The role of cannabinoids in the regulation of the blood brain barrier in the context of NeuroHIV and anti-retroviral therapy

大麻素在 NeuroHIV 和抗逆转录病毒治疗背景下调节血脑屏障的作用

• 批准号: 10376762
• 负责人: Yuri Persidsky
• 金额: $ 61.14万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10376762
• 关键词: ABCG2 gene; ATP-Binding Cassette Transporters; Address; Adhesions; Affect; Agonist; Animal Model; Antiinflammatory Effect; Aseptic Meningitis; Attenuated; Biological Assay; Blood - brain barrier anatomy; Brain; CD44 gene; CNR1 gene; CNR2 gene; Cannabinoids; Cannabis; Cells; Cellular biology; Chronic; Clinical Research; Cognitive; Communities; Complex; Desire for food; Drug Kinetics; Dwarfism; Encephalitis; Endocannabinoids; Endothelium; Environment; Enzymes; Evaluation; Functional disorder; Gatekeeping; Genes; HIV; HIV Infections; HIV antiretroviral; HIV therapy; Human; Immune; Immunologic Surveillance; Immunologics; Individual; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Inhalation; Inhalation Drug Administration; Kinetics; Maintenance; Mediating; Medical Marijuana; Microfluidic Microchips; Microfluidics; Microglia; Modeling; Modernization; Molecular; Molecular Analysis; Molecular Weight; Neurocognitive; Neurons; Oral; Oral Administration; Outcome; Output; PPAR gamma; Pathology; Pathway Analysis; Pathway interactions; Persons; Physical assessment; Physiological; Pre-Clinical Model; Property; Proteins; Proto-Oncogene Proteins c-akt; RNA; Receptor Signaling; Regulation; Role; Route; Signal Transduction; Stimulus; System; Technology; Tight Junctions; Tissue Engineering; Tracer; Transcriptional Regulation; Vascular Cell Adhesion Molecule-1; Viral; Viremia; Virus; Virus Replication; antiretroviral therapy; beta catenin; blood-brain barrier function; blood-brain barrier permeabilization; brain endothelial cell; brain tissue; cannabinoid receptor; cerebrovascular; chronic pain; cytokine; endogenous cannabinoid system; experience; experimental study; fluid flow; humanized mouse; immunoregulation; in vivo; indexing; innovation; macrophage; marijuana use; member; migration; monocyte; mouse model; nervous system disorder; neural network; neuroAIDS; neuroinflammation; neurovascular unit; novel; operation; phytocannabinoid; pre-clinical; protein expression; receptor; response; tool; vaping THC

PROJECT SUMARY/ABSTRACT Despite antiretroviral therapy (ART), neurocognitive complications continue to be highly prevalent in people living with HIV (PLWH). One explanation could be the constant compromise of the blood brain barrier (BBB) driven by chronic inflammatory responses. The introduction of medicinal marijuana into HIV treatment practice appear to be beneficial for several virus associated complications (ranging from chronic pain to appetite stimulation). Yet, the effects and mechanisms of cannabis on HIV associated chronic inflammation, the endocannabinoid system, immune modulation and neurologic disorders are minimally understood. As indicated in the RFA, preclinical models can provide a rigorous in-depth analysis of the molecular and cellular mechanisms at the intersection between phytocannabinoids, HIV and ART. To this end, we propose a comprehensive evaluation of the two most used cannabinoid compounds (THC, CBD) on BBB function, immune-endothelial interactions and neuroinflammation. We will utilize state of the art chip microfluidics models of the neurovascular unit (NVU) and animal models for HIV (w/ w/o ART). Previously, we discovered that the brain endothelium upregulate CB2 in HIV infected human brain tissue. We have also found that modulation of CB2 affects indices of HIV pathology (in-vivo) and regulates the BBB. Our preliminary studies identify the diverse effects that phytocannabinoids can have on the different properties of the BBB. Specifically, cannabinoids (THC, CBD) alone can enhance the physical barrier, partially reduce endothelial activation and augment efflux transporter activity. Although some of these effects may appear beneficial, the presence of HIV and ART changes how the function of the BBB is regulated by cannabinoid substances. For example, the augmented transporter activity by THC has important considerations for altering ART-CNS penetrability. Thus, we hypothesize that phytocannabinoids differentially modulates BBB function that are both beneficial and deleterious in NeuroHIV. In Aim 1, using our latest tissue-engineered microfluidic NVU model, we will perform analyses of the kinetic changes in BBB permeability, transporter status and immune-endothelial interaction. Then, in Aim 2, we will compare outcomes between widely used routes of cannabinoid administration (oral vs. inhaled) in vivo using two relevant models of HIV infection (‘humanized’ mice and a model of aseptic meningitis/encephalitis). Experiments will evaluate changes in the BBB in the context of ART and cannabinoid exposure. Finally, we propose to identify novel crosstalk mechanisms that bridge cannabinoid receptor signaling to signals that control BBB maintenance (Aim 3). It’s clear that cannabinoids exert unknown cell specific effects that contribute to the tumultuous interpretation of how these compounds impact NeuroHIV. Using innovative preclinical tools, our studies will contribute significantly towards understanding the consequences of cannabinoid use on the BBB in the modern era of NeuroHIV.

