The effect of cannabidiol and the role of GPR3 in experimental autoimmune uveitis

大麻二酚和 GPR3 在实验性自身免疫性葡萄膜炎中的作用

• 批准号: 9898375
• 负责人: HUI SHAO
• 金额: $ 19.25万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898375
• 关键词: Adoptive Transfer; Adverse effects; Affect; Agonist; Analgesics; Animal Model; Anti-Inflammatory Agents; Antigen-Presenting Cells; Autoimmune Diseases; Autoimmune Process; B-Lymphocytes; Biological Assay; Blindness; Cannabidiol; Cannabinoids; Cannabis; Cell Proliferation; Cells; Clinical Trials; Coculture Techniques; Cyclic AMP; Dendritic Cells; Development; Disease; Eye; Eye diseases; Family; Fibromyalgia; Flow Cytometry; Future; GPR3 gene; Goals; Immune; Immunization; Immunize; Immunomodulators; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Knockout Mice; Lead; Ligands; Local Therapy; MHC Class II Genes; Malignant Neoplasms; Marijuana; Measures; Mediating; Microglia; Modeling; Molecular Target; Multiple Sclerosis; Mus; Neoplasms; Neurodegenerative Disorders; Orphan; Pathologic; Patients; Peptides; Pharmaceutical Preparations; Phase; Photoreceptors; Physiological; Pilot Projects; Play; Production; Protective Agents; Reporting; Retinol Binding Proteins; Role; Severities; Spleen; Substance abuse problem; Systemic Therapy; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Uveitis; Vision; Visual; Western World; Wild Type Mouse; autoimmune uveitis; cannabinoid treatment; cell injury; cytokine; disability; immunomodulatory therapies; in vivo; monocyte; novel; novel therapeutics; phytocannabinoid; pre-clinical; receptor; recruit

Abstract Non-infectious autoimmune uveitis is a sight-threatening inflammatory eye disease which accounts for 10% of preventable blindness, despite currently available therapies. There is a high demand for medications which not only provide anti-inflammatory efficacy but are well tolerated by the patient. Cannabinoid (CBD) is one of the major components of marijuana without psychotropic effects. It is being explored for treating a number of pathological conditions in animal models and in patients, including cancer, inflammatory diseases, neuro-degenerative diseases, substance abuse disorders, etc. Currently, evidence supports CBD as an immune-modulating agent, affecting T cells, B cells, monocytes and microglia cells, causing an overall reduction in pro-inflammatory cytokine expression and an increase in anti-inflammatory cytokines. However, CBD has not been studied in animal models of autoimmune uveitis or the patients with uveitis. G protein-coupled receptor 3 (GPR3) belongs to a family of closely related orphan receptors. Although it has been reported to play important roles in many normal physiological functions and be involved in a variety of pathological conditions, until recently we found that CBD is an inverse ligand for GPR3. This discovery highlights this orphan receptor as a potential new molecular target for CBD with a novel mechanism of CBD action. In our pilot study, we discovered that GPR3 is expressed at low levels in the spleen, and barely detectable in the eye in naïve mice. The expression, however, is dramatically increased during intraocular inflammation. Further, we identified that T cells and antigen presenting cells (APCs) of B cells, and dendritic cells (DCs) express GPR3. The role of GPR3 on these cells is unknown. It is also unknown whether CBD produces GPR3-mediated therapeutic effects in EAU. In this application, we will use our well-established T cell-mediated experimental autoimmune uveitis (EAU) models to test the potential therapeutic effects of CBD on EAU (Aim 1), and the functional impact of GPR3 on EAU development (Aim 2), and whether the therapeutic effects of CBD on EAU is mediated by GPR3 in vivo and in vitro (Aim 3) These studies will provide a preclinical proof for CBD as a potent anti-inflammatory, photoreceptor protective and analgesic drug for patients with uveitis and advance our understanding of CBD –GPR3 interaction in the development of autoimmune uveitis.

摘要 非传染性自身免疫性葡萄膜炎是一种威胁视力的炎症性眼病，其原因是 对于10%的可预防失明，尽管目前有治疗方法。对…的需求量很大 不仅具有消炎功效，而且患者耐受性良好的药物。 大麻素(CBD)是大麻中无精神作用的主要成分之一。它是 正在探索用于治疗动物模型和患者的一些病理情况，包括 癌症、炎症疾病、神经退行性疾病、物质滥用障碍等。目前， 有证据支持CBD是一种免疫调节剂，影响T细胞、B细胞、单核细胞和 小胶质细胞，导致促炎细胞因子表达全面减少，而 抗炎细胞因子。然而，CBD还没有在自身免疫性葡萄膜炎的动物模型中进行研究。 或者是葡萄膜炎患者。 G蛋白偶联受体3(GPR3)属于一个密切相关的孤儿受体家族。 尽管据报道，它在许多正常的生理功能和BE中起着重要的作用 参与了多种病理条件，直到最近我们发现CBD是一种反向配体 GPR3。这一发现突出了这种孤儿受体作为CBD潜在新分子靶点的作用 CBD作用的新机制。在我们的初步研究中，我们发现GPR3在 脾，在幼稚小鼠的眼睛里几乎检测不到。然而，这个表达是戏剧性的 在眼内炎症期间增加。此外，我们还鉴定了T细胞和抗原提呈细胞 B细胞(APC)和树突状细胞(DC)表达GPR3。GPR3在这些细胞上的作用尚不清楚。它 CBD是否在EAU中产生GPR3介导的治疗效果也是未知的。 在这项应用中，我们将使用我们成熟的T细胞介导的实验性自身免疫 建立葡萄膜炎(EAU)模型，测试CBD对EAU的潜在治疗作用(目标1)，以及功能性 GPR3对EAU发展的影响(目标2)，以及CBD对EAU的治疗效果是否 GPR3在体内和体外的介导作用(目标3) 这些研究将为CBD作为一种有效的抗炎、光感受器提供临床前证据 葡萄膜炎患者的保护和止痛药物及对CBD-GPR3的认识 自身免疫性葡萄膜炎发病过程中的相互作用。