Mechanism and optimization of CBD-mediated analgesic effects (Admin Supplement)

CBD介导的镇痛作用的机制和优化（行政补充）

基本信息

批准号：
10712799
负责人：
ZHIGANG HE
金额：
$ 7.47万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10712799
关键词：
Absence of pain sensation Age Months Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Amyloid beta-Protein Amyloidosis Analgesics Anatomy Animal Model Anti-Inflammatory Agents Antiepileptic Agents Antiinflammatory Effect Applications Grants Behavioral Brain Brain region Cannabidiol Cannabinoids Cannabis sativa plant Characteristics Chronic Complex Data Development Disease Fluorescence-Activated Cell Sorting Goals Hippocampus Human Hyperactivity Impaired cognition Label Measurement Measures Medial Mediating Methods Microglia Modeling Molecular Molecular Profiling Mus Mutation Neurofibrillary Tangles Neurons Outcomes Research Pathogenesis Pathologic Pathology Pathway interactions Pattern Population Prefrontal Cortex Process Property Reporter Reporting Research Research Project Grants Safety Senile Plaques Signal Transduction Spinal Synapses Synaptic Transmission System Testing Therapeutic Time United States National Institutes of Health Vertebral column Viral Vector Virus abeta deposition cellular transduction clinical imaging entorhinal cortex extracellular glial activation imaging study in vivo mouse model neural neuromechanism pain model painful neuropathy parent project pharmacologic response single-cell RNA sequencing somatosensory spatiotemporal tau Proteins tau aggregation therapeutic development uptake

项目摘要

Project Summary The pathogenesis of Alzheimer’s Disease (AD) is a complex process involving multiple steps and players, which poses major challenges for mechanistic understanding and therapeutic development. The primary pathologic criteria for AD diagnosis include extracellular deposition of β-amyloid plaques and intracellular accumulation of tau neurofibrillary tangles. Clinical imaging studies suggest that the spatiotemporal spread of tau pathology typically starts from the entorhinal cortex and correlates closely with cognitive impairment. Furthermore, mechanistic research in animal models suggest that tau release and uptake across synaptically connected neurons are regulated by both neuronal and microglia activity. Due to the paucity of disease-modifying agents for AD, there is a critical need to test potential therapeutic strategies that may halt the spread of tau pathology by modulating neural and microglia activity. Cannabidiol (CBD) is the main non-psychoactive cannabinoid in Cannabis sativa with a range of reported pharmacological effects, including anti-inflammatory, anti-epileptic, and analgesic properties. The parent project of this research supplement is entitled “Mechanism and optimization of CBD-mediated analgesic effects”, with major goals to identify the neural mechanisms involved in the in vivo actions of CBD in order to optimize its analgesic effects. Our research from the parent project has provided evidence that CBD treatment modulates both neuronal and microglial activity in the brain with good safety profile. The overall objective of this AD-focused supplement is to investigate the mechanistic effects of CBD on the spread of tau pathology in mouse models. We hypothesize that CBD treatment can suppress excessive neural and microglial activity thereby reducing the spread of tau pathology in brain circuits. To explore this hypothesis, we will use a recently established, efficient viral vector model to study the propagation of human tau protein in mouse brain circuits. Specifically, we will determine if CBD suppresses activity-dependent propagation of tau protein from the entorhinal cortex, and if CBD alters microglia reactivity states to limit the spread of tau pathology. The outcomes of this research will inform potential development of cannabinoid-based therapies to reduce tau spreading in AD via suppression of excessive microglial and neuronal activity.

项目概要阿尔茨海默病（AD）的发病机制是一个复杂的过程，涉及多个步骤和参与者，对机制理解和治疗发展提出了重大挑战。 AD 诊断标准包括细胞外β-淀粉样蛋白斑块沉积和细胞内β-淀粉样蛋白沉积 tau 神经原纤维缠结的临床影像学研究表明 tau 病理学的时空扩散。通常从内嗅皮层开始，与认知障碍密切相关。动物模型的机制研究表明，突触连接的 tau 蛋白释放和摄取由于缺乏疾病缓解剂，神经元受到神经元和小胶质细胞活性的调节。对于 AD，迫切需要测试可能阻止 tau 病理学传播的潜在治疗策略通过调节神经和小胶质细胞活性，大麻二酚（CBD）是主要的非精神活性大麻素。大麻具有一系列已报道的药理作用，包括抗炎、抗癫痫和该研究补充品的母项目名为“镇痛特性的机制和优化”。 “CBD介导的镇痛作用”，主要目标是确定体内参与的神经机制我们的母项目研究提供了 CBD 的作用，以优化其镇痛效果。有证据表明 CBD 治疗可调节大脑中的神经元和小胶质细胞活动，具有良好的安全性。这种以 AD 为重点的补充品的总体目标是研究 CBD 对 AD 的机械影响我们勇敢地相信 CBD 治疗可以抑制过度的 tau 病理学传播。神经和小胶质细胞的活动，从而减少 tau 病理学在脑回路中的传播。假设，我们将使用最近建立的高效病毒载体模型来研究人类 tau 的传播具体来说，我们将确定 CBD 是否抑制活性依赖性传播。来自内嗅皮层的 tau 蛋白，如果 CBD 改变小胶质细胞反应状态以限制 tau 蛋白的扩散这项研究的结果将为基于大麻素的疗法的潜在开发提供信息。通过抑制过度的小胶质细胞和神经元活动来减少 AD 中 tau 蛋白的扩散。