Cannabinoid Modulation of Neuroinflammation in Human iPSC Models of HIV Infection

大麻素对 HIV 感染的人类 iPSC 模型中神经炎症的调节

• 批准号: 10257502
• 负责人: ALEXANDER STARR
• 金额: $ 4.6万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10257502
• 关键词: Activation Analysis; Agonist; Anti-Inflammatory Agents; Automobile Driving; Behavior Disorders; Biological Assay; Brain; CASP1 gene; CNR2 gene; Cannabinoids; Cannabis; Cell model; Cells; DNA biosynthesis; Disease; Drug Prescriptions; Effectiveness; Enzymes; Event; Experimental Autoimmune Encephalomyelitis; Exposure to; G-Protein-Coupled Receptors; Gene Expression; Genes; Genetic Transcription; Glutamates; HIV; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; Human; Immune; Impaired cognition; In Vitro; Individual; Infection; Inflammasome; Inflammation; Inflammatory; Interleukin-1 beta; Interleukin-18; Kinetics; Knowledge; Label; Learning; Lentivirus; Measures; Mediating; Mediator of activation protein; Memory; Microglia; Modeling; Molecular; Moods; Morphology; Motor; Neuraxis; Neurocognitive Deficit; Neuroglia; Neurologic; Neurons; Pathologic; Pathway interactions; Patients; Peripheral; Pharmacology; Plasma; Population; Productivity; Recreational Drugs; Regulation; Risk; Severities; Supplementation; Therapeutic; Therapeutic Intervention; United States; Viral Load result; Virus; Work; antiretroviral therapy; cannabinoid receptor; chemokine; cytokine; endogenous cannabinoid system; excitotoxicity; experience; exposed human population; fetal; human model; immune system function; immunoregulation; induced pluripotent stem cell; inhibitor/antagonist; macrophage; marijuana use; monocyte; motor disorder; neuroAIDS; neuroinflammation; neurotoxic; neurotoxicity; prevent; receptor; small molecule; stem cell differentiation; stem cell model; therapeutic target; tool; transmission process; viral DNA

PROJECT SUMMARY / ABSTRACT Despite effective combined antiretroviral therapies, 30-50% of people living with human immunodeficiency virus-1 (HIV) infection experience mood, memory, learning, and/or motor disfunction, collectively labeled HIV associated neurocognitive disorders. Mounting evidence suggests that HIV infects brain-resident macrophages and microglia, providing a persistent reservoir for HIV replication in the central nervous system. Because HIV does not infect neurons, the neurotoxic mechanisms driving neurocognitive decline are likely mediated by infected glia, which become activated and secrete proinflammatory cytokines and chemokines, neurotoxic HIV components, and excitotoxic levels of glutamate. Activation of the NLRP3 inflammasome, an NF-κB-driven assembly that facilitates IL-1β and IL-18 release and initiates pyroptosis, has been identified as an HIV-induced mediator of neurotoxicity. Recent studies suggest that NLRP3 activation is suppressed by activation of cannabinoid receptor 2 (CB2), an immunomodulatory GPCR which has been separately identified as a neuroprotective target in in vitro HIV models. I hypothesize that CB2 agonism decreases HIV-associated macrophage/microglial activation and macrophage/microglia-mediated neurotoxicity by suppressing the NLRP3 inflammasome. This proposal leverages primary human monocyte-derived macrophages (MDMs) in parallel with human induced pluripotent stem cells (iPSC) differentiated into microglia (iMg) and glutamatergic cortical neurons to understand the cell-specific effects of CB2 agonists on HIV infection and subsequent neuroinflammation. This will be accomplished in three aims: (I) identify how CB2 agonism effects macrophage and microglial infection dynamics, broad pro-inflammatory activation, and endocannabinoid system component expression in human models exposed to intact HIV, (II) specifically determine the effects of CB2 agonism on NLRP3 inflammasome priming, assembly, and pro-inflammatory cytokine release, and (III) examine whether CB2 agonism is protective against indirect macrophage- and microglia-mediated neurotoxicity, and whether that protection occurs via modulation of the NLRP3 inflammasome. These studies will increase our understanding of the effects of cannabinoid exposure in HIV- induced neuroinflammation and determine whether CB2 is a potential therapeutic target for NLRP3 inflammasome suppression in HIV infection and other pathologic neuroinflammatory contexts.

项目摘要/摘要