Mechanism and Optimization of CBD-mediated analgesic effects

CBD介导的镇痛作用机制及优化

• 批准号: 10288673
• 负责人: ZHIGANG HE
• 金额: $ 13.22万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10288673
• 关键词: AD transgenic mice; APP-PS1; Aftercare; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid beta-Protein; Amyloidosis; Analgesics; Anti-Inflammatory Agents; Antiinflammatory Effect; Behavioral; Biochemical; Bioinformatics; Brain; Cannabidiol; Cannabinoids; Chronic; Data; Disease; Fluorescence-Activated Cell Sorting; Fluorescent Dyes; Genetic study; Homeostasis; Human; Human Genetics; Image; In Vitro; Inflammation; Label; Mediating; Membrane; Microglia; Molecular; Molecular Profiling; Morphology; Mus; Neurodegenerative Disorders; Pathogenesis; Pathology; Phenotype; Population; Reporter; Reporting; Research; Role; Route; Senile Plaques; Signaling Molecule; Societies; Techniques; Testing; Therapeutic; Time; Transgenic Mice; abeta accumulation; amyloid pathology; base; beta amyloid pathology; cannabinoid receptor; cell motility; cellular pathology; effective therapy; experimental study; frontal lobe; hyperphosphorylated tau; improved; in vivo; in vivo imaging; in vivo two-photon imaging; innovation; insight; molecular phenotype; mouse model; neuroinflammation; normal aging; novel; novel therapeutic intervention; phytocannabinoid; programs; protective effect; receptor; response; risk variant; single-cell RNA sequencing; tau Proteins; transgenic model of alzheimer disease; two photon microscopy

Project Summary/Abstract Alzheimer's Disease (AD) is a severe neurodegenerative disorder that poses a major burden on human society. The pathology of AD is characterized by the accumulation of beta-amyloid plaques and hyperphosphorylated tau protein as well as neuroinflammation involving microglia. There is no effective treatment for AD currently, and new therapeutic strategies based on the mechanistic understanding of AD pathology are critically needed. Cannabidiol (CBD) is a non-psychoactive phytocannabinoid that has broad anti-inflammatory effects. Several recent studies have reported the ability of CBD to reduce neuroinflammatory responses and improve behavioral functions in AD mouse models. However, the in vivo actions and mechanisms of CBD on microglia and AD pathology remain unknown. The overall objective of this proposal is to identify the mechanistic effects of CBD on AD-related cellular pathology in order to optimize its therapeutic potentials. Several lines of evidence suggest that microglia are a strong candidate to mediate the in vivo actions of CBD and contribute to its therapeutic potentials in AD models. First, the accumulation of reactive microglia around amyloid plaques has long been recognized as a hallmark of AD pathology. Recent human genetic studies have further identified multiple AD risk genes involved in microglia function, implicating a casual role of microglia in AD pathogenesis. Second, single-cell RNA-sequencing studies have revealed significant activation diversity in AD microglia population, including disease associated microglia (DAM). Experimental manipulations that reprogram reactive microglia to restore their homeostatic functions have shown protective effects against AD pathology, suggesting the therapeutic potentials of microglia. Third, CBD is known to interact biochemically with multiple membrane receptors and intracellular signaling molecules that are expressed in microglia, including cannabinoid receptors. Fourth, prior in vitro cellular studies and our preliminary chronic in vivo imaging data show that CBD modulates microglia activity and morphology. How CBD will interact with microglia and impact amyloid plaques in AD transgenic models remains to be investigated. Our central hypothesis is that CBD treatment will alter the cellular activity and molecular profile of microglia and reduce AD pathology in the brain. To test this hypothesis, we specifically aim to 1) determine CBD's impacts on microglia activity and beta amyloid pathology in AD transgenic mouse models by chronic in vivo imaging, and 2) evaluate CBD's effects on the molecular phenotypes of microglia in AD models by single-cell RNA sequencing. Identifying the effects of CBD on microglia and AD-related pathology in vivo will not only provide novel insights into the cellular and molecular mechanisms underlying CBD's action in the brain, but also suggest new routes to develop therapeutic strategies for AD.

项目摘要/摘要 阿尔茨海默病(AD)是一种严重的神经退行性疾病，给人类社会带来了重大负担。 阿尔茨海默病的病理特征是β-淀粉样斑块积聚和过度磷酸化。 Tau蛋白以及涉及小胶质细胞的神经炎症。目前尚无有效的治疗AD的方法， 迫切需要基于对AD病理机制的理解的新的治疗策略。 大麻二酚(CBD)是一种非精神活性的植物大麻素，具有广泛的抗炎作用。几个 最近的研究报道了CBD能够减少神经炎性反应和改善行为 在AD小鼠模型中起作用。然而，CBD对小胶质细胞和AD的体内作用及其机制 病理仍不清楚。这项建议的总体目标是确定以下机制的影响 CBD对AD相关细胞病理的研究，以期优化其治疗潜力。几行 有证据表明，小胶质细胞是介导CBD体内作用的有力候选者，并有助于 其在AD模型中的治疗潜力。首先，淀粉样斑块周围反应性小胶质细胞的聚集 长期以来一直被认为是AD病理的标志。最近的人类遗传学研究进一步确定了 多个AD危险基因参与了小胶质细胞的功能，提示小胶质细胞在AD发病机制中起着偶然的作用。 其次，单细胞RNA测序研究揭示了AD小胶质细胞显著的激活多样性 人口，包括疾病相关的小胶质细胞(DAM)。对反应性重新编程的实验操作 小胶质细胞恢复其体内平衡功能已显示出对AD病理的保护作用，提示 小胶质细胞的治疗潜力。第三，已知CBD与多个膜以生化方式相互作用。 在小胶质细胞中表达的受体和细胞内信号分子，包括大麻素受体。 第四，先前的体外细胞研究和我们初步的慢性体内成像数据表明，CBD调节 小胶质细胞的活性和形态。阿尔茨海默病中CBD如何与小胶质细胞相互作用并影响淀粉样斑块 转基因模型仍有待研究。我们的中心假设是，CBD的治疗将改变 小胶质细胞的细胞活性和分子图谱，减少脑内AD的病理改变。为了测试这一点 假设，我们的具体目标是1)确定CBD对小胶质细胞活性和β淀粉样蛋白病理的影响 通过慢性体内显像法建立AD转基因小鼠模型，2)评价CBD对分子水平的影响 单细胞RNA测序法检测AD模型小胶质细胞表型的研究鉴定CBD对小胶质细胞的影响 而与AD相关的体内病理学不仅将为AD的细胞和分子机制提供新的见解 CBD在大脑中的作用，但也为开发AD治疗策略提供了新的途径。