Cannabis, inflammation, and the brain in persons with HIV

大麻、炎症和艾滋病毒感染者的大脑

基本信息

批准号：
10440508
负责人：
Jennifer E Iudicello
金额：
$ 63.19万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10440508
关键词：
2-arachidonylglycerol Acquired Immunodeficiency Syndrome Address Adverse event Affect Anti-Inflammatory Agents Antiinflammatory Effect Biological Biological Markers Blood Blood specimen Body Fluids Brain Brain imaging CNR1 gene CNR2 gene Cannabidiol Cannabinoids Cannabis Cell Culture Techniques Cell surface Cerebrospinal Fluid Chronic Clinical Cohort Studies Collection Consequences of HIV Data Disease Dose Emotions Endocannabinoids Enzymes Etiology Experimental Models Family Frequencies Functional disorder General Population HIV HIV Infections HIV therapy HLA-DR Antigens Health Immune Immune response Inflammasome Inflammation Inflammatory Inflammatory Response Interleukin-6 Knowledge Label Link Macrophage Activation Measurement Measures Mediating Medical Mental Depression Methods Microglia Monoacylglycerol Lipases Myelogenous Nausea Neuraxis Neurocognitive Neurocognitive Deficit Neurodegenerative Disorders Noise Organ Outcome Pain Participant Pathway interactions Persons Pharmaceutical Preparations Population Positron-Emission Tomography Prevalence Primary Cell Cultures Proteins Psychological Stress RNA Research Research Priority Research Project Grants Risk Role Sampling Signal Transduction Source Specimen Standardization Stress System TREM2 gene Tetrahydrocannabinol Therapeutic Variant Virus Replication anandamide antiretroviral therapy cannabinoid receptor cohort comorbidity cytokine endogenous cannabinoid system experimental study fatty acid amide hydrolase immune activation in vivo insight marenostrin marijuana use marijuana user monocyte multimodality neuroinflammation neuropsychiatry novel organ injury radiotracer receptor receptor expression response sex treatment strategy

项目摘要

PROJECT SUMMARY During suppressive antiretroviral therapy (ART), chronic inflammation persists among people with HIV (PWH) and appears to be driven by low levels of HIV replication, monocyte/macrophage activation, and other mechanisms. This persistent inflammation has been linked to adverse neuropsychiatric (e.g., depression, psychological stress, emotion dysfunction), neurocognitive, and medical outcomes. Cannabis, which is used more commonly by PWH than people without HIV, appears to have anti-inflammatory effects and therefore may have therapeutic applications for inflammation and end-organ complications. Cannabinoids exert their effects in part via the endocannabinoid (EC) system (ECS), which includes cannabinoid receptors that are expressed on the surface of cells of the immune and central nervous systems. Cannabinoids have demonstrated clinical benefits for conditions like pain and nausea, but less is known about its effects on inflammation in HIV. Moreover, the range of cannabis exposure (e.g., dose and frequency of use) that may be effective, ineffective, or unsafe for different neuropsychiatric and medical conditions is unknown. In response to RFA-DA-20-022, this application proposes to address key scientific gaps by examining the effects of chronic cannabis use and the role of the ECS in persistent inflammation in PWH who are taking suppressive ART. We propose to assess 120 participants (60 PWH on suppressive ART and 60 HIV- persons) across a spectrum of cannabis use from persons who have never used cannabis to daily users. We will comprehensively evaluate participants with multimodal in vivo and ex vivo assessments of the biological pathways underlying the effects of chronic cannabis use on persistent inflammation in PWH and its corresponding impact on neuropsychiatric and neurocognitive complications. In vivo assessments will include standardized medical, neuropsychiatric, and neurocognitive assessments, including collection of cerebrospinal fluid and blood. Current cannabis users within this sample (n=80) will also be assessed with novel brain imaging of microglial activation with [(18)F]FEPPA translocator protein (TSPO) positron emission tomography. In the collected specimens, we will measure soluble (e.g., pro- and anti- inflammatory cytokines) and cellular (e.g., HLA-DR, CD38) biomarkers of inflammation and immune activation as well as components of the ECS (e.g., anandamide, CB2 receptors). Blood specimens will also serve as the source for primary cell cultures for ex vivo mechanistic experiments that will assess the effects of cannabinoids, HIV, and ART on biological pathways such as the TREM2 and the NLRP3 inflammasome. Data from all assessments and experiments will be integrated and analyzed centrally to identify cross-cutting signals and reduce noise from our multimodal assessments. Knowledge gained from this study will contribute to OAR priorities (e.g., comorbidities, end organ injury) and provide valuable insight into strategies for treatment of persistent inflammation in PWH and its health-related consequences.

项目概要在抑制性抗逆转录病毒治疗 (ART) 期间，艾滋病毒感染者 (PWH) 中持续存在慢性炎症似乎是由低水平的 HIV 复制、单核细胞/巨噬细胞激活和其他因素驱动的机制。这种持续性炎症与不良神经精神疾病（例如抑郁症、心理压力、情绪功能障碍）、神经认知和医疗结果。大麻，用于与未感染艾滋病毒的人相比，感染者更常见，似乎具有抗炎作用，因此可能具有治疗炎症和终末器官并发症的应用。大麻素发挥其作用部分通过内源性大麻素（EC）系统（ECS），其中包括表达于免疫和中枢神经系统细胞的表面。大麻素已被临床证明它对疼痛和恶心等病症有好处，但对其对艾滋病毒炎症的影响知之甚少。而且，可能有效、无效或不安全的大麻暴露范围（例如剂量和使用频率）对于不同的神经精神和医学状况的影响尚不清楚。为了响应 RFA-DA-20-022，本申请提议通过研究长期使用大麻的影响以及大麻的作用来解决关键的科学差距 ECS 治疗正在接受抑制性 ART 的 PWH 的持续炎症。我们建议评估 120 名参与者（60 名接受抑制性抗逆转录病毒疗法的感染者和 60 名艾滋病毒感染者）从未对日常使用者使用过大麻。我们将通过体内多模态综合评估参与者对长期使用大麻对持久性影响的生物途径进行离体评估 PWH 中的炎症及其对神经精神和神经认知并发症的相应影响。在体内评估将包括标准化的医学、神经精神病学和神经认知评估，包括脑脊液和血液的采集。该样本中当前的大麻使用者 (n=80) 也会通过 [(18)F]FEPPA 易位蛋白 (TSPO) 的小胶质细胞激活的新型脑成像进行评估正电子发射断层扫描。在收集的样本中，我们将测量可溶性（例如，亲和抗）炎症细胞因子）和炎症和免疫激活的细胞（例如 HLA-DR、CD38）生物标志物以及 ECS 的成分（例如 anandamide、CB2 受体）。血液样本也将作为用于评估大麻素影响的离体机制实验的原代细胞培养物的来源， HIV 和 ART 对 TREM2 和 NLRP3 炎性体等生物途径的影响。数据来自所有人评估和实验将被集中整合和分析，以识别跨领域信号和减少多模式评估中的噪音。从这项研究中获得的知识将为 OAR 做出贡献优先事项（例如合并症、终末器官损伤）并为治疗策略提供有价值的见解感染者中的持续炎症及其与健康相关的后果。