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

基本信息

批准号：
10890228
负责人：
CHRISTINA S MEADE
金额：
$ 80.3万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
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 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10890228
关键词：
Address Adult Adverse effects Age Anti-Inflammatory Agents Antiinflammatory Effect Attenuated Axon Brain Brain Injuries Brain region CNR1 gene Cannabidiol Cannabinoids Central Nervous System Chronic Clinical Cognitive deficits Complex Cytokine Signaling Data Disease Drug Use Disorder Fiber Foundations Goals HIV HIV Infections HIV Seronegativity HIV-associated neurocognitive disorder HIV/AIDS Immune Inflammation Inflammatory Link Magnetic Resonance Imaging Marijuana Marketing Mediating Medical Medicine Modeling Nerve Degeneration Nervous System Physiology Neurobiology Neurologic Neuronal Dysfunction Neuronal Injury Neurons Neuropsychological Tests Outcome Participant Pathway interactions Patients Persons Process Prospective cohort Qualifying Receptor Down-Regulation Recommendation Recreation Reporting Research Research Priority Role Sampling Science Structure Substance abuse problem Testing Tetrahydrocannabinol Therapeutic Therapeutic Agents 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 translational potential ultra high resolution white matter

项目摘要

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，但长期使用大麻仍然是一种治疗方法。还与艾滋病毒疾病的潜在神经生物学危害有关。即使在联合抗逆转录病毒治疗时代，这个问题仍然持续存在。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，并与艾滋病毒感染者复杂的大脑异常有关。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使用这种转化方法，我们的目标是艾滋病毒相关脑功能障碍的病理生理机制。 (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）模拟长期吸食大麻的纵向关系 HIV 引起的炎症及其与脑损伤的关系；以及 (3) 确定以下关系：大麻素代谢物对炎症和神经元标记物的前瞻性队列，对 140 名成年人进行了分层。大麻状态将完成尖端的神经影像学、免疫和细胞因子分析，以及利用超高分辨率磁共振在 2 年内进行 3 次神经心理学测试。杜克大学的成像（MRI）能力，我们将使用多模式、多参数序列来研究基线将包括 80 名 HIV-患者的对照组。核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。我们的提案直接响应 RFA-DA-20-022，该提案要求机制研究“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该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] 通过考虑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。