Pathogenesis of Neuroinflammation and Neurocognitive Impairment In HIV-infected Young Adult Cannabis Users

感染艾滋病毒的年轻成年大麻使用者神经炎症和神经认知障碍的发病机制

• 批准号: 10621691
• 负责人: DAVID MARTIN MURDOCH
• 金额: $ 75.9万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621691
• 关键词: Address; Adult; Affect; Affinity; Anti-Inflammatory Agents; Automobile Driving; Benzodiazepine Receptor; Biological Markers; Biology; Brain; CCL2 gene; Cannabinoids; Cell physiology; Cells; Cerebrospinal Fluid; Clinical; Clinical Trials; Cognition; Complication; Data; Diagnosis; Disease Management; Drug Modulation; Drug abuse; Drug usage; Future; Genes; Goals; HIV; HIV Infections; HIV diagnosis; HIV-associated neurocognitive disorder; HIV-infected adolescents; Immune; Immune System Diseases; Immunologics; Immunology; Impaired cognition; Impairment; In Vitro; Infection; Inflammation; Inflammatory; Infrastructure; Institution; Intervention; Intuition; Label; Legal; Ligands; Macrophage; Magnetic Resonance Imaging; Marijuana; Measures; Methods; Microglia; Morbidity - disease rate; Myelogenous; Myeloid Cell Activation; Myeloid Cells; Neopterin; Neurocognition; Neurocognitive; Neurocognitive Deficit; Neurologic; Neuronal Injury; Participant; Pathogenesis; Pathway interactions; Patients; Peripheral; Persons; Pharmaceutical Preparations; Positioning Attribute; Positron-Emission Tomography; Productivity; Research; Research Infrastructure; Resolution; Role; Severities; Structure; Substance abuse problem; Synapses; T-Lymphocyte; TREM2 gene; Techniques; Technology; Testing; Tracer; Work; Youth; antiretroviral therapy; axon injury; biomarker validation; candidate marker; cannabinoid receptor; clinical practice; comorbidity; daily functioning; density; detection assay; drug of abuse; glial activation; imaging capabilities; immune modulating agents; immunoregulation; improved; inflammatory marker; innovation; insight; marijuana use; marijuana user; monocyte; neuroAIDS; neurocognitive test; neurofilament; neuroimaging; neuroinflammation; neuroprotection; novel; novel therapeutics; performance tests; predictive marker; preservation; prospective; public health relevance; radiotracer; response; single molecule; single-cell RNA sequencing; systemic inflammatory response; therapy development; tool; transcriptome; transcriptomic profiling; transcriptomics; young adult

Project Summary HIV-associated neurocognitive disorders (HAND) and neurocognitive impairment (NCI) remain long-term complications of HIV infection despite effective antiretroviral therapy (ART). Even in early HIV infection and in young adults who comprise 37% of new HIV infections, HAND impacts daily functioning and increases morbidity. This impact of HAND in the young will impact the productivity of the work force worldwide. Currently, our mechanistic insight into HAND pathogenesis in people living with HIV (PLWH) remains limited, and no validated biomarkers exist to diagnose and manage NCI. HAND is believed to result from sustained neuroinflammation. Unfortunately, growing evidence suggests inflammation is modulated by drugs of abuse, including the drug of choice among young adults with HIV: marijuana. Marijuana's immunomodulatory effects are largely anti-inflammatory, including suppression of T cell function and monocyte activation, the latter of which is pivotal to HAND immunopathogenesis. This proposal leverages an existing multi-institutional infrastructure focused on drugs of abuse in adult and adolescent HIV+ patients. Data from our group has found that 1) THC treatment reduces monocyte activation; 2) compared to unimpaired, impaired patients have increased CSF markers of neuronal injury (neurofilament (NFL), and 3) single cell RNA sequencing (scRNA- seq) of cerebrospinal fluid (CSF) from HIV-infected subjects reveals differentiated myeloid cells expressing damage-associated microglia (DAM) genes (APOE and TREM2) and other markers of monocyte activation. This proposal will investigate the role of marijuana in modulating neuroinflammation and HAND and identify a set of candidate biomarkers with potential to perform in the immunomodulatory context of substance abuse. An ideal candidate biomarker is one that can perform in the context of HIV driven inflammation and immunomodulation by drugs of abuse. This proposal will be the first to perform comprehensive, multi-domain immune and transcriptomic profiling to investigate the effects of marijuana on systemic and neuroinflammation, and its impact on cognition in young people living with HIV (YLWH). Within four groups (NCI-/MJ-, NCI+/MJ-, NCI-/MJ+, NCI+/MJ+) we will 1) quantify differences in CNS and peripheral inflammatory biomarkers and markers of neuronal injury; 2) evaluate the potential anti-inflammatory and neuroprotective impact of marijuana use; 3) determine the impact of marijuana on the cerebrospinal fluid (CSF) cellular transcriptome via single cell RNA sequencing (scRNA-seq) to identify inflammatory pathways for future interventions; and 4) using novel PET/MR techniques, quantify microglial activation and neuroinflammation and synaptic density via radiotracers (peripheral benzodiazepine receptor (PBR)111 and UCB-J, respectively). Via these objectives, this proposal will provided needed insight into HAND pathogenesis in the context of drug use. From an increased understanding of its pathogenesis using novel immunological and neuroimaging, results will ultimately help identify modulatory pathways of inflammation. Results from this study will add to our understanding of the interplay between cannabinoids and inflammation both within HIV-infected and uninfected young adults. This proposal has strong potential to lay the groundwork for studies to test novel therapeutics, such as cannabinoid receptor ligands, and clinical interventions to reduce HAND morbidity in young adults with HIV.

