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（PWH）患者仍然容易受到中枢神经系统并发症的影响（例如，神经认知 损害）抗逆转录病毒疗法（ART），可抑制病毒复制。虽然这些病因 存在并发症，对血脑屏障（BBB），炎症和线粒体功能障碍的损害是 一贯实施，但很少同时进行研究。 PWH也比大麻更频繁地使用大麻 我们小组和其他人的一般人口和最新证据表明，大麻可以保护PWH免受 通过减少炎症和促进线粒体稳态来损害BBB。提议 多学科的翻译项目将结合临床检查研究与两个临床前模型：a） BBB和B）的技术先进的大脑芯片模型 线粒体在BBB细胞中的毒性确定大麻使用对PWH中BBB的影响。使用此 多级方法，我们将检验以下假设：大麻对BBB的影响根据使用方式而变化： 由于大麻的抗炎特性，中等用途将与有益作用有关，但是 慢性每日使用将产生有害影响。在PWH的队列中，没有艾滋病毒的人（PWOH） 大麻范围从天真到日常用户，我们将测量血浆和脑脊液（CSF） 反映BBB，注射和线粒体功能障碍的生物标志物面板。这些读数将是 与高级渗透性和多区域扩散磁共振成像相关 确定BBB泄漏的全局和区域变化以及神经元和神经胶质微结构特性 （目标1）。我们将使用脑内皮和副型细胞亚群的3D微流体培养物对BBB进行建模 测量HIV和大麻素对BBB渗透性，炎症基因表达和 线粒体功能的标记（AIM 2）。因为对艾滋病毒和大麻的反应通常是特定于 个体或一组个人，我们将使用PWH和 在观察性研究中，PWOH确定大麻（和HIV）对BBB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BBB 生物标志物基因表达（AIM 3）。这是拟议的项目将在 独特的队列与BBB的最新建模以及致病性的个性化研究 机制。这项高度创新的多学科研究建议很可能会产生影响力 关于发病机理机制的翻译知识并指导未来的治疗干预措施。和 我们在HIV感染，滥用药物，BBB生物学和成像以及 线粒体稳态，我们非常适合进行拟议的研究。