Targeting Inflammasomes in Substance Abuse and HIV

摘要 本申请旨在调查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同发病率。我们最近 发现脑感染艾滋病毒会增加缺血性中风的易感性，导致 艾滋病毒的重新激活。重要的是，这种效应与炎症小体的激活有关。 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 有证据表明长期接触阿片类药物会增加缺血性中风患者的组织损伤 并激活发炎小体。与这些观察结果一致的是， 目前的资助是艾滋病毒和处方阿片类药物激活中枢神经系统中的炎症小体， 可恶化卒中结局，包括卒中后HIV在中枢和出口的重新激活 进入外围。在拟议工作的目标1中，我们将评估 艾滋病毒感染和处方阿片类药物引起的炎症体激活。在目标2中，我们将 治疗靶向线粒体以保护HIV和阿片类药物诱导的炎症体 激活，导致中风预后和康复的改善。在目标3中，我们将研究 阿片类药物诱导的炎性小体激活对HIV在中枢神经系统和出口进入的影响 缺血性卒中的外周病变。这方面的几个概念、机制和技术方面 应用程序具有很高的创新性。例如，重点关注艾滋病毒和处方的影响 阿片类药物对缺血性卒中预后的影响是一个研究不足的领域，并构成了 提案的理念创新。我们发现炎性小体可能与HIV病毒有关 从大脑储存库中重新激活以前从未报道过。 同时，AIMS 1和AIMS 2将提供对炎症小体在中风中的作用的重要见解 发展成为阿片类药物滥用者的艾滋病毒感染患者。目标3将提供重要的 关于艾滋病毒从大脑重新激活并由此播撒到外周的信息 中风时炎性小体激活的可能性。拟议的研究具有很高的创新性，因为它 关注血管合并症的新机制，如缺血性中风 在阿片类药物滥用的背景下感染艾滋病毒的大脑。这些研究还可能发现新的 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.