Targeting Inflammasomes in Substance Abuse and HIV

摘要 该应用旨在调查HIV脑感染和处方阿片类药物对 缺血性中风是感染人群和阿片类药物滥用者的主要共病。我们最近 发现大脑感染HIV会增加缺血性中风的易感性， 艾滋病毒的复活重要的是，这种作用与炎性小体的激活有关。 虽然阿片类药物（如吗啡和羟考酮）对这些事件的影响尚不清楚，但我们 有证据表明，长期暴露于阿片类药物可以增强缺血性中风的组织损伤 激活炎性小体根据这些观察， 目前的研究表明，HIV和处方阿片类药物激活了CNS中的炎性小体， 可能会恶化卒中结局，包括卒中后CNS中的HIV再激活和流出 到外围。在目标1的拟议工作，我们将评估的机制， HIV感染和处方阿片类药物引起的炎性小体活化。在目标2中，我们 用于保护免受HIV和阿片样物质诱导炎性小体的治疗靶向线粒体 激活，从而改善卒中结局和恢复。在目标3中，我们将研究 阿片样物质诱导的炎性小体活化对中枢神经系统中HIV再活化和进入 缺血性中风的外周。这个问题的几个概念、机制和技术方面 应用具有很强的创新性。例如，关注艾滋病毒和处方的影响 阿片类药物对缺血性卒中结局的影响是一个研究不足的领域， 提案的概念创新。我们的发现表明炎性小体可能与HIV有关 以前从未报道过脑储库的再激活。 目的1和2将共同提供炎性小体在中风中作用的重要见解 艾滋病毒感染者的发展是阿片类药物滥用者。目标3将提供重要的 关于艾滋病毒从大脑中重新激活并因此传播到外周的信息 中风时炎性小体的激活。这项研究具有很高的创新性，因为它 关注血管合并症（如缺血性卒中）的新机制， 阿片类药物滥用背景下的艾滋病毒感染大脑。这些研究也可能发现新的 治疗干预的机会。

ABSTRACT This application aims to investigate the impact of HIV brain infection and prescription opioids on ischemic stroke, a major co-morbidity in the infected population and opioid abusers. We recently identified that brain infection by HIV increases susceptibility to ischemic stroke, leading to reactivation of HIV. Importantly, this effect was associated with activation of the inflammasome. While the impact of opioids, such as morphine and oxycodone, on these events is unknown, we have evidence that chronic exposure to opioids can enhance tissue damage in ischemic stroke and activate the inflammasome. In line with these observations, the central hypothesis of the current grant is that HIV and prescription opioids activate inflammasome in the CNS that can worsen stroke outcome, including post-stroke HIV reactivation in the CNS and egress into the periphery. In Aim 1 of the proposed work, we will evaluate the mechanisms of inflammasome activation by HIV infection and prescription opioids. In Aim 2, we will therapeutically target mitochondria for protection against HIV and opioid-induced inflammasome activation, leading to improvement of stroke outcome and recovery. In Aim 3, we will study the impact of opioid-induced inflammasome activation on HIV reactivation in the CNS and egress into the periphery in ischemic stroke. Several conceptual, mechanistic, and technical aspects of this application are highly innovative. For example, the focus on the impact of HIV and prescription opioids on ischemic stroke outcome is an understudied area of research and constitutes a conceptual innovation of the proposal. Our findings that the inflammasome can be involved in HIV reactivation from brain reservoirs has never been reported before. In concert, Aims 1 and 2 will provide critical insight into the role of inflammasome in stroke development of HIV-infected patients who are opioid abusers. Aim 3 will provide important information on the reactivation of HIV from the brain and seeding into the periphery as the result of inflammasome activation in stroke. The proposed research is highly innovative because of its focus on novel mechanisms underlying vascular comorbidities, such as ischemic stroke, in the HIV-infected brain in the context of opioid abuse. These studies are also likely to identify new opportunities for therapeutic intervention.