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

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.

项目总结/摘要 创伤性脑损伤（TBI）是美国与损伤相关的死亡和残疾的主要原因， 国际吧由于头部撞击、打击或震动或穿透性脑损伤，TBI破坏了正常的大脑 功能分为两个阶段：首先是冲击时的原发性损伤，然后是免疫/炎症 反应，也称为二次损伤。继发性损伤时发生的炎症反应， 极大地促进神经系统的变化，包括认知障碍，执行功能缺陷，情绪 和行为失调目前，没有批准的药物治疗TBI，尽管 TBI的发病率在过去十年中不断上升。因此，迫切需要新的 药理学靶点来控制异常的继发性损伤反应。TBI病理学的一个标志性特征 是血管破坏和血脑屏障（BBB）高渗透性。战略目标是 神经血管系统的研究可以为新的有效疗法打开大门。已知内源性大麻素 系统是神经元稳态和免疫功能的主要调节器。内源性大麻素系统， 大麻素2受体（CB 2）是炎症消退的主要贡献者。重要的是，我们的实验室 先前显示CB 2在脑微血管内皮细胞上以低基础水平表达， 在神经炎症中上调。然而，TBI研究的一个未研究的方面是CB 2的动力学 以及其作为脑内皮水平的治疗靶点的潜力。具体来说，我们在这里探索 新型CB 2激动剂在实验性神经创伤后恢复BBB完整性的能力。初步数据 在体外使用合成的基于色烯吡唑的CB 2激动剂，其特征在于增加的亲和力和溶解度， 在恢复BBB功能和减弱内皮活化方面显示出改善。此外，本发明还提供了一种方法， 对从撞击区域分离的微血管中的基因表达的分析显示， CNR 2基因，编码CB 2。因此，我们假设TBI后内皮细胞CB 2的激活 促进BBB修复和血管保护。将使用以下具体的方法来探讨这一假设 目的：1）表征内皮细胞损伤后CB 2表达的受体动力学和治疗性 有效的CB 2激动剂在TBI的体外和体内模型中提供血管保护的潜力。这些 研究采用先进的成像技术、神经行为评估和新型高度特异性CB 2 激动剂，2）鉴定将CB 2受体信号传导与 调节BBB功能。总之，本研究提出的目标将提供深入了解TBI的机制- 病理学和新型CB 2激动剂对抗神经炎症有害作用的有效性。