Therapeutic targeting of monoacylglycerol lipase after traumatic brain injury

项目摘要 创伤性脑损伤（TBI）是人类残疾，医疗费用和损失方面的主要健康问题 生产力除了直接的机械创伤，继发性神经血管功能障碍，包括 脑水肿、脑血流受损和神经元细胞死亡， 也就是创伤性脑损伤后几天髓样细胞上Toll样受体4（TLR 4）的急性激活加剧炎症， 实验性TBI后水肿与临床TBI后不良结局相关。髓样TLR 4的激活 增加幼稚辅助性T细胞（TH 0）向促炎性TH 1和TH 17细胞的极化，持续数周 在TBI表型之后。由于TH 1和TH 17细胞增强T细胞介导的免疫， 巨噬细胞/小胶质细胞活化，并使神经变性永久化，确定新的策略， 减少创伤后炎症可能会大大改善患者的预后。内源性大麻素，如 花生四烯酸酯（N-花生四烯酸乙醇酰胺，AEA）和2-花生四烯酸甘油（2-AG）是基于花生四烯酸酯的 激活大麻素受体CB 1 R和CB 2 R的脂质。CB 2 R激活恢复免疫平衡， 减少水肿，改善血管功能，并增强行为结果，表明保护性 TBI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），其选择性地将单酰基甘油如2-AG降解成游离脂肪酸， 酸和甘油，脑损伤后的预后。然而，MAGL的作用仍然没有得到明确界定， 在TBI之后我们的长期目标是确定eCS的调节机制和功能影响， TBI，这可能建立一个机制框架，以促进免疫调节的发展 治疗，以提高患者的治疗效果。我们的中心假设是内源性大麻素代谢 MAGL酶是TBI后促炎激活的分子开关。为了验证我们的假设， 我们提出了三个具体目标：具体目标1将检验髓样CB 2 R激活 通过抑制TBI后的MAGL改善神经血管功能。具体目标2将检验假设 骨髓特异性TLR 4在TBI后先天免疫激活中调节MAGL。第3章测试 假设骨髓特异性MAGL缺失限制了骨髓-淋巴相互作用，从而保护了白色 脑外伤后的物质损伤（TBI）和慢性行为缺陷。预期成果：我们提出的研究 具有深远的翻译意义，作为髓样MAGL-CB 2 R-TLR 4在 炎症的调节和慢性炎症的消退可能导致改善的长期TBI结果。

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.