Inter- and Intra-cellular effects of cannabinoids, HIV and ART in the CNS

大麻素、HIV 和 ART 对中枢神经系统的细胞间和细胞内影响

• 批准号: 10452486
• 负责人: Kelly L Jordan-Sciutto
• 金额: $ 70.81万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10452486
• 关键词: Agonist; Anti-Inflammatory Agents; Anti-Retroviral Agents; Antiinflammatory Effect; Anxiety; Astrocytes; Attenuated; CNR1 gene; CNR2 gene; Cannabinoids; Cannabis; Cell Lineage; Cells; Central Nervous System Diseases; Chronic; Colitis; Colon; Complex; Dendritic Cells; Disease; Dissection; Drug Side Effects; Environment; Exhibits; Experimental Autoimmune Encephalomyelitis; Functional disorder; Gene Expression; Gene Expression Profile; HIV; HIV Infections; HIV antiretroviral; HIV therapy; Heart; Human; Immunomodulators; Inflammasome; Inflammation; Inflammatory; Kidney; Kinetics; Life Expectancy; Liver; Mental Depression; Microglia; Modeling; Morphology; Myelogenous; Myocardial Infarction; Neuraxis; Neurologic Dysfunctions; Neuronal Dysfunction; Neurons; Oxidative Stress; Pain; Pathway interactions; Patients; Pattern; Persons; Production; Property; Reporting; Role; Signal Pathway; Signal Transduction; Stress; T-Lymphocyte; Tissues; Viral; antiretroviral therapy; biological adaptation to stress; body system; comorbidity; cytokine; experience; fetal; immunoregulation; induced pluripotent stem cell; macrophage; marijuana use; painful neuropathy; phytocannabinoid; pleasure; receptor; side effect

Abstract: Antiretroviral therapy (ART) has dramatically extended the lives of people living with HIV (PLWH); however, they continue to experience a plethora of co-morbid conditions including neuronal disorders and pain. Between 40 and 72% of PLWH use cannabis to mitigate anxiety, stress, ART side effects, pain, and/or for pleasure with over 55% of patients using cannabis at least daily. Interestingly, a recent study found that people who use cannabis heavily had reduced inflammatory signatures in PLWH on ART. These and a numerous other studies support the anti-inflammatory and immunomodulator effects of phytocannabinoids in a number of organ systems including heart, colon, kidney, liver and the gut; however, their medicinal use is confounded by the psychotropic activities. Efforts to separate the anti-inflammatory effects from the psychotropic effects have revealed differential activities of 3 endogenous receptors including cannabis receptor 1 (CB2) CB2 which exhibit differential tissue expression and agonism with endo- and phyto-cannabinoids. Several reports have shown that cannabinoids attenuate HIV infection and/or replication in T-cells, macrophages, dendritic cells and human fetal microglia cultured ex vivo. However, the effect of cannabinoids on HIV infection of microglia in the context of ART and the normal cellular environment of neighboring neurons and astrocytes in the CNS has not been examined. Several studies specifically implicate CB2 agonism which has been shown to have anti- inflammatory properties in the heart, gut, experimental autoimmune encephalitis and neuropathic pain via inflammasome activation. This has led us to hypothesize that Cannabinoid signaling influences HIV infection and chronic inflammation in the presence of ARV in the central nervous system by attenuating the inflammasome. In order to examine HIV infection in the context of cells of the CNS, we have developed a human induced pluripotent stem cell tri-culture model composed of iNeurons, iAstrocytes, and iMicroglia. This model recapitulates several key aspects of HIV infection in the CNS including increased cytokine production, oxidative stress response, inflammatory signaling, and integrated stress response. ARV treatment reduces HIV infection and inflammatory signaling pathways; however, a subset of pathways remain elevated despite viral suppression. We propose to further develop this model to determine the ability of cannabinoids to modulate HIV-induced inflammation and subsequent neuronal dysfunction via reducing inflammasome activation by: 1) Determining the effect of cannabinoids on chronic HIV infection and ART in the context of iMgl/iNrn/iAstr triculture. 2) Determining the effect of cannabinoids on cytokine levels, inflammatory gene expression profile, and microglial activation in iMgl/iNrn/iAstr triculture. 3) Determining the effect of cannabinoids on neurons and astrocytes in HIV infection and ART in iMgl/iNrn/iAstr triculture.

抽象的： 抗逆转录病毒治疗 (ART) 极大地延长了艾滋病毒感染者 (PLWH) 的生命；然而， 他们继续经历大量的并发症，包括神经元疾病和疼痛。 40% 至 72% 的 PLWH 使用大麻来缓解焦虑、压力、ART 副作用、疼痛和/或 超过 55% 的患者至少每天使用大麻感到高兴。有趣的是，最近的一项研究发现，人们 大量使用大麻的人在接受抗逆转录病毒疗法后减少了感染者的炎症特征。这些以及众多 其他研究支持植物大麻素在许多方面的抗炎和免疫调节作用 器官系统，包括心脏、结肠、肾脏、肝脏和肠道；然而，它们的药用用途却受到以下因素的困扰： 精神治疗活动。将抗炎作用与精神作用分开的努力已经 揭示了 3 种内源性受体的差异活性，包括大麻受体 1 (CB2) CB2 表现出差异的组织表达和与内源性大麻素和植物性大麻素的激动作用。多份报告已 研究表明，大麻素可以减弱 T 细胞、巨噬细胞、树突细胞和 HIV 感染和/或复制。 离体培养的人胎儿小胶质细胞。然而，大麻素对 HIV 小胶质细胞感染的影响 ART 的背景以及中枢神经系统中邻近神经元和星形胶质细胞的正常细胞环境并没有 被检查。几项研究特别表明 CB2 激动剂已被证明具有抗- 心脏、肠道的炎症特性、实验性自身免疫性脑炎和神经性疼痛 炎症小体激活。这使我们推测大麻素信号传导会影响艾滋病毒感染 以及中枢神经系统存在抗逆转录病毒药物时的慢性炎症，通过减弱 炎症小体。 为了在中枢神经系统细胞的背景下检查艾滋病毒感染，我们开发了一种人类 诱导性多能干细胞三元培养模型，由 iNeurons、iAstrulates 和 iMicroglia 组成。这个型号 概括了中枢神经系统中艾滋病毒感染的几个关键方面，包括细胞因子产生的增加， 氧化应激反应、炎症信号传导和综合应激反应。抗逆转录病毒治疗可减少 HIV感染和炎症信号通路；然而，尽管有一部分途径仍然升高 病毒抑制。我们建议进一步开发这个模型来确定大麻素的能力 通过减少炎症小体调节 HIV 诱导的炎症和随后的神经元功能障碍 激活方式： 1) 确定大麻素对慢性 HIV 感染和 ART 的影响 iMgl/iNrn/iAstr 三耕栽培。 2) 确定大麻素对细胞因子水平、炎症基因的影响 iMgl/iNrn/iAstr 三培养中的表达谱和小胶质细胞激活。 3) 确定效果 大麻素对 HIV 感染和 ART 中 iMgl/iNrn/iAstr 三培养中神经元和星形胶质细胞的影响。