Targeting Inflammasomes in Substance Abuse and HIV

摘要 血脑屏障(BBB)是一层半透明的细胞层，对脑保护和动态平衡至关重要。 虽然内皮细胞在形成主要物理屏障中的作用已经被认识到，但正在出现 有证据表明，周细胞在维持血脑屏障功能中起着关键作用。有证据表明， 血脑屏障功能障碍和调节血脑屏障完整性的紧密连接蛋白的破坏涉及几个 严重的情绪和精神障碍。血脑屏障周细胞可成为HIV感染的靶点并长期支持 病毒在中枢神经系统中的复制。物质滥用，包括阿片类药物滥用，是艾滋病毒感染和 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CNS之间的相互作用，我们假设周细胞功能障碍可以影响 在艾滋病毒感染的背景下，阿片成瘾行为和加强缺血性中风的严重性。 为了验证这一假设，我们将使用三种不同和独特的小鼠品系，它们从温和的 严重时，表现为血脑屏障通透性增加，周细胞数量减少。我们将分析成瘾 用条件性位置偏爱试验研究周细胞缺陷小鼠的行为。紧密连接蛋白 并将在这些小鼠身上测试血脑屏障通透性，以了解血脑屏障如何有助于改变 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及周细胞缺乏对缺血性卒中的影响 结果和复苏。EcoHIV将通过颈内动脉进入中枢神经系统，并暴露在 大脑中动脉闭塞所致的缺血性中风。将对组织进行分析，以确定梗塞的变化 规模和行为分析将被用来研究中风后的恢复。作为结果所获得的知识 我们的建议将深入了解周细胞在HIV感染期间脑血管健康中的作用，阿片类药物 虐待和上瘾。

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.