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.

大麻是美国最广泛使用的非法药物，在人群中非常普遍 患有艾滋病毒。尽管大麻素有望作为艾滋病毒疾病的治疗剂，但长期使用大麻 还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一个 即使在联合抗逆转录病毒治疗时代，这也是持续存在的临床问题。我们之前的工作表明 长期吸食大麻会加剧与艾滋病毒相关的认知缺陷，即使对于持续感染艾滋病毒的患者也是如此 抑制，并且与艾滋病毒感染者复杂的大脑异常有关。附加初步 数据显示，与非大麻使用者相比，大麻使用者的炎症细胞因子水平降低 具有认知功能。建立在我们的神经艾滋病毒和成瘾研究的坚实基础上 多学科团队，这个假设驱动的提案将使用体内模型来研究潜在的 HIV相关脑功能障碍的病理生理机制。使用这种转化方法，我们的目标是 (1) 调查艾滋病毒疾病和长期吸食大麻对健康的独立影响和相加影响 与脑损伤相关的炎症过程； (2) 建立长期吸食大麻的纵向关系模型 HIV 引起的炎症及其与脑损伤的关系； (3) 确定关系 大麻素代谢产物为炎症和神经元标记物。 140 名成年人的前瞻性队列分层 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 2年内进行3次神经心理学测试。利用超高分辨率磁共振 杜克大学的成像（MRI）能力，我们将使用多模式、多参数序列来研究 神经炎症和神经退行性过程。基线将包括 80 名 HIV- 消极的成年人。中心假设是，吸食大麻会通过以下两种方式扰乱中枢神经系统： 抗炎和神经毒性途径。我们的提案直接响应 RFA-DA-20-022，其中要求 机制研究“辨别长期和/或大量使用大麻对两者之间相互作用的影响” 内源性大麻素系统功能和艾滋病毒引起的炎症”及其对神经的后续影响 系统功能。”这项研究采用团队科学方法来解决与 NIH HIV/AIDS 相关的主题 研究重点，包括关注持续性炎症和与艾滋病毒相关的共病 [NOT- 20-018]。考虑到美国市场上大麻的有利和不利影响， 我们的提案具有强大的转化潜力，可以指导医疗和娱乐的临床建议 艾滋病毒感染者吸食大麻。这项及时且生态有效的研究也有望推动我们的研究 了解大麻素调节神经系统疾病的炎症机制 以及艾滋病毒感染者的其他合并症。