Cannabis and Pathogenic Mechanisms influencing Blood Brain Barrier Function in HIV

大麻和影响艾滋病毒血脑屏障功能的致病机制

• 批准号: 10683027
• 负责人: Jerel Adam Fields
• 金额: $ 124.27万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10683027
• 关键词: 3-Dimensional; Adhesions; Adverse effects; Affect; Agonist; Anti-Inflammatory Agents; Astrocytes; Biological Markers; Biology; Blood; Blood - brain barrier anatomy; Brain; Cannabidiol; Cannabinoids; Cannabis; Cardiovascular Diseases; Cell Adhesion Molecules; Cells; Central Nervous System; Cerebrospinal Fluid; Chronic; Clinical; Cognition Disorders; Cytoskeleton; DNA; Data; Diffusion Magnetic Resonance Imaging; Dose; Endocannabinoids; Endothelial Cells; Endothelium; Etiology; Extravasation; Frequencies; Future; Gene Expression; General Population; HIV; HIV Infections; Homeostasis; Image; In Vitro; Individual; Individual Differences; Infection; Inflammation; Inflammation Mediators; Inflammatory; Injury; Interdisciplinary Study; Investigation; Leukocytes; Link; Macrophage; Measures; Metabolic; Microfluidics; Microglia; Mitochondria; Modeling; Mood Disorders; Nervous System Trauma; Neurocognitive; Neurocognitive Deficit; Neuroglia; Neurons; Neurotoxins; Observational Study; Outcome; Oxidative Phosphorylation; Participant; Pathogenesis; Pathogenicity; Patients; Pattern; Pericytes; Permeability; Persons; Pharmaceutical Preparations; Plants; Plasma; Pre-Clinical Model; Property; Proteins; Public Health; RNA; Research; Research Proposals; Risk; Role; Route; Structure; Substance abuse problem; Techniques; Technology; Testing; Tetrahydrocannabinol; Therapeutic Intervention; Tight Junctions; Toxic effect; Variant; Viral; Virus Replication; Vulnerable Populations; antagonist; antiretroviral therapy; biomarker panel; blood-brain barrier function; blood-brain barrier permeabilization; cannabinoid receptor; cannabis use behavior; cohort; imaging modality; improved; in vitro Model; in vivo; inflammatory milieu; innovation; insight; knowledge translation; marijuana use; migration; mitochondrial dysfunction; monocyte; multidisciplinary; multimodality; neuroimaging; novel therapeutics; pre-clinical; receptor binding; recruit; research clinical testing; response; substance use

People with HIV (PWH) remain vulnerable to central nervous system complications (e.g., neurocognitive impairment) despite antiretroviral therapy (ART) that suppresses viral replication. While many etiologies of these complications exist, damage to the blood-brain-barrier (BBB), inflammation, and mitochondrial dysfunction are consistently implicated, yet seldom studied simultaneously. PWH also use cannabis more frequently than the general population and recent evidence by our group and others indicates that cannabis may protect PWH from BBB damage by reducing inflammation and promoting mitochondrial homeostasis. The proposed multidisciplinary, translational project will combine a clinical observational study with two preclinical models: a) a technologically advanced brain chip model for BBB and b) personalized ex vivo/in vitro modeling of mitochondrial toxicity in BBB cells to determine the effects of cannabis use on the BBB in PWH. Using this multilevel approach, we will test the hypothesis that cannabis effects on the BBB vary based on patterns of use: moderate use will be associated with beneficial effects, due to the anti-inflammatory properties of cannabis, but chronic daily use will have detrimental effects. In a cohort of PWH and people without HIV (PWoH) across a range of cannabis use from naïve to daily users, we will measure in plasma and cerebrospinal fluid (CSF) a panel of biomarkers that reflect the BBB, inflammation, and mitochondrial dysfunction. These readouts will be correlated with advanced permeability and multicompartment diffusion magnetic resonance imaging that will identify global and regional variations in BBB leakage along with neuronal and glial microstructural properties (Aim 1). We will model the BBB using 3D microfluidic cultures of brain endothelial and parenchymal cell subsets to measure the effects of HIV and cannabinoids on BBB permeability, inflammatory gene expression, and markers of mitochondrial function (Aim 2). Because responses to HIV and cannabis are often specific to individuals or groups of individuals, we will use monocyte-derived macrophages and sera from the PWH and PWoH in the observational study to determine the effects of cannabis (and HIV) on BBB cellular components (astrocytes and endothelial cells), and on mitochondrial function, inflammatory gene expression, and BBB biomarker gene expression (Aim 3). Thus, the proposed project will provide innovative clinical readouts in a unique cohort alongside state-of-the-art modeling of the BBB and personalized investigation of pathogenic mechanisms. This highly innovative, multidisciplinary research proposal is very likely to generate impactful translational knowledge regarding mechanisms of pathogenesis and guide future therapeutic interventions. With our combined clinical and pre-clinical expertise in HIV infection, substance abuse, BBB biology and imaging, and mitochondrial homeostasis, we are uniquely suited to perform the proposed research.

艾滋病毒携带者(PWH)仍然容易出现中枢神经系统并发症(例如，神经认知 损害)，尽管抗逆转录病毒治疗(ART)抑制病毒复制。虽然这些疾病的许多病因 存在并发症，血脑屏障(BBB)受损，炎症和线粒体功能障碍 始终如一地牵涉其中，但很少同时研究。威尔斯亲王使用大麻的频率也比 普通人群以及我们小组和其他人最近的证据表明，大麻可能会保护威尔斯亲王免受 通过减少炎症和促进线粒体动态平衡来破坏血脑屏障。建议数 多学科、转化性项目将结合临床观察性研究和两个临床前模型：a) 用于血脑屏障的技术先进的脑芯片模型和b)个性化的体外/体外建模 确定大麻使用对PWH患者血脑屏障的影响。使用这个 通过多层次的方法，我们将检验大麻对血脑屏障的影响根据使用模式的不同而变化的假设： 由于大麻的抗炎特性，适量使用将产生有益的效果，但 长期的日常使用会产生有害的影响。在威斯康星医院和没有感染艾滋病毒(PWoH)的人群中 大麻的使用范围从幼稚到日常使用，我们将测量血浆和脑脊液(CSF)中的a 反映血脑屏障、炎症和线粒体功能障碍的一组生物标志物。这些读数将是 与先进的渗透率和多间隔扩散磁共振成像相关，将 确定血脑屏障渗漏的全球和区域差异以及神经元和神经胶质的微结构特征 (目标1)。我们将使用脑内皮细胞和实质细胞亚群的3D微流控培养来模拟血脑屏障 目的：检测HIV和大麻素对血脑屏障通透性、炎症基因表达和 线粒体功能标记物(目标2)。因为对艾滋病毒和大麻的反应通常是针对 个人或个人团体，我们将使用来自威尔斯亲王医院的单核细胞来源的巨噬细胞和血清以及 PWoH在观察性研究中确定大麻(和艾滋病毒)对血脑屏障细胞成分的影响 (星形胶质细胞和内皮细胞)，以及线粒体功能、炎症基因表达和血脑屏障 生物标记物基因表达(AIM 3)。因此，拟议的项目将在 独特的队列，以及最先进的血脑屏障建模和个性化的病因调查 机制。这一高度创新、多学科的研究提案很可能会产生 关于发病机制的翻译知识，并指导未来的治疗干预。使用 我们在HIV感染、药物滥用、血脑屏障生物学和成像方面的临床和临床前综合专业知识，以及 由于线粒体的动态平衡，我们非常适合进行这项拟议的研究。