will test the hypothesis that myeloid-specific TLR4 regulates MAGL in innate immune activation after TBI. Specific Aim 3 will test the hypothesis that myeloid-specific deletion of MAGL limits myeloid-lymphoid interaction and thus, protects white matter injury (WMI) and chronic behavioral deficits after TBI. Expected outcomes: Our proposed studies have far-reaching translational implications, as demonstration of a key role for myeloid MAGL-CB2R-TLR4 in regulation of inflammation and chronic WMI resolution may result in improved long-term TBI outcomes.