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Targeting Inflammasomes in Substance Abuse and HIV

针对药物滥用和艾滋病毒中的炎症小体

基本信息

批准号：
10208845
负责人：
Michal Toborek
金额：
$ 44.4万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
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/10208845
关键词：
Antioxidants Area Belief Blood Vessels Brain CASP1 gene Cells Cerebrum Chronic Clinical Complex Data Development Drug abuse Drug toxicity Event Exposure to Grant HIV HIV Infections Infection Inflammasome Inflammatory Interleukin-1 beta Interleukin-18 Ischemic Stroke Laboratories Link Mitochondria Morphine Mus Nanotechnology Nature Opioid Opioid abuser Outcome Oxycodone Pathologic Patients Pattern recognition receptor Population Predisposition Process Publications Publishing Reaction Recovery Reporting Research Role Stimulus Stroke Substance abuse problem Text Therapeutic Intervention Time Tissues Toxic effect Work antiretroviral therapy base comorbidity compare effectiveness innovation insight interest ischemic injury mitochondrial dysfunction nanoparticle neuroinflammation novel opioid abuse opioid exposure post stroke prescription opioid response stroke outcome stroke recovery therapeutic effectiveness therapeutic target virtual

项目摘要

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.

抽象的该应用程序旨在调查 HIV 脑部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并发症。我们最近发现艾滋病毒的大脑感染会增加缺血性中风的易感性，导致 HIV重新激活。重要的是，这种效应与炎症小体的激活有关。虽然吗啡和羟考酮等阿片类药物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加剧缺血性中风的组织损伤并激活炎症小体。根据这些观察，中心假设目前的资助是，艾滋病毒和处方阿片类药物会激活中枢神经系统中的炎症小体，可能会恶化中风结果，包括中风后 HIV 在 CNS 和出口处重新激活进入外围。在拟议工作的目标 1 中，我们将评估以下机制： HIV 感染和处方阿片类药物激活炎症小体。在目标 2 中，我们将治疗性靶向线粒体以预防艾滋病毒和阿片类药物诱导的炎症小体激活，从而改善中风结果和恢复。在目标 3 中，我们将研究阿片类药物诱导的炎症小体激活对中枢神经系统中艾滋病毒再激活和进入体内的影响缺血性中风的外周。这涉及到几个概念、机制和技术方面应用具有高度创新性。例如，关注艾滋病毒和处方药的影响阿片类药物对缺血性中风结果的影响是一个尚未得到充分研究的研究领域，并构成了提案的理念创新。我们的研究结果表明炎症小体可能与艾滋病毒有关以前从未报道过脑储存库的重新激活。目标 1 和 2 一致将为炎症小体在中风中的作用提供重要的见解阿片类药物滥用者的艾滋病毒感染者的发展。目标 3 将提供重要的有关艾滋病毒从大脑重新激活并因此传播到外周的信息中风中炎症小体激活的研究。拟议的研究具有高度创新性，因为它重点关注血管合并症（例如缺血性中风）的新机制阿片类药物滥用背景下感染艾滋病毒的大脑。这些研究也可能会发现新的治疗干预的机会。