Targeting Inflammasomes in Substance Abuse and HIV

针对药物滥用和艾滋病毒中的炎症小体

• 批准号: 10371747
• 负责人: Michal Toborek
• 金额: $ 5.07万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10371747
• 关键词: Affect; Behavior; Behavioral; Blood - brain barrier anatomy; Brain; Cell Count; Cells; Cerebrovascular Disorders; Development; Endothelial Cells; Exhibits; Exposure to; Functional disorder; HIV; HIV Infections; Health; Homeostasis; Individual; Infarction; Inflammasome; Internal carotid artery structure; Ischemic Stroke; Knowledge; Mental disorders; Middle Cerebral Artery Occlusion; Mood Disorders; Mouse Strains; Mus; Opiate Addiction; Paracrine Communication; Pericytes; Positioning Attribute; Preventive treatment; Proteins; Research; Risk; Risk Factors; Role; Severities; Substance abuse problem; Testing; Tight Junctions; Tissues; Virus Replication; addiction; base; blood-brain barrier disruption; blood-brain barrier function; blood-brain barrier permeabilization; cerebrovascular health; comorbidity; conditioned place preference; high risk; improved; insight; opioid abuse; opioid exposure; post stroke; stroke outcome; stroke recovery

ABSTRACT The blood brain barrier (BBB) is a semipermeable cell layer that is essential for brain protection and homeostasis. While the role of endothelial cells in formation of the main physical barrier has been recognized, emerging evidence indicates a critical role of pericytes in maintaining the BBB functions. Evidence indicates that dysfunction of the BBB and disruption of tight junction proteins that regulate BBB integrity are involved in several major mood and psychiatric disorders. BBB pericytes can be a target of HIV infection and support long term replication of the virus in the CNS. Substance abuse, including opioid abuse, is a risk factor for HIV infection and contributes to the development of HIV-associated comorbidities. Indeed, both HIV infection and opioid abuse increase an individual's risk for cerebrovascular disease and ischemic stroke. Due to the position of BBB pericytes in the interplay between HIV and the CNS, we hypothesize that pericyte dysfunction can affect opioid addiction behavior and potentiate ischemic stroke severity in the context of HIV infection. To test this hypothesis, we will employ three different and unique strains of mice that progressively, from modest to severe, exhibit increased BBB permeability and decreased pericyte cell number. We will analyze addiction behavior in pericyte deficient mice through the use of a Conditioned Place Preference test. Tight junction proteins and BBB permeability will be tested in these mice to understand how the BBB can contribute to a change in behavior. Our second aim will focus on studying the impact of pericyte deficiency on paracrine signals critical to BBB health in the context of opioid abuse and studying the influence of pericyte deficiency on ischemic stroke outcomes and recovery. EcoHIV will be delivered into the CNS via the internal carotid artery and exposed to ischemic stroke via middle cerebral artery occlusion. Tissues will be analyzed to determine changes in infarct size and behavioral analysis will be used to study post-stroke recovery. The knowledge gained as the results of our proposal will provide insight into the role of pericytes in cerebrovascular health during HIV infection, opioid abuse, and addiction.

抽象的 血脑屏障（BBB）是半透性细胞层，对于大脑保护和体内平衡至关重要。 虽然内皮细胞在主要物理屏障形成中的作用已得到认识，但新兴的 有证据表明周细胞在维持血脑屏障功能中发挥着关键作用。有证据表明 BBB 功能障碍和调节 BBB 完整性的紧密连接蛋白破坏与多种因素有关 主要情绪和精神疾病。 BBB 周细胞可以成为 HIV 感染的目标并提供长期支持 病毒在中枢神经系统中复制。药物滥用，包括阿片类药物滥用，是艾滋病毒感染的危险因素， 有助于艾滋病毒相关合并症的发展。事实上，艾滋病毒感染和阿片类药物滥用 增加个体患脑血管疾病和缺血性中风的风险。由于BBB的位置 周细胞在艾滋病毒和中枢神经系统之间的相互作用中，我们假设周细胞功能障碍会影响 在艾滋病毒感染的情况下，阿片类药物成瘾行为会加剧缺血性中风的严重程度。 为了检验这一假设，我们将使用三种不同且独特的小鼠品系，它们逐渐从适度的 严重时，表现出血脑屏障通透性增加和周细胞数量减少。我们将分析成瘾 通过使用条件位置偏好测试来观察周细胞缺陷小鼠的行为。紧密连接蛋白 并将在这些小鼠中测试 BBB 通透性，以了解 BBB 如何有助于改变 行为。我们的第二个目标将集中于研究周细胞缺陷对旁分泌信号的影响，这些信号对于生命至关重要 阿片类药物滥用背景下的 BBB 健康以及研究周细胞缺乏对缺血性中风的影响 结果和恢复。 EcoHIV 将通过颈内动脉输送到中枢神经系统并暴露于 大脑中动脉闭塞导致缺血性中风。将分析组织以确定梗塞的变化 尺寸和行为分析将用于研究中风后恢复。所获得的知识作为结果 我们的提案将深入了解周细胞在艾滋病毒感染、阿片类药物期间脑血管健康中的作用 滥用和成瘾。