Therapeutic targeting of monoacylglycerol lipase after traumatic brain injury

单酰甘油脂肪酶在脑外伤后的治疗靶向

• 批准号: 10218284
• 负责人: Kumar Vaibhav
• 金额: $ 36.19万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10218284
• 关键词: 2-arachidonylglycerol; Acquired Immunodeficiency Syndrome; Acute; Adoptive Transfer; Advanced Development; Attenuated; Behavioral; Brain Injuries; CNR1 gene; CNR2 gene; Cells; Cellular Immunity; Cerebral Edema; Cerebrovascular Circulation; Chronic; Clinical; Core-Binding Factor; Deterioration; Development; Edema; Endocannabinoids; Enzymes; Equilibrium; Functional disorder; Genetic; Gliosis; Glycerol; Goals; Health; Helper-Inducer T-Lymphocyte; Hour; Human; Immune; Immunomodulators; Impairment; Individual; Infiltration; Inflammation; Inflammatory; Injury; Ligands; Lipids; Lymphoid; Mechanics; Medical; Microglia; Molecular; Monoacylglycerol Lipases; Monoglycerides; Multiple Sclerosis; Mutant Strains Mice; Myelogenous; Myeloid Cells; Nerve Degeneration; Neurologic; Nonesterified Fatty Acids; Outcome; Patient-Focused Outcomes; Patients; Pharmacology; Phenotype; Productivity; Public Health; Regulation; Reporting; Resolution; Role; Spinal cord injury; T-Lymphocyte; TLR4 gene; Testing; Trauma; Traumatic Brain Injury; anandamide; arachidonate; attenuation; base; behavioral outcome; cannabinoid receptor; central nervous system injury; disability; endogenous cannabinoid system; excitotoxicity; high risk; immune activation; improved; innovation; macrophage; malignant breast neoplasm; mortality; neuroinflammation; neuron loss; neurovascular; neurovascular injury; novel; novel strategies; novel therapeutic intervention; potential biomarker; prospective; protective effect; therapeutic target; vasoconstriction; white matter injury

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.

项目摘要 创伤性脑损伤（TBI）是人类残疾，医疗费用和损失的主要健康问题 生产率。除了立即机械创伤外，继发性神经血管功能障碍，包括 脑水肿，脑血流量受损和神经元细胞死亡，在小时内使患者结局恶化 和TBI之后的几天。髓样细胞上的Toll样受体4（TLR4）的急性激活加剧注射和 实验性TBI后的水肿与临床TBI后的结局不佳相关。激活髓样TLR4 将幼稚的辅助T细胞（TH0）的极化为促炎性TH1和TH17细胞的极化数周 在TBI表型之后。随着Th1和Th17细胞增强T细胞介导的免疫力，放大促炎性 巨噬细胞/小胶质细胞激活，并使神经变性永久化，鉴定新的策略 减少创伤后炎症可能会大大改善患者预后。内源性大麻素，例如 Anandamide（N-芳基烯丙基甲醇酰胺，AEA）和2-芳基烯丙基甘油（2-AG）是基于蛛网膜酸的 激活大麻素受体CB1R和CB2R的脂质。 CB2R激活恢复免疫平衡， 减少水肿，改善脉管功能并增强行为结果，表明受保护 TBI后内源性大麻素的影响。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）有选择地降解单酰甘油，例如2-AG 酸和甘油，脑损伤后的结局恶化。但是，MAGL的作用仍然很差 在TBI之后。我们的长期目标是定义EC之后EC的调节机制和功能含义 TBI，它可能建立一个机械框架来推动免疫调节的发展 可以增强患者预后的治疗剂。我们的中心假设是内源性大麻素代谢 MAGL酶是TBI后促炎激活的基础分子开关。为了检验我们的假设， 我们提出了三个具体目标：特定目标1将检验髓样-CB2R激活的假设 通过TBI后的MAGL抑制改善神经血管功能。具体目标2将检验假设 TBI后，髓样特异性TLR4在先天免疫激活中调节MAGL。特定目标3将测试 MAGL的髓样特异性缺失限制了髓样淋巴机的相互作用，因此保护白色 物质损伤（WMI）和慢性行为定义了TBI。预期的结果：我们提出的研究已有 深远的翻译含义，作为髓样MAGL-CB2R-TLR4的关键作用的演示 炎症和慢性WMI分辨率的调节可能会改善长期TBI结局。