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.

HIV 感染者 (PWH) 仍然容易出现中枢神经系统并发症（例如神经认知功能障碍） 尽管抗逆转录病毒疗法（ART）可以抑制病毒复制，但仍会造成损害）。虽然这些疾病的病因有很多 存在并发症，血脑屏障（BBB）损伤、炎症和线粒体功能障碍 一直受到牵连，但很少同时研究。感染者也比其他人更频繁地使用大麻 一般人群以及我们小组和其他人的最新证据表明，大麻可以保护感染者免受感染 通过减少炎症和促进线粒体稳态来损害 BBB。拟议的 多学科转化项目将临床观察研究与两个临床前模型相结合：a) 技术先进的 BBB 脑芯片模型和 b) 个性化离体/体外建模 BBB 细胞中的线粒体毒性，以确定大麻使用对 PWH 中 BBB 的影响。使用这个 多层次方法，我们将检验大麻对 BBB 的影响因使用模式而异的假设： 由于大麻具有抗炎特性，适度使用会产生有益效果，但是 长期日常使用会产生不利影响。在一组 PWH 和未感染 HIV 的人 (PWoH) 中 从初次使用者到日常使用者的大麻使用范围，我们将在血浆和脑脊液 (CSF) 中进行测量 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 与先进的磁导率和多室扩散磁共振成像相关，这将 识别 BBB 渗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）。我们将使用脑内皮细胞和实质细胞亚群的 3D 微流体培养物对 BBB 进行建模 测量 HIV 和大麻素对 BBB 通透性、炎症基因表达和 线粒体功能标记（目标 2）。因为对艾滋病毒和大麻的反应通常是针对特定人群的 个人或个人群体，我们将使用来自 PWH 的单核细胞衍生的巨噬细胞和血清， PWoH 参与观察性研究，以确定大麻（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（目标 3）。因此，拟议的项目将提供创新的临床读数 独特的队列以及最先进的 BBB 模型和个性化致病性研究 机制。这项高度创新、多学科的研究提案很可能产生有影响力的成果 有关发病机制的转化知识并指导未来的治疗干预。和 我们在 HIV 感染、药物滥用、BBB 生物学和成像方面的综合临床和临床前专业知识，以及 线粒体稳态，我们非常适合进行拟议的研究。