The role of Cannabinoid Receptor 2 in cerebrovascular protection following traumatic brain injury

大麻素受体2在脑外伤后脑血管保护中的作用

• 批准号: 10607700
• 负责人: Trent A Bullock
• 金额: $ 3.57万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607700
• 关键词: Abnormal coordination; Address; Affinity; Agonist; Alzheimer' s disease risk; Area; Attenuated; Behavioral; Blood - brain barrier anatomy; Blood Vessels; Brain; CNR1 gene; CNR2 gene; Cannabinoids; Cell Adhesion Molecules; Centers for Disease Control and Prevention (U.S.); Cerebrovascular system; Cerebrum; Clinical; Data; Effectiveness; Emotional; Endothelial Cells; Endothelium; Evaluation; Executive Dysfunction; Exhibits; Functional disorder; Gene Expression Profiling; Genes; Goals; Government; Head; Homeostasis; Imaging Techniques; Immune; Impaired cognition; In Vitro; Incidence; Inflammation; Inflammatory; Inflammatory Response; Injury; Kinetics; Lipopolysaccharides; Modeling; Molecular; Nervous System Trauma; Neuroimmune; Neurologic; Neurons; Neuropsychology; Pathology; Pathway interactions; Penetrating Brain Injury; Pharmaceutical Preparations; Pharmacological Treatment; Prevalence; Property; Receptor Activation; Receptor Signaling; Recovery; Reporting; Research; Resolution; Role; Solubility; Stretching; Substance Use Disorder; TBI treatment; Testing; Therapeutic; Tight Junctions; Time; Traumatic Brain Injury; United States; Up-Regulation; age group; blood-brain barrier crossing; blood-brain barrier disruption; blood-brain barrier function; brain endothelial cell; cerebral microvasculature; cerebrovascular; cognitive development; controlled cortical impact; cytokine; disability; druggable target; endogenous cannabinoid system; immune function; improved; in vivo; in vivo Model; injury-related death; insight; nanomolar; neurobehavioral; neuroinflammation; novel; pharmacologic; protein expression; receptor; receptor expression; repaired; response; response to injury; side effect; systemic inflammatory response; therapeutic target; therapeutically effective; vascular injury; Abnormal coordination; Address; Affinity; Agonist; Alzheimer' s disease risk; Area; Attenuated; Behavioral; Blood - brain barrier anatomy; Blood Vessels; Brain; CNR1 gene; CNR2 gene; Cannabinoids; Cell Adhesion Molecules; Centers for Disease Control and Prevention (U.S.); Cerebrovascular system; Cerebrum; Clinical; Data; Effectiveness; Emotional; Endothelial Cells; Endothelium; Evaluation; Executive Dysfunction; Exhibits; Functional disorder; Gene Expression Profiling; Genes; Goals; Government; Head; Homeostasis; Imaging Techniques; Immune; Impaired cognition; In Vitro; Incidence; Inflammation; Inflammatory; Inflammatory Response; Injury; Kinetics; Lipopolysaccharides; Modeling; Molecular; Nervous System Trauma; Neuroimmune; Neurologic; Neurons; Neuropsychology; Pathology; Pathway interactions; Penetrating Brain Injury; Pharmaceutical Preparations; Pharmacological Treatment; Prevalence; Property; Receptor Activation; Receptor Signaling; Recovery; Reporting; Research; Resolution; Role; Solubility; Stretching; Substance Use Disorder; TBI treatment; Testing; Therapeutic; Tight Junctions; Time; Traumatic Brain Injury; United States; Up-Regulation; age group; blood-brain barrier crossing; blood-brain barrier disruption; blood-brain barrier function; brain endothelial cell; cerebral microvasculature; cerebrovascular; cognitive development; controlled cortical impact; cytokine; disability; druggable target; endogenous cannabinoid system; immune function; improved; in vivo; in vivo Model; injury-related death; insight; nanomolar; neurobehavioral; neuroinflammation; novel; pharmacologic; protein expression; receptor; receptor expression; repaired; response; response to injury; side effect; systemic inflammatory response; therapeutic target; therapeutically effective; vascular injury

