Targeting Inflammasomes in Substance Abuse and HIV

摘要 血脑屏障（BBB）是一个半透性细胞层，对脑保护和体内平衡至关重要。 虽然已经认识到内皮细胞在形成主要物理屏障中的作用，但正在出现 有证据表明周细胞在维持血脑屏障功能中起关键作用。证据表明 BBB的功能障碍和调节BBB完整性的紧密连接蛋白的破坏参与了几种 严重的情绪和精神障碍血脑屏障周细胞可以成为HIV感染的靶点， 病毒在中枢神经系统的复制。药物滥用，包括阿片类药物滥用，是艾滋病毒感染的一个危险因素， 有助于HIV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 增加了个人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HIV和中枢神经系统之间的相互作用，我们假设周细胞功能障碍可以影响 阿片类药物成瘾行为和增强缺血性卒中的严重程度在HIV感染的背景下。 为了验证这一假设，我们将采用三种不同的独特品系的小鼠，从温和的 至重度，表现出BBB通透性增加和周细胞数减少。我们将分析成瘾 行为在周细胞缺陷小鼠通过使用条件位置偏好测试。紧密连接蛋白 和BBB通透性将在这些小鼠中进行测试，以了解BBB如何有助于 行为我们的第二个目标是研究周细胞缺乏对旁分泌信号的影响， 阿片类药物滥用背景下的血脑屏障健康以及研究周细胞缺乏对缺血性卒中的影响 结果和恢复。EcoHIV将通过颈内动脉输送到CNS，并暴露于 大脑中动脉闭塞引起的缺血性中风将对组织进行分析，以确定梗死的变化， 大小和行为分析将用于研究中风后恢复。作为结果获得的知识 我们的建议将提供深入了解周细胞在艾滋病毒感染期间脑血管健康中的作用， 滥用和成瘾

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.