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.

抽象的 非感染性自身免疫性葡萄膜炎是一种威胁性的炎症性眼病 对于10％的可预防失明，Dospite目前可用的疗法。对 不仅提供抗炎效率，而且受患者耐受性良好的药物。 大麻素（CBD）是没有精神效应的大麻的主要组成部分之一。这是 在动物模型和患者中治疗许多病理状况的探索中，包括 癌症，炎症性疾病，神经过多疾病，药物滥用疾病等 证据支持CBD作为一种免疫调节剂，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的总体降低，并增加 抗炎细胞因子。但是，CBD尚未研究自身免疫性葡萄膜炎的动物模型 或葡萄膜炎患者。 G蛋白偶联受体3（GPR3）属于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中起着重要作用，并且是 涉及各种病理状况，直到最近我们发现CBD是一个反向配体 GPR3。该发现突出了该孤儿接收器是CBD的潜在新分子靶标 CBD动作的新型机制。在我们的试点研究中，我们发现GPR3在低水平中表达 然而，在眼睛中大量检测到该表达。 眼内炎症期间增加。此外，我们确定了T细胞和抗原呈递细胞 B细胞和树突状细胞（DC）的（APC）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介导的治疗作用也尚不清楚。 在此应用程序中，我们将使用良好的T细胞介导的实验自身免疫 葡萄膜炎（EAU）模型，以测试CBD对EAU的潜在治疗作用（AIM 1）和功能 GPR3对EAU开发的影响（AIM 2），以及CBD对EAU的治疗作用是否为 由GPR3体内和体外介导（AIM 3） 这些研究将为CBD提供临床前证明，作为潜在的抗炎，感光器 葡萄膜炎患者的保护性和镇痛药，并提高我们对CBD –GPR3的理解 自身免疫性葡萄膜炎的发展中的相互作用。