PROJECT SUMMARY/ABSTRACT Traumatic brain injury (TBI) is the leading cause of injury-related death and disability in the United States and worldwide. The result of a bump, blow, or jolt to the head or penetrating brain injury, TBI disrupts normal brain function in two stages: first, the primary injury at the moment of impact, and later, the immune/inflammatory response, also called secondary injury. The inflammatory response that occurs during secondary injury can contribute greatly to neurological changes including cognitive impairment, executive function deficits, emotional and behavioral dysregulation. Currently, there are no approved pharmacological treatments for TBI despite the incidence of TBI increasing over the past decade. Consequently, there is an urgent need for novel pharmacological targets to control the aberrant secondary injury response. A hallmark feature of TBI pathology is vascular disruption and Blood Brain Barrier (BBB) hyperpermeability. Strategies that target the neurovasculature could open the door to new, effective therapeutics. It is known that the endocannabinoid system is a major regulator of neuronal homeostasis and immune function. Of the endocannabinoid system, the Cannabinoid 2 Receptor (CB2) is a major contributor to inflammation resolution. Importantly, our lab previously showed CB2 is expressed at low basal levels on cerebral microvascular endothelial cells and is upregulated during neuroinflammation. However, an unstudied aspect of TBI research is the kinetics of CB2 and its potential as a therapeutic target at the level of the cerebral endothelium. Specifically, here we explore the ability of novel CB2 agonists to restore BBB integrity following experimental neurotrauma. Preliminary data in vitro using synthetic chromenopyrazole based CB2 agonists, featuring increased affinity and solubility, demonstrate improvements in restoring BBB function and attenuating endothelial activation. In addition, analysis of gene expression in microvessels isolated from the area of impact shows rapid upregulation of the CNR2 gene, which encodes for CB2. Therefore, we hypothesize that activation of endothelial CB2 following TBI promotes BBB repair and vascular protection. This hypothesis will be explored using the following specific aims: 1) to characterize the receptor dynamics of endothelial CB2 expression post-injury and the therapeutic potential for potent CB2 agonists to provide vascular protection in both in vitro and in vivo models of TBI. These studies feature advanced imaging techniques, neurobehavioral evaluations and novel highly specific CB2 agonists, 2) Identification of molecular mechanisms that bridge CB2 receptor signaling with pathways that modulate BBB function. Together the aims proposed in this study will provide insight into mechanisms of TBI- pathology and the effectiveness of novel CB2 agonists against the harmful effects of neuroinflammation.

项目摘要/摘要 创伤性脑损伤（TBI）是美国和残疾的主要原因 全世界。 TBI撞击头部或穿透脑损伤的结果，破坏了正常的大脑 在两个阶段的功能：首先，撞击时的主要损伤，然后是免疫/炎症 反应，也称为继发伤害。继发期间发生的炎症反应可以 为神经系统变化做出巨大贡献，包括认知障碍，执行功能缺陷，情感 和行为失调。目前，尽管有批准的TBI药理治疗 在过去十年中，TBI的发病率增加。因此，迫切需要小说 控制异常的继发损伤反应的药理靶标。 TBI病理学的标志性特征 是血管破坏和血脑屏障（BBB）超重性。针对目标的策略 神经血管管可能打开新的有效治疗剂的大门。众所周知，内源性大麻素 系统是神经元稳态和免疫功能的主要调节剂。内源性大麻素系统的 大麻素2受体（CB2）是炎症分辨率的主要因素。重要的是，我们的实验室 先前显示的CB2在脑微血管内皮细胞上以低基础水平表达，IS 神经炎症期间上调。但是，TBI研究的一个未研究的方面是CB2的动力学 它的潜力是在大脑内皮水平上的治疗靶标。具体来说，我们在这里探索 实验性神经瘤后，新型CB2激动剂恢复BBB完整性的能力。初步数据 在体外使用基于合成铬吡就唑的CB2激动剂，具有增加的亲和力和溶解度， 证明恢复BBB功能并衰减内皮激活方面有所改善。此外， 从影响区域分离出的微血管中基因表达的分析显示了 CNR2基因，该基因编码CB2。因此，我们假设TBI之后的内皮CB2激活 促进BBB修复和血管保护。该假设将使用以下特定 目的：1）表征内皮CB2表达的受体动力学和治疗性 有效的CB2激动剂在体外和体内TBI模型中提供血管保护的潜力。这些 研究具有高级成像技术，神经行为评估和新型高度特异性CB2 激动剂，2）鉴定分子机制，这些机制将CB2受体信号传导与途径桥接 调节BBB功能。这项研究中提出的目的共同将深入了解TBI的机制 病理学和新型CB2激动剂对神经炎症的有害作用的有效性。