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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：
10459575
负责人：
CHRISTINA S MEADE
金额：
$ 98.56万
依托单位：
DUKE UNIVERSITY
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10459575
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 translational potential 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，在人群中普遍存在