项目摘要 与HIV相关的神经认知障碍（手）和神经认知障碍（NCI）长期保持 尽管有效的抗逆转录病毒疗法（ART），HI​​V感染并发症。即使在早期的艾滋病毒感染和 占新艾滋病毒感染的37％的年轻人，手动影响每日功能并增加 发病率。在年轻人中，这种影响将影响全球劳动力的生产力。现在， 我们对艾滋病毒（PLWH）患者的手发病机理的机械洞察力仍然有限，没有 存在验证的生物标志物来诊断和管理NCI。据信手是由持续的 神经炎症。不幸的是，越来越多的证据表明炎症是由滥用药物调节的 包括艾滋病毒：大麻的年轻人中选择的药物。大麻的免疫调节作用 在很大程度上是抗炎药，包括抑制T细胞功能和单核细胞激活，后者 这对于手动免疫发作至关重要。该建议利用现有的多机构 基础设施的重点是成人和青少年艾滋病毒+患者的滥用药物。我们小组的数据发现 1）THC处理减少了单核细胞的激活； 2）与未受损的患者相比 神经元损伤（神经丝（NFL）和3）单细胞RNA测序的CSF标记增加（SCRNA- 来自HIV感染受试者的脑脊液（CSF）的Seq）揭示了表达的分化的髓样细胞 与损伤相关的小胶质细胞（DAM）基因（APOE和TREM2）以及单核细胞激活的其他标记。 该提案将调查大麻在调节神经炎症和手中的作用 一组在药物滥用的免疫调节背景下具有潜力的候选生物标志物。 理想的候选生物标志物是可以在艾滋病毒驱动的炎症和 通过滥用药物进行免疫调节。该建议将是第一个执行全面的多域 免疫和转录组分析以研究大麻对系统性和神经炎症的影响， 及其对艾滋病毒（YLWH）年轻人认知的影响。在四组内（NCI-/MJ-，NCI+/MJ-，， NCI-/MJ+，NCI+/MJ+）我们将1）量化CNS和外围炎症生物标志物的差异 神经元损伤的标记； 2）评估大麻的潜在抗炎和神经保护作用 使用; 3）确定大麻对通过单细胞的脑脊液（CSF）细胞转录组的影响 RNA测序（SCRNA-SEQ）以确定未来干预措施的炎症途径； 4）使用新颖 PET/MR技术，通过放射性示例量化小胶质细胞激活和神经炎症和突触密度 （分别是外周苯二氮卓受体（PBR）111和UCB-J）。通过这些目标，该提议 将在药物使用的背景下提供有关手部发病机理的必要洞察力。从增加 使用新型免疫学和神经影像学了解其发病机理，结果最终将有助于 确定炎症的调节途径。这项研究的结果将增加我们对 大麻素和炎症之间的相互作用均在HIV感染和未感染的年轻人中。这 提案具有强大的潜力，可以为研究新的治疗剂（例如大麻素）奠定基础。 受体配体和临床干预措施可降低HIV年轻人的手部发病率。