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.

项目概要/摘要 在美国和美国，创伤性脑损伤 (TBI) 是导致伤害相关死亡和残疾的主要原因 全世界。 TBI 是头部碰撞、打击或摇晃或穿透性脑损伤的结果，会破坏正常的大脑 功能分两个阶段：首先是撞击时的主要损伤，然后是免疫/炎症 反应，也称为继发性损伤。继发性损伤时发生的炎症反应可以 极大地促进神经系统变化，包括认知障碍、执行功能缺陷、情绪障碍 和行为失调。目前，尽管有治疗 TBI 的药物，但尚无批准的药物治疗方法 过去十年中，TBI 的发病率不断增加。因此，迫切需要一种新颖的 控制异常继发性损伤反应的药理学目标。 TBI 病理学的一个标志性特征 是血管破坏和血脑屏障（BBB）渗透性过高。针对的策略 神经血管系统可以为新的、有效的治疗方法打开大门。据了解，内源性大麻素 系统是神经元稳态和免疫功能的主要调节者。内源性大麻素系统， 大麻素 2 受体 (CB2) 是炎症消退的主要贡献者。重要的是，我们的实验室 先前表明CB2在脑微血管内皮细胞上以低基础水平表达，并且 神经炎症期间上调。然而，TBI 研究中一个未经研究的方面是 CB2 的动力学 及其作为脑内皮水平治疗靶点的潜力。具体来说，我们在这里探索 新型 CB2 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苯并吡唑的 CB2 激动剂，具有增加的亲和力和溶解度， 证明在恢复 BBB 功能和减弱内皮激活方面有所改善。此外， 对从影响区域分离出的微血管中的基因表达进行分析表明， CNR2 基因，编码 CB2。因此，我们假设 TBI 后内皮 CB2 的激活 促进血脑屏障修复和血管保护。将使用以下具体内容来探讨该假设 目的：1) 表征损伤后内皮 CB2 表达的受体动态以及治疗方法 强效 CB2 激动剂在 TBI 体外和体内模型中提供血管保护的潜力。这些 研究以先进的成像技术、神经行为评估和新颖的高度特异性 CB2 为特色 激动剂，2) 鉴定连接 CB2 受体信号转导通路的分子机制 调节 BBB 功能。本研究提出的目标将共同深入了解 TBI 的机制 病理学和新型 CB2 激动剂对抗神经炎症有害影响的有效性。