Modeling the effects of chronic marijuana use on neuroinflammation and HIV-related neuronal injury

模拟长期吸食大麻对神经炎症和 HIV 相关神经元损伤的影响

• 批准号: 10267730
• 负责人: CHRISTINA S MEADE
• 金额: $ 99.1万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10267730
• 关键词: AIDS/HIV problem; Address; Adult; Adverse effects; Age; Anti-Inflammatory Agents; Antiinflammatory Effect; Attenuated; Axon; Brain; Brain Injuries; Brain region; CNR1 gene; Cannabidiol; Cannabinoids; Chronic; Clinical; Cognitive deficits; Complex; Cytokine Signaling; Data; Disease; Drug Use Disorder; Fiber; Foundations; Goals; HIV; HIV Infections; HIV Seronegativity; HIV-associated neurocognitive disorder; Immune; Inflammation; Inflammatory; Link; Magnetic Resonance Imaging; Marijuana; Mediating; Medical; Modeling; Nerve Degeneration; Nervous System Physiology; Neuraxis; Neurobiology; Neurologic; Neuronal Dysfunction; Neuronal Injury; Neurons; Neuropsychological Tests; Outcome; Participant; Pathway interactions; Patients; Persons; Process; Prospective cohort; Recommendation; Reporting; Research; Research Priority; Resolution; Role; Sampling; Science; Structure; Substance abuse problem; Testing; Tetrahydrocannabinol; Therapeutic; Therapeutic Agents; Time; Tissues; Translations; United States; United States National Institutes of Health; Universities; Work; addiction; antiretroviral therapy; brain abnormalities; brain dysfunction; brain metabolism; cognitive function; cognitive process; cohort; comorbidity; comparison group; cytokine; drug of abuse; endogenous cannabinoid system; experience; illicit drug use; imaging capabilities; immune activation; improved; in vivo; in vivo Model; innovation; marijuana use; marijuana user; multidisciplinary; multimodality; nervous system disorder; neuroAIDS; neurobehavioral; neuroimaging; neuroinflammation; neurotoxic; preservation; programs; protective effect; public health relevance; receptor downregulation; systemic inflammatory response; translational approach; white matter

Marijuana, the mostly widely used illicit drug in the United States, is disproportionately prevalent in persons with HIV. Despite the promise of cannabinoids as a therapeutic agent for HIV disease, chronic marijuana use is also associated with potential neurobiological harms. Neurological complications of HIV disease remain a persistent clinical problem even in the age of combination antiretroviral therapy. Our prior work demonstrates that chronic marijuana use exacerbates HIV-associated cognitive deficits, even in patients with sustained HIV suppression, and is associated with complex brain abnormalities in persons with HIV. Additional preliminary data shows reduced levels of inflammatory cytokines in marijuana users compared to non users that correlate with cognitive function. Building on a strong foundation of neuroHIV and addiction research by our multidisciplinary team, this hypothesis-driven proposal will use an in vivo model to investigate the underlying pathophysiological mechanisms of HIV-associated brain dysfunction. Using this translational approach, we aim to: (1) investigate the independent and additive effects of HIV disease and chronic marijuana use on inflammatory processes linked to brain injury; (2) model the longitudinal relationship of chronic marijuana use to HIV-induced inflammation and its relationship to brain injury; and (3) determine the relationship of cannabinoid metabolites to inflammatory and neuronal markers. A prospective cohort of 140 adults stratified marijuana status will complete cutting-edge neuroimaging, immune and cytokine profiling, and neuropsychological testing three times over 2 years. Capitalizing on ultrahigh-resolution magnetic resonance imaging (MRI) capabilities at Duke, we will use multimodal, multi-parametric sequences to investigate neuroinflammatory and neurodegenerative processes. The baseline will include comparison groups of 80 HIV- negative adults. The central hypothesis is that marijuana use disrupts the central nervous system through both anti-inflammatory and neurotoxic pathways. Our proposal responds directly to RFA-DA-20-022, which calls for mechanistic studies to “discern the impact of chronic and/or heavy use of cannabis on the interaction between endocannabinoid system function and HIV-induced inflammation” and “its consequent effects on nervous system function.” This research uses a team science approach to address topics aligned with NIH HIV/AIDS research priorities, including a focus on persistent inflammation and HIV-relevant comorbid conditions [NOT- 20-018]. By considering both beneficial and adverse effects of marijuana available in the United States market, our proposal has strong translational potential to guide clinical recommendations for medical and recreational marijuana in persons with HIV. This timely and ecologically valid research is also expected to advance our understanding of the inflammatory mechanisms through which cannabinoids modulate neurological disorders and other comorbidities in persons with HIV.

大麻是美国使用最广泛的非法药物，在人中普遍存在 与艾滋病毒。尽管大麻素作为艾滋病毒疾病的治疗剂有望，但使用慢性大麻是 也与潜在的神经生物学危害有关。 HIV疾病的神经系统并发症仍然是 即使在抗逆转录病毒疗法的时代，持续的临床问题也是如此。我们先前的工作证明了 慢性大麻使用加剧了与HIV相关的认知防御，即使在患有持续HIV的患者中 抑制作用，与​​艾滋病毒患者的复杂大脑异常有关。其他初步 数据显示，与非用户相比，大麻使用者的炎症细胞因子水平降低了 具有认知功能。以我们的神经凝血和成瘾研究的强大基础为基础 多学科团队，该假设驱动的建议将使用体内模型来研究基础 HIV相关脑功能障碍的病理生理机制。使用这种翻译方法，我们的目标 至：（1）研究HIV疾病和慢性大麻对艾滋病毒疾病的独立和加性作用对 与脑损伤有关的炎症过程； （2）模拟慢性大麻使用的纵向关系 艾滋病毒引起的炎症及其与脑损伤的关系； （3）确定 大麻素代谢产物炎症和神经元标记物。 140名成年人分层的前瞻性队列 大麻状态将完成尖端的神经影像学，免疫和细胞因子分析，以及 神经心理学测试在2年内进行了三次。利用超高分辨率的磁共振 杜克大学的成像（MRI）功能，我们将使用多模式，多参数序列进行研究 神经炎症和神经退行性过程。基线将包括80 HIV-的比较组 负成年人。中心假设是，大麻的使用通过两者都破坏了中枢神经系统 抗炎和神经毒性途径。我们的建议直接回应RFA-DA-20-022 机械研究，以“辨别大麻的慢性和/或大麻对之间的相互作用的影响 内源性大麻素系统功能和HIV引起的感染”及其对神经的影响 系统功能。“这项研究使用团队科学方法来解决与NIH HIV/AIDS一致的主题 研究优先级，包括关注持续感染和与HIV相关的合并症[不 - 20-018]。通过考虑大麻在美国市场上可用的有益和不利影响， 我们的建议具有强大的转化潜力，可以指导医疗和娱乐的临床建议 大麻在患有艾滋病毒的人身上。这项及时和生态上有效的研究也有望促进我们的 了解大麻素调节神经系统疾病的炎症机制 以及其他艾滋病毒的人的合并症。