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Therapeutic Targeting of Monoacylglycerol Lipase After Traumatic Brain Injury

脑外伤后单酰甘油脂肪酶的治疗靶向

基本信息

批准号：
10617723
负责人：
Kumar Vaibhav
金额：
$ 36.19万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
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/10617723
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 Impairment Individual Infiltration Inflammation Inflammatory Injury Ligands Lipids Lymphoid Macrophage 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 Phenotype Productivity Public Health Regulation Reporting Resolution Role Spinal cord injury T-Lymphocyte TBI Patients TLR4 gene Testing Trauma Traumatic Brain Injury anandamide arachidonate attenuation behavioral outcome cannabinoid receptor central nervous system injury disability endogenous cannabinoid system excitotoxicity high risk immune activation immune modulating agents improved innovation malignant breast neoplasm mortality neuroinflammation neuron loss neurovascular neurovascular injury novel novel strategies novel therapeutic intervention pharmacologic potential biomarker prospective protective effect therapeutic target vasoconstriction white matter injury

项目摘要

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.

项目概要创伤性脑损伤 (TBI) 是人类残疾、医疗费用和损失方面的主要健康问题生产率。除了直接机械创伤外，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，在数小时内使患者的预后恶化以及 TBI 后几天。骨髓细胞上 Toll 样受体 4 (TLR4) 的急性激活会加剧炎症，实验性 TBI 后水肿与临床 TBI 后不良结局相关。髓系 TLR4 的激活增加初始辅助 T 细胞 (TH0) 转化为促炎性 TH1 和 TH17 细胞的极化，持续数周 TBI 表型后。 TH1 和 TH17 细胞增强 T 细胞介导的免疫力，增强促炎性巨噬细胞/小胶质细胞激活，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显着改善患者的治疗效果。内源性大麻素，例如花生四烯酸乙醇酰胺（N-花生四烯酰乙醇酰胺，AEA）和 2-花生四烯酰甘油 (2-AG) 是基于花生四烯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，改善脉管系统功能，并增强行为结果，表明具有保护作用 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)，选择性地将单酰基甘油（例如 2-AG）降解为游离脂肪酸和甘油会使脑损伤后的结果恶化。然而，MAGL 的作用仍然不明确 TBI 后。我们的长期目标是定义 eCS 的监管机制和功能影响 TBI，可能会建立一个机制框架来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。为了检验我们的假设，我们提出了三个具体目标：具体目标 1 将检验骨髓-CB2R 激活的假设 TBI 后通过抑制 MAGL 改善神经血管功能。具体目标 2 将检验假设骨髓特异性 TLR4 在 TBI 后先天免疫激活中调节 MAGL。具体目标 3 将测试假设 MAGL 的骨髓特异性缺失限制了骨髓-淋巴相互作用，从而保护白细胞 TBI 后的物质损伤 (WMI) 和慢性行为缺陷。预期结果：我们提出的研究具有深远的转化意义，证明了骨髓 MAGL-CB2R-TLR4 在调节炎症和慢性 WMI 消退可能会改善长期 TBI 结局。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A potential role for cannabichromene in modulating TRP channels during acute respiratory distress syndrome.

DOI：
10.1186/s42238-021-00101-0
发表时间：
2021-10-01
期刊：
Journal of cannabis research
影响因子：
3.7
作者：
Khodadadi H;Salles ÉL;Shin E;Jarrahi A;Costigliola V;Kumar P;Yu JC;Morgan JC;Hess DC;Vaibhav K;Dhandapani KM;Baban B
通讯作者：
Baban B

Revisiting Traumatic Brain Injury: From Molecular Mechanisms to Therapeutic Interventions.

DOI：
10.3390/biomedicines8100389
发表时间：
2020-09-29
期刊：
Biomedicines
影响因子：
4.7
作者：
Jarrahi A;Braun M;Ahluwalia M;Gupta RV;Wilson M;Munie S;Ahluwalia P;Vender JR;Vale FL;Dhandapani KM;Vaibhav K
通讯作者：
Vaibhav K

Recombinant human DNase-I improves acute respiratory distress syndrome via neutrophil extracellular trap degradation.

DOI：
10.1016/j.jtha.2023.04.044
发表时间：
2023-09
期刊：
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
影响因子：
10.4
作者：
Jarrahi, Abbas;Khodadadi, Hesam;Moore, Nicholas S.;Lu, Yujiao;Awad, Mohamed E.;Salles, Evila L.;Vaibhav, Kumar;Baban, Babak;Dhandapani, Krishnan M.
通讯作者：
Dhandapani, Krishnan M.

Conditioning medicine for ischemic and hemorrhagic stroke.

缺血性和出血性中风的调理药。

DOI：
发表时间：
2021
期刊：
Conditioning medicine
影响因子：
0
作者：
Hess,DavidC;Khan,MohammadBadruzzaman;Kamat,Pradip;Vaibhav,Kumar;Dhandapani,KrishnanM;Baban,Babak;Waller,JenniferL;Hoda,MdNasrul;Blauenfeldt,RolfAnkerlund;Andersen,Grethe
通讯作者：
Andersen,Grethe

Understanding Acquired Brain Injury: A Review.