项目总结/摘要 尽管进行了抗逆转录病毒治疗（ART），神经认知并发症在人群中仍然非常普遍 艾滋病毒感染者（PLWH）。一种解释可能是血脑屏障 (BBB) 的不断受损 由慢性炎症反应驱动。将药用大麻引入艾滋病毒治疗实践 似乎对多种病毒相关并发症（从慢性疼痛到食欲不振）有益 刺激）。然而，大麻对艾滋病毒相关慢性炎症的影响和机制， 人们对内源性大麻素系统、免疫调节和神经系统疾病知之甚少。如图所示 在 RFA 中，临床前模型可以提供对分子和细胞的严格深入分析 植物大麻素、HIV 和 ART 之间的交叉机制。为此，我们提出一个 综合评价两种最常用的大麻素化合物（THC、CBD）对血脑屏障功能的影响， 免疫内皮相互作用和神经炎症。我们将利用最先进的芯片微流体技术 神经血管单元 (NVU) 模型和 HIV 动物模型（不含 ART）。此前，我们发现 脑内皮上调 HIV 感染的人脑组织中的 CB2。我们还发现 CB2 的调节影响 HIV 病理学指标（体内）并调节 BBB。我们的初步研究 确定植物大麻素对血脑屏障不同特性的不同影响。具体来说， 大麻素（THC、CBD）单独可以增强物理屏障，部分减少内皮激活和 增强外排转运蛋白活性。尽管其中一些影响可能看起来是有益的，但艾滋病毒的存在 ART 改变了大麻素物质调节 BBB 功能的方式。例如， THC 增强的转运蛋白活性对于改变 ART-CNS 渗透性具有重要的考虑因素。因此， 我们假设植物大麻素可以差异调节 BBB 功能，这两者都是有益的 对 NeuroHIV 有害。在目标 1 中，使用我们最新的组织工程微流控 NVU 模型，我们将 对 BBB 通透性、转运蛋白状态和免疫内皮细胞的动力学变化进行分析 相互作用。然后，在目标 2 中，我们将比较广泛使用的大麻素途径之间的结果 使用两种相关的 HIV 感染模型（“人源化”小鼠和 无菌性脑膜炎/脑炎模型）。实验将评估 ART 背景下 BBB 的变化 和大麻素暴露。最后，我们建议确定桥接大麻素的新型串扰机制 受体信号传导至控制 BBB 维持的信号（目标 3）。很明显，大麻素发挥着未知的作用 细胞特异性效应导致了对这些化合物如何影响 NeuroHIV 的混乱解释。 使用创新的临床前工具，我们的研究将极大地有助于理解 在现代 NeuroHIV 时代，大麻素的使用对血脑屏障的